{"id":27055,"date":"2024-01-03T21:41:53","date_gmt":"2024-01-03T19:41:53","guid":{"rendered":"https:\/\/hho-bulgaria.com\/h2-treatment-in-ra-associated-interstitial-lung-disease\/"},"modified":"2024-01-29T21:10:25","modified_gmt":"2024-01-29T19:10:25","slug":"h2-treatment-in-ra-associated-interstitial-lung-disease","status":"publish","type":"post","link":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/","title":{"rendered":"H2 treatment in RA-associated interstitial lung disease"},"content":{"rendered":"<div class=\"jig-ncbiinpagenav\" data-jigconfig=\"smoothScroll: false, allHeadingLevels: ['h2'], headingExclude: ':hidden,.nomenu'\" id=\"ui-ncbiinpagenav-1\">\n<div class=\"fm-sec half_rhythm no_top_margin\">\n<div class=\"fm-flexbox\">\n<div class=\"fm-citation\">\n<div class=\"citation-default\">\n<div class=\"part1\"><span role=\"menubar\"><a href=\"#\" role=\"menuitem\" aria-expanded=\"false\" aria-haspopup=\"true\">J Cell Mol Med.<\/a><\/span> 2019 Oct; 23(10): 7043\u20137053. <\/div>\n<div class=\"part2\"><span class=\"fm-vol-iss-date\">Published online 2019 Aug 19. <\/span>  <span class=\"doi\"><span>doi:&nbsp;<\/span><a href=\"\/\/doi.org\/10.1111%2Fjcmm.14603\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CFront%20Matter&amp;TO=Content%20Provider%7CCrosslink%7CDOI\">10.1111\/jcmm.14603<\/a><\/span><\/div>\n<\/div>\n<\/div>\n<div class=\"fm-ids\">\n<div class=\"fm-citation-pmcid\"><span class=\"fm-citation-ids-label\">PMCID: <\/span><span>PMC6787460<\/span><\/div>\n<div class=\"fm-citation-pmid\">PMID: <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/31424157\">31424157<\/a><\/div>\n<\/div>\n<\/div>\n<h1 class=\"content-title\">Effect of H<sub>2<\/sub> treatment in a mouse model of rheumatoid arthritis\u2010associated interstitial lung disease<\/h1>\n<div class=\"half_rhythm\">\n<div class=\"contrib-group fm-author\"><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Terasaki%20Y%5BAuthor%5D\" id=\"jcmm14603-cr-0001\" class=\"affpopup\" co-rid=\"_co_idm139785371600416\" co-class=\"co-affbox\">Yasuhiro Terasaki<\/a>,<sup><img decoding=\"async\" src=\"\/corehtml\/pmc\/pmcgifs\/corrauth.gif\" alt=\"corresponding author\"><\/sup><sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Terasaki%20M%5BAuthor%5D\" id=\"jcmm14603-cr-0002\" class=\"affpopup\" co-rid=\"_co_idm139785371598128\" co-class=\"co-affbox\">Mika Terasaki<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kanazawa%20S%5BAuthor%5D\" id=\"jcmm14603-cr-0003\" class=\"affpopup\" co-rid=\"_co_idm139785371596080\" co-class=\"co-affbox\">Satoshi Kanazawa<\/a>,<sup><br \/>\n2<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kokuho%20N%5BAuthor%5D\" id=\"jcmm14603-cr-0004\" class=\"affpopup\" co-rid=\"_co_idm139785371594032\" co-class=\"co-affbox\">Nariaki Kokuho<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Urushiyama%20H%5BAuthor%5D\" id=\"jcmm14603-cr-0005\" class=\"affpopup\" co-rid=\"_co_idm139785371591872\" co-class=\"co-affbox\">Hirokazu Urushiyama<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kajimoto%20Y%5BAuthor%5D\" id=\"jcmm14603-cr-0006\" class=\"affpopup\" co-rid=\"_co_idm139785374598128\" co-class=\"co-affbox\">Yusuke Kajimoto<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kunugi%20S%5BAuthor%5D\" id=\"jcmm14603-cr-0007\" class=\"affpopup\" co-rid=\"_co_idm139785374595520\" co-class=\"co-affbox\">Shinobu Kunugi<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Maruyama%20M%5BAuthor%5D\" id=\"jcmm14603-cr-0008\" class=\"affpopup\" co-rid=\"_co_idm139785374592912\" co-class=\"co-affbox\">Motoyo Maruyama<\/a>,<sup><br \/>\n3<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Akimoto%20T%5BAuthor%5D\" id=\"jcmm14603-cr-0009\" class=\"affpopup\" co-rid=\"_co_idm139785374590304\" co-class=\"co-affbox\">Toshio Akimoto<\/a>,<sup><br \/>\n3<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Miura%20Y%5BAuthor%5D\" id=\"jcmm14603-cr-0010\" class=\"affpopup\" co-rid=\"_co_idm139785374587696\" co-class=\"co-affbox\">Yoko Miura<\/a>,<sup><br \/>\n2<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Igarashi%20T%5BAuthor%5D\" id=\"jcmm14603-cr-0011\" class=\"affpopup\" co-rid=\"_co_idm139785373295808\" co-class=\"co-affbox\">Tsutomu Igarashi<\/a>,<sup><br \/>\n4<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Ohsawa%20I%5BAuthor%5D\" id=\"jcmm14603-cr-0012\" class=\"affpopup\" co-rid=\"_co_idm139785373293200\" co-class=\"co-affbox\">Ikuroh Ohsawa<\/a>,<sup><br \/>\n5<br \/>\n<\/sup> and  <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Shimizu%20A%5BAuthor%5D\" id=\"jcmm14603-cr-0013\" class=\"affpopup\" co-rid=\"_co_idm139785373290592\" co-class=\"co-affbox\">Akira Shimizu<\/a><sup><br \/>\n1<br \/>\n<\/sup><\/div>\n<div style=\"display:none\" class=\"contrib-group aff-tip\">\n<div id=\"_co_idm139785371600416\">\n<h3 class=\"no_margin\">Yasuhiro Terasaki<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Terasaki%20Y%5BAuthor%5D\">Yasuhiro Terasaki<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785371598128\">\n<h3 class=\"no_margin\">Mika Terasaki<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Terasaki%20M%5BAuthor%5D\">Mika Terasaki<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785371596080\">\n<h3 class=\"no_margin\">Satoshi Kanazawa<\/h3>\n<p>\n<sup>2<\/sup><br \/>\nDepartment of Molecular and Cellular Biology,<br \/>\nNagoya City University,<br \/>\nNagoya,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kanazawa%20S%5BAuthor%5D\">Satoshi Kanazawa<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785371594032\">\n<h3 class=\"no_margin\">Nariaki Kokuho<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kokuho%20N%5BAuthor%5D\">Nariaki Kokuho<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785371591872\">\n<h3 class=\"no_margin\">Hirokazu Urushiyama<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Urushiyama%20H%5BAuthor%5D\">Hirokazu Urushiyama<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785374598128\">\n<h3 class=\"no_margin\">Yusuke Kajimoto<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kajimoto%20Y%5BAuthor%5D\">Yusuke Kajimoto<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785374595520\">\n<h3 class=\"no_margin\">Shinobu Kunugi<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Kunugi%20S%5BAuthor%5D\">Shinobu Kunugi<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785374592912\">\n<h3 class=\"no_margin\">Motoyo Maruyama<\/h3>\n<p>\n<sup>3<\/sup><br \/>\nDivision of Laboratory Animal Science, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Maruyama%20M%5BAuthor%5D\">Motoyo Maruyama<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785374590304\">\n<h3 class=\"no_margin\">Toshio Akimoto<\/h3>\n<p>\n<sup>3<\/sup><br \/>\nDivision of Laboratory Animal Science, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Akimoto%20T%5BAuthor%5D\">Toshio Akimoto<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785374587696\">\n<h3 class=\"no_margin\">Yoko Miura<\/h3>\n<p>\n<sup>2<\/sup><br \/>\nDepartment of Molecular and Cellular Biology,<br \/>\nNagoya City University,<br \/>\nNagoya,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Miura%20Y%5BAuthor%5D\">Yoko Miura<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785373295808\">\n<h3 class=\"no_margin\">Tsutomu Igarashi<\/h3>\n<p>\n<sup>4<\/sup><br \/>\nDepartment of Ophthalmology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Igarashi%20T%5BAuthor%5D\">Tsutomu Igarashi<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785373293200\">\n<h3 class=\"no_margin\">Ikuroh Ohsawa<\/h3>\n<p>\n<sup>5<\/sup><br \/>\nBiological Process of Aging,<br \/>\nTokyo Metropolitan Institute of Gerontology,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Ohsawa%20I%5BAuthor%5D\">Ikuroh Ohsawa<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139785373290592\">\n<h3 class=\"no_margin\">Akira Shimizu<\/h3>\n<p>\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Shimizu%20A%5BAuthor%5D\">Akira Shimizu<\/a><\/div>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"half_rhythm\">\n<div class=\"togglers fm-copyright-license\"><a href=\"#\" class=\"pmctoggle\" rid=\"idm139785373589472_ai\">Author information<\/a> <a href=\"#\" class=\"pmctoggle\" rid=\"idm139785373589472_an\">Article notes<\/a> <a href=\"#\" class=\"pmctoggle\" rid=\"idm139785373589472_cpl\">Copyright and License information<\/a> <a href=\"\/pmc\/about\/disclaimer\/\" style=\"margin-left: 1em\">PMC Disclaimer<\/a><\/div>\n<div class=\"fm-authors-info hide half_rhythm\" id=\"idm139785373589472_ai\" style=\"display:none\">\n<div class=\"fm-affl\" id=\"jcmm14603-aff-0001\">\n<sup>1<\/sup><br \/>\nDepartment of Analytic Human Pathology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/div>\n<div class=\"fm-affl\" id=\"jcmm14603-aff-0002\">\n<sup>2<\/sup><br \/>\nDepartment of Molecular and Cellular Biology,<br \/>\nNagoya City University,<br \/>\nNagoya,<br \/>\nJapan\n<\/div>\n<div class=\"fm-affl\" id=\"jcmm14603-aff-0003\">\n<sup>3<\/sup><br \/>\nDivision of Laboratory Animal Science, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/div>\n<div class=\"fm-affl\" id=\"jcmm14603-aff-0004\">\n<sup>4<\/sup><br \/>\nDepartment of Ophthalmology, Graduate School of Medicine,<br \/>\nNippon Medical School,<br \/>\nTokyo,<br \/>\nJapan\n<\/div>\n<div class=\"fm-affl\" id=\"jcmm14603-aff-0005\">\n<sup>5<\/sup><br \/>\nBiological Process of Aging,<br \/>\nTokyo Metropolitan Institute of Gerontology,<br \/>\nTokyo,<br \/>\nJapan\n<\/div>\n<div><span class=\"fm-affl\">Yasuhiro Terasaki, <\/span><span class=\"fm-affl\"><span class=\"email-label\">Email: <\/span><a href=\"mailto:dev@null\" data-email=\"pj.ca.smn@ikasaret\" class=\"oemail\">pj.ca.smn@ikasaret<\/a><\/span>.<\/div>\n<div><sup><img decoding=\"async\" src=\"\/corehtml\/pmc\/pmcgifs\/corrauth.gif\" alt=\"corresponding author\"><\/sup>Corresponding author.<\/div>\n<div id=\"correspondenceTo\"><sup>*<\/sup><strong>Correspondence<\/strong><br \/>\nYasuhiro Terasaki, Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, 1\u201025\u201016 Nezu, Bunkyo\u2010ku, Tokyo 113\u20100031, Japan.<br \/>\nEmail: <a href=\"mailto:dev@null\" data-email=\"pj.ca.smn@ikasaret\" class=\"oemail\">pj.ca.smn@ikasaret<\/a><span style=\"unicode-bidi:bidi-override\">, <\/span><\/div>\n<\/div>\n<div class=\"fm-article-notes hide half_rhythm\" id=\"idm139785373589472_an\" style=\"display:none\">\n<div class=\"fm-pubdate half_rhythm\">Received 2019 Mar 13; Revised 2019 Jul 24; Accepted 2019 Jul 30.<\/div>\n<\/div>\n<div class=\"permissions half_rhythm hide\" id=\"idm139785373589472_cpl\" style=\"display:none\">\n<div class=\"fm-copyright half_rhythm\"><a href=\"\/pmc\/about\/copyright\/\">Copyright<\/a> \u00a9 2019 The Authors. <em>Journal of Cellular and Molecular Medicine <\/em> published by John Wiley &amp; Sons Ltd and Foundation for Cellular and Molecular Medicine.<\/div>\n<div class=\"license half_rhythm\">This is an open access article under the terms of the <a href=\"http:\/\/creativecommons.org\/licenses\/by\/4.0\/\" data-ga-action=\"click_feat_suppl\" ref=\"reftype=extlink&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CFront%20Matter&amp;TO=External%7CLink%7CURI\" target=\"_blank\" rel=\"noopener\">http:\/\/creativecommons.org\/licenses\/by\/4.0\/<\/a> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.<\/div>\n<\/div>\n<\/div>\n<div id=\"pmclinksbox\" class=\"links-box whole_rhythm hidden\" role=\"complementary\" aria-label=\"Related or updated information about this article.\"><\/div>\n<\/div>\n<div class=\"sec\"><\/div>\n<div id=\"ass-data\" class=\"tsec fm-sec whole_rhythm\" data-section=\"Featured_PMC_Datacitation\">\n<h2 class=\"nomenu\">Associated Data<\/h2>\n<dl data-count=\"3\" class=\"box-data-suppmats whole_rhythm no_bottom_margin\">\n<dt><a href=\"#\" rid=\"data-suppmats\" data-ga-action=\"click_feat_toggler\" data-ga-label=\"Supplementary Materials\" class=\"pmctoggle\">Supplementary Materials<\/a><\/dt>\n<dd id=\"data-suppmats\" style=\"display: none;\">\n<div class=\"half_rhythm\">\n<div class=\"caption half_rhythm no_bottom_margin\">&nbsp;<\/div>\n<div><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/bin\/JCMM-23-7043-s001.tiff\" data-ga-action=\"click_feat_suppl\">JCMM-23-7043-s001.tiff<\/a><span style=\"color:gray\"> (1.4M)<\/span><\/div>\n<div class=\"small guid\">GUID:&nbsp;F319C10A-EA29-4284-98F2-F133372B933E<\/div>\n<\/div>\n<div class=\"half_rhythm\">\n<div class=\"caption half_rhythm no_bottom_margin\">&nbsp;<\/div>\n<div><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/bin\/JCMM-23-7043-s002.tiff\" data-ga-action=\"click_feat_suppl\">JCMM-23-7043-s002.tiff<\/a><span style=\"color:gray\"> (1.4M)<\/span><\/div>\n<div class=\"small guid\">GUID:&nbsp;CA5B64C7-2AB1-4090-B9C0-276C7C421828<\/div>\n<\/div>\n<div class=\"half_rhythm\">\n<div class=\"caption half_rhythm no_bottom_margin\">&nbsp;<\/div>\n<div><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/bin\/JCMM-23-7043-s003.tiff\" data-ga-action=\"click_feat_suppl\">JCMM-23-7043-s003.tiff<\/a><span style=\"color:gray\"> (1.4M)<\/span><\/div>\n<div class=\"small guid\">GUID:&nbsp;5BFDF403-549B-4BE3-B806-520E901AF6EE<\/div>\n<\/div>\n<\/dd>\n<\/dl>\n<dl data-length=\"117\" class=\"box-data-avail whole_rhythm no_bottom_margin\">\n<dt><a href=\"#\" rid=\"data-avl-stmnt\" data-ga-action=\"click_feat_toggler\" data-ga-label=\"Data Availability Statement\" class=\"pmctoggle\">Data Availability Statement<\/a><\/dt>\n<dd id=\"data-avl-stmnt\" style=\"display: none;\">\n<p class=\"p p-first-last\">The data that support the findings of this study are available from the corresponding author upon reasonable request.<\/p>\n<\/dd>\n<\/dl>\n<\/div>\n<div id=\"jcmm14603-abs-0001\" lang=\"en\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><span role=\"menubar\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"menuitem\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/span><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-abs-0001title\">Abstract<\/h2>\n<p><!--article-meta--><\/p>\n<div>\n<p class=\"p p-first-last\">Rheumatoid arthritis (RA)\u2010associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II\u2010induced polyarthritis and anti\u2010cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H<sub>2<\/sub>) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species\u2010induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H<sub>2<\/sub> treatment effects. We injected D1CC mice with type II collagen and supplied them with H<sub>2<\/sub>\u2010rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10&nbsp;months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8\u2010hydroxy\u20102\u02b9\u2010deoxyguanosine\u2010positive cell numbers and tumour necrosis factor\u2010\u03b1, BAX, transforming growth factor\u2010\u03b2, interleukin\u20106 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H<sub>2<\/sub> treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H<sub>2<\/sub> treatment and chronic interstitial pneumonia pathophysiology in humans. H<sub>2<\/sub> appears to protect against RA\u2010ILD by alleviating oxidative stress.<\/p>\n<\/div>\n<div class=\"sec\"><strong class=\"kwd-title\">Keywords: <\/strong><span class=\"kwd-text\">D1CC transgenic mice, molecular hydrogen, reactive oxygen species, rheumatoid arthritis\u2010associated interstitial lung disease<\/span><\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0001\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0001title\">1.\u2003INTRODUCTION<\/h2>\n<p class=\"p p-first\">In most patients, rheumatoid arthritis (RA) is characterized by increased rheumatoid factor and anti\u2010cyclic citrullinated peptide antibody levels, which can be detected using commercially available assays.<a href=\"#jcmm14603-bib-0001\" rid=\"jcmm14603-bib-0001\" class=\" ref\">1<\/a>, <a href=\"#jcmm14603-bib-0002\" rid=\"jcmm14603-bib-0002\" class=\" ref\">2<\/a> The aetiology of RA may involve the combination of a specific genetic background (certain major histocompatibility complex class II molecules) and environmental triggers, such as infection and smoking,<a href=\"#jcmm14603-bib-0003\" rid=\"jcmm14603-bib-0003\" class=\" ref\">3<\/a>, <a href=\"#jcmm14603-bib-0004\" rid=\"jcmm14603-bib-0004\" class=\" ref\">4<\/a> causing defects in immune regulation and inflammatory mechanisms associated with oxidative stress\u2010induced joint tissue damage.<a href=\"#jcmm14603-bib-0001\" rid=\"jcmm14603-bib-0001\" class=\" ref\">1<\/a>, <a href=\"#jcmm14603-bib-0004\" rid=\"jcmm14603-bib-0004\" class=\" ref\">4<\/a> The main manifestation of RA is joint disease; however, recent estimates suggest that more than half of all patients with RA develop some form of extra\u2010articular lung disease.<a href=\"#jcmm14603-bib-0005\" rid=\"jcmm14603-bib-0005\" class=\" ref\">5<\/a> In addition, approximately 30% of patients with RA with lung involvement develop RA\u2010associated interstitial lung disease (RA\u2010ILD), a serious diffuse parenchymal lung disease associated with impaired gas exchange and fibrotic injury of alveolar septa. The most common histological patterns of RA\u2010ILD are usual and non\u2010specific interstitial pneumonia,<a href=\"#jcmm14603-bib-0006\" rid=\"jcmm14603-bib-0006\" class=\" ref\">6<\/a> which are the primary causes of morbidity and mortality in such patients <a href=\"#jcmm14603-bib-0007\" rid=\"jcmm14603-bib-0007\" class=\" ref\">7<\/a&gt;; however, the pathogenesis of RA\u2010ILD is unclear, and treatment options are limited.<\/p>\n<p>We previously established a model of arthritis\u2010prone D1CC mice to provide a basis for the development of therapeutic interventions for RA\u2010ILD. This novel mouse RA model is transgenic for the DBA\/1 background. The model uses a class II transactivator and collagen type II (CII) promoter and features aberrant major histocompatibility complex class II gene expression in the joints.<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a>\n<\/p>\n<p>The administration of a low CII concentration to D1CC mice, which are highly susceptible to arthritogenic stimuli, induces the gradual development of chronic inflammatory arthritis. This contrasts with the conventional mouse model of collagen\u2010induced arthritis, which is characterized by acute inflammation. D1CC mice exhibit interstitial pneumonitis, in addition to RA\u2010like synovitis with pannus formation and joint destruction, and develop anti\u2010cyclic citrullinated peptide antibodies.<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a> Thus, we expected D1CC mice to serve as a model that is considerably similar to RA\u2010ILD in humans and function as an important investigative tool to model human RA\u2010ILD and chronic interstitial pneumonia. However, to date, we have only obtained data on lung histology 6&nbsp;months after CII injection in D1CC mice using elastica and Kernechtrot staining.<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a>\n<\/p>\n<p>Autoreactive T cells that infiltrate the synovial tissue in RA promote an immune response and result in the overproduction of pro\u2010inflammatory cytokines such as tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and interleukin\u20106 (IL\u20106). Thus, therapy in early RA targets aggressive biological disease alteration by regulating synovial T cells and decreasing the levels of cytokines associated with the disease.<a href=\"#jcmm14603-bib-0009\" rid=\"jcmm14603-bib-0009\" class=\" ref\">9<\/a> Current treatment options for RA\u2010ILD include disease\u2010modifying anti\u2010rheumatic drugs and biological anti\u2010TNF\u2010\u03b1 therapies. However, evidence suggests that although these treatments benefit joint disease, they can exacerbate pulmonary dysfunction as a side effect.<a href=\"#jcmm14603-bib-0010\" rid=\"jcmm14603-bib-0010\" class=\" ref\">10<\/a>\n<\/p>\n<p>In addition to these immunogenic factors, reactive oxygen species (ROS) are important therapeutic targets because they occur upstream of cytokine\u2010mediated inflammatory cascades.<a href=\"#jcmm14603-bib-0011\" rid=\"jcmm14603-bib-0011\" class=\" ref\">11<\/a> The synovial fluid and peripheral blood of patients with RA contain high levels of ROS and ROS\u2010induced molecules such as superoxide, hydroxyl radicals (\u2022OH) and peroxynitrite (ONOO<sup>\u2212<\/sup>).<a href=\"#jcmm14603-bib-0001\" rid=\"jcmm14603-bib-0001\" class=\" ref\">1<\/a>, <a href=\"#jcmm14603-bib-0012\" rid=\"jcmm14603-bib-0012\" class=\" ref\">12<\/a>, <a href=\"#jcmm14603-bib-0013\" rid=\"jcmm14603-bib-0013\" class=\" ref\">13<\/a>, <a href=\"#jcmm14603-bib-0014\" rid=\"jcmm14603-bib-0014\" class=\" ref\">14<\/a>, <a href=\"#jcmm14603-bib-0015\" rid=\"jcmm14603-bib-0015\" class=\" ref\">15<\/a>, <a href=\"#jcmm14603-bib-0016\" rid=\"jcmm14603-bib-0016\" class=\" ref\">16<\/a>, <a href=\"#jcmm14603-bib-0017\" rid=\"jcmm14603-bib-0017\" class=\" ref\">17<\/a>\n<\/p>\n<p>Molecular hydrogen (H<sub>2<\/sub>) only quenches harmful ROS, including \u2022OH and ONOO<sup>\u2212<\/sup>, and permeates cell membranes; thus, it can easily target organelles, including mitochondria and nuclei. Inhaled H<sub>2<\/sub> suppresses oxidative stress\u2010induced injury in several organs, such as ischaemia\/reperfusion injury in the brain,<a href=\"#jcmm14603-bib-0018\" rid=\"jcmm14603-bib-0018\" class=\" ref\">18<\/a> liver <a href=\"#jcmm14603-bib-0019\" rid=\"jcmm14603-bib-0019\" class=\" ref\">19<\/a> and heart,<a href=\"#jcmm14603-bib-0020\" rid=\"jcmm14603-bib-0020\" class=\" ref\">20<\/a> and irradiation\u2010induced injury in the lungs.<a href=\"#jcmm14603-bib-0021\" rid=\"jcmm14603-bib-0021\" class=\" ref\">21<\/a> Furthermore, continuous consumption of H<sub>2<\/sub>\u2010rich water protects against oxidative damage, including manifestations of oxidative stress associated with diabetes in humans,<a href=\"#jcmm14603-bib-0022\" rid=\"jcmm14603-bib-0022\" class=\" ref\">22<\/a> cisplatin\u2010induced renal injury in mice,<a href=\"#jcmm14603-bib-0023\" rid=\"jcmm14603-bib-0023\" class=\" ref\">23<\/a> naphthalene\u2010evoked acute lung injury in mice<a href=\"#jcmm14603-bib-0024\" rid=\"jcmm14603-bib-0024\" class=\" ref\">24<\/a> and non\u2010alcoholic steatohepatitis<a href=\"#jcmm14603-bib-0025\" rid=\"jcmm14603-bib-0025\" class=\" ref\">25<\/a>, <a href=\"#jcmm14603-bib-0026\" rid=\"jcmm14603-bib-0026\" class=\" ref\">26<\/a> in animal models. Thus, H<sub>2<\/sub> may be used clinically as a safe and effective antioxidant with few side effects.<\/p>\n<p class=\"p p-last\">In this study, we re\u2010evaluated fibrotic lung lesions in D1CC mice as a model of RA\u2010ILD. Furthermore, we investigated the effect of H<sub>2<\/sub> treatment in this model to evaluate its therapeutic use against chronic lung fibrosis.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0002\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0002title\">2.\u2003MATERIALS AND METHODS<\/h2>\n<div id=\"jcmm14603-sec-0003\" class=\"sec sec-first\">\n<h3 id=\"jcmm14603-sec-0003title\">2.1. Production of H<sub>2<\/sub>\u2010rich water<\/h3>\n<p class=\"p p-first-last\">H<sub>2<\/sub>\u2010rich water was prepared using a previously described method.<a href=\"#jcmm14603-bib-0021\" rid=\"jcmm14603-bib-0021\" class=\" ref\">21<\/a> Briefly, H<sub>2<\/sub> gas (purity&nbsp;&gt;&nbsp;99.999%; Iwatani) was dissolved in reverse osmosis water under high pressure (0.4&nbsp;MPa) to a super\u2010saturated level in a stainless steel tank (Unicontrols). During the preparation of H<sub>2<\/sub>\u2010rich water, the H<sub>2<\/sub> concentration in the air was carefully monitored using a H<sub>2<\/sub> sensor with an alarm for safety. The saturated water was poured into 70\u2010mL glass vessels equipped with an outlet line containing two ball bearings, which prevented the water from being degassed. The H<sub>2<\/sub> concentration in the water was measured using a needle\u2010type H<sub>2<\/sub> sensor (Unisense). H<sub>2<\/sub>\u2010rich water was approximately 80% saturated (640&nbsp;\u03bcM) at 0.1&nbsp;MPa at room temperature. Water obtained by degassing H<sub>2<\/sub> from H<sub>2<\/sub>\u2010rich water with gentle stirring overnight was used as a control.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0004\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0004title\">2.2. Animal treatment<\/h3>\n<p class=\"p p-first\">D1CC mouse production was described previously by Kanazawa et al,<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a> and the mice (male, 8&nbsp;weeks old) used in all experiments were obtained by interbreeding six D1CC mice (three male and three female) provided by Satoshi Kanazawa. The male D1CC mice were immunized via several 10\u2010\u00b5g injections of bovine CII (bCII; Collagen Research Center) emulsified in an equal volume of complete Freund&#8217;s adjuvant (Difco Laboratories). Mice received intradermal injections at the base of the tail, near the inguinal and axillary lymph nodes. The day of the first injection was designated Day 0. Mice received booster injections of bCII in the same location using incomplete Freund&#8217;s adjuvant (Difco Laboratories) on days 21, 42 and 63. Animals consumed H<sub>2<\/sub>\u2010rich or control water from day 0 until analysis, and they were housed with five mice per cage under standard laboratory conditions, with food and water available ad libitum. We randomly distributed the mice into three groups (n&nbsp;=&nbsp;20 in each group) as follows: (a) control, normal water and injected with adjuvant without bCII; (b) H<sub>2<\/sub> treatment (\u2212), normal water and injected with bCII; and (c) H<sub>2<\/sub> treatment (+), H<sub>2<\/sub>\u2010rich water and injected with bCII. We evaluated the subgroups at 10&nbsp;months after bCII injection (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0001\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0001\" rid-ob=\"ob-jcmm14603-fig-0001\" co-legend-rid=\"lgnd_jcmm14603-fig-0001\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure1).<\/span><\/span><span>1<\/span><\/a>). The Animal Care and Use Committee of Nippon Medical School approved the animal protocols (27\u2010152).<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"jcmm14603-fig-0001\" co-legend-rid=\"lgnd_jcmm14603-fig-0001\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0001\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0001\" rid-ob=\"ob-jcmm14603-fig-0001\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139785408394928\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g001.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g001.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/JCMM-23-7043-g001.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785408394928\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0001\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0001\" rid-ob=\"ob-jcmm14603-fig-0001\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0001\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_jcmm14603-fig-0001\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0001\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0001\" rid-ob=\"ob-jcmm14603-fig-0001\" rel=\"noopener\">Figure 1<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Study experimental design. D1CC mice were immunized using four 10\u2010\u00b5g injections of bovine type II collagen (bCII) and evaluated 10&nbsp;months later. Mice consumed H<sub>2<\/sub>\u2010rich or control water from day 0 after the first injection until analysis. The mice were randomly assigned to three groups (n&nbsp;=&nbsp;20 in each group): (a) control, normal water and not injected with bCII; (b) H<sub>2<\/sub> treatment (\u2212), normal water and injected with bCII; and (c) H<sub>2<\/sub> treatment (+), H<sub>2<\/sub>\u2010rich water and injected with bCII<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0005\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0005title\">2.3. Evaluation of joint arthritis<\/h3>\n<p class=\"p p-first\">D1CC mice with or without H<sub>2<\/sub> treatment were monitored twice weekly. The clinical severity of arthritis was quantified according to a previously reported simple scoring system<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a> (Table <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/table\/jcmm14603-tbl-0001\/\" target=\"table\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-tbl-0001\" rid-ob=\"ob-jcmm14603-tbl-0001\" co-legend-rid=\"\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3em;\">(Table1)<\/span><\/span><span>1<\/span><\/a>) as follows: 0, no clinical symptom; 1, swelling and redness of one or two joints; 2, moderate swelling and redness of three or more joints; and 3, severe swelling and redness of the entire paw. All scores were summed to generate the total clinical score, which had a maximum value of 12 (four severely affected joints, 4&nbsp;\u00d7&nbsp;3).<\/p>\n<p><!--table ft1--><!--table-wrap mode=\"anchored\" t5--><\/p>\n<div class=\"table-wrap anchored whole_rhythm\" id=\"jcmm14603-tbl-0001\">\n<h3>Table 1<\/h3>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Clinical score for inflammatory arthritis<\/p>\n<\/div>\n<div class=\"xtable\">\n<table frame=\"hsides\" rules=\"groups\" class=\"rendered small default_table\">\n<thead valign=\"top\">\n<tr style=\"border-bottom:solid 1px #000000\">\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\">Score<\/th>\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\">Criteria<\/th>\n<\/tr>\n<\/thead>\n<tbody>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">0<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">No effects<sup><a href=\"#jcmm14603-note-0002\" rid=\"jcmm14603-note-0002\" class=\" fn\">a<\/a><\/sup>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">1<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Redness and swelling (one or two joints)<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">2<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Redness and moderate swelling (three or more joints)<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">3<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Redness, severe swelling (entire paw) and functional impairment<sup><a href=\"#jcmm14603-note-0100\" rid=\"jcmm14603-note-0100\" class=\" fn\">b<\/a><\/sup>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785410288672\"><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/table\/jcmm14603-tbl-0001\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"tblwrap-foot\">\n<div id=\"jcmm14603-note-0002\"><sup>a<\/sup>All joints are examined and evaluated, no differences with untreated mice are found.<\/div>\n<div id=\"jcmm14603-note-0100\"><sup>b<\/sup>Maximal score for all four extremities is 12.<\/div>\n<\/div>\n<div class=\"small permissions half_rhythm\"><\/div>\n<\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0006\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0006title\">2.4. Sample collection<\/h3>\n<p class=\"p p-first-last\">We anesthetized the mice and exsanguinated them via the abdominal aorta at specific times after bCII injection. After blood sampling and micro\u2010computed tomography (micro\u2010CT), we cannulated the trachea and removed the lungs. For each animal, the left lung (two lobes) was immediately frozen at&nbsp;\u2212&nbsp;80\u00b0C and later used for Western blot analyses and real\u2010time reverse transcription\u2010quantitative polymerase chain reaction (RT\u2010qPCR). The right lung (three lobes), which was used for microscopic analyses, was fixed for 8&nbsp;hours at 4\u00b0C in 4% paraformaldehyde in 0.1&nbsp;mol\/L phosphate buffer (pH 7.4) at a H<sub>2<\/sub>O inflation pressure of 20&nbsp;cm and then embedded in paraffin.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0007\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0007title\">2.5. Biochemical analysis of serum<\/h3>\n<p class=\"p p-first\">Serum surfactant protein D (SP\u2010D) levels were measured using a specific enzyme immunoassay kit (Yamasa) according to the manufacturer&#8217;s protocol. The kit consisted of a 96\u2010well microtiter plate coated with monoclonal anti\u2010SP\u2010D antibodies,<a href=\"#jcmm14603-bib-0027\" rid=\"jcmm14603-bib-0027\" class=\" ref\">27<\/a> and colour changes were determined using a microplate reader (iMark, Bio\u2010Rad Laboratories, Inc) at 450&nbsp;nm. The SP\u2010D concentration was determined by comparing the sample absorption with a standard curve.<\/p>\n<p class=\"p p-last\">Lipid peroxide (LPO) levels were determined using the thiobarbituric acid\u2010reactive substance method according to the protocol provided by Naito and Yamanaka.<a href=\"#jcmm14603-bib-0028\" rid=\"jcmm14603-bib-0028\" class=\" ref\">28<\/a>\n<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0008\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0008title\">2.6. Histology and fibrosis score<\/h3>\n<p class=\"p p-first-last\">We utilized haematoxylin and eosin to stain paraffin\u2010embedded sections for routine histological examinations and elastica Masson\u2010Goldner staining to investigate collagen deposition. For immunohistochemical studies, we utilized the remaining sections of the right lungs. Ashcroft scores were used to evaluate the severity of lung fibrosis (a lung lesion with inflammatory and fibrotic changes), as described previously.<a href=\"#jcmm14603-bib-0029\" rid=\"jcmm14603-bib-0029\" class=\" ref\">29<\/a> Briefly, we scanned eight fields of sections of the right lung (three lobes) at \u00d7100, and we visually graded each field using scores of 0 (normal) to 8 (complete obliteration of the field by fibrosis). We defined the visual fibrosis score as the mean value of grades obtained from all inspected fields. Certain histological parameters of all samples were independently analysed by two blinded observers (N. K. and M. T.).<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0009\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0009title\">2.7. Collagen assay<\/h3>\n<p class=\"p p-first-last\">The soluble collagen content of the left lung was determined using a Sircol assay (Biocolor) according to the manufacturer&#8217;s instructions. Bound Sircol dye was assessed using a microplate reader (iMark) at 555&nbsp;nm. Collagen standards supplied with the kit were used as assay controls.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0010\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0010title\">2.8. Immunohistochemistry<\/h3>\n<p class=\"p p-first-last\">We microwaved lung sections in DakoCytomation Target Retrieval Solution (Dako) for 10&nbsp;minutes at 100\u00b0C and restricted endogenous peroxidase activity using the method of Brown et al.<a href=\"#jcmm14603-bib-0030\" rid=\"jcmm14603-bib-0030\" class=\" ref\">30<\/a> We immunostained sections using a Histofine Simple Stain kit (Nichirei Corporation) with rabbit polyclonal anti\u2010CD3 (1:400; DakoCytomation), rabbit monoclonal anti\u2010PAX5 (1:50; D7H5X; Cell Signaling Technology), rat monoclonal anti\u2010F4\/80 (1:50; CI\u2010A3\u20101; Novus Biologicals), goat polyclonal anti\u2010TNF\u2010\u03b1 (1:100; Santa Cruz Biotechnology), mouse monoclonal anti\u2010IL\u20106 (1:100; Leica Biosystems Newcastle Ltd.), transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2, 1:100; Santa Cruz Biotechnology), anti\u2010BAX (1:100; Santa Cruz Biotechnology) or mouse monoclonal anti\u20108\u2010hydroxydeoxyguanosine (8\u2010OHdG) antibody (5&nbsp;\u00b5g\/mL; JaICA; Nikken SEIL Co., Ltd.), as previously described.<a href=\"#jcmm14603-bib-0021\" rid=\"jcmm14603-bib-0021\" class=\" ref\">21<\/a> We counted the 8\u2010OHdG\u2010positive cell numbers per field of view in lungs from each group (n&nbsp;=&nbsp;6) in a blinded manner. Further, we compared the means of the positive values between each group using an image analysis system (MacScoop version 2.5, Mitani).<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0011\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0011title\">2.9. Micro\u2010CT<\/h3>\n<p class=\"p p-first-last\">We performed micro\u2010CT using an LCT\u2010200 micro\u2010CT system (LaTheta; Aloka). The intensity of X\u2010rays in air is \u22121000 Hounsfield units and that in water is 0 Hounsfield units. We acquired the CT images with the X\u2010ray source biased at 50&nbsp;kVp and 1&nbsp;mA, and slices were 0.3&nbsp;mm in thickness. The image size was 480&nbsp;\u00d7&nbsp;480 pixels, with a field of view of 48&nbsp;mm at a resolution of 0.10&nbsp;mm per pixel. For lung analysis, we designated areas with intensities between \u2212400 and \u2212200 Hounsfield units as areas of abnormally high density. The ratio of an area of abnormally high density to the whole lung field was determined using LCT\u2010200 system software and compared between control and bCII\u2010injected mice with and without H<sub>2<\/sub> treatment.<a href=\"#jcmm14603-bib-0021\" rid=\"jcmm14603-bib-0021\" class=\" ref\">21<\/a>\n<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0012\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0012title\">2.10. Western blot analysis<\/h3>\n<p class=\"p p-first-last\">Western blotting was performed in each experiment according to the standard procedure. We quantified proteins using a BCA Protein Assay kit (Thermo Scientific). We homogenized frozen left lung tissues in a mammalian protein extraction reagent that contained a protein\u2010stabilizing cocktail (Halt Protease Inhibitor Cocktail; Thermo Scientific), 150&nbsp;mmol\/L NaCl, and 1&nbsp;mmol\/L EDTA. Samples were centrifuged at 17712<em>g<\/em> for 5&nbsp;minutes, and supernatants containing equal amounts of protein were boiled for 5&nbsp;minutes in sodium dodecyl sulphate sample buffer, separated via 10% sodium dodecyl sulphate\u2010polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes (Thermo Scientific) using an electroblot apparatus (Invitrogen). We incubated the membranes with protein\u2010free T20 Tris\u2010buffered saline (TBS) blocking buffer (Thermo Scientific) for 1&nbsp;hour at room temperature and then incubated them with antibodies against TGF\u2010\u03b2, TNF\u2010\u03b1 BAX, or \u03b2\u2010actin at a dilution of 1:1000 (Sigma\u2010Aldrich) at 4\u00b0C for approximately 16&nbsp;hours. The membranes were washed several times with TBS containing 0.1% Tween 20, incubated for 45&nbsp;minutes with the appropriate horseradish peroxidase\u2010conjugated secondary antibodies (Promega), washed again with TBS containing 0.1% Tween 20 and developed using SuperSignal West Femto Luminol\/Enhancer solution (Thermo Scientific). We detected the immunoreactivity on blots using an LAS\u20104000 Luminescent Image Analyzer (Fujifilm) and quantified the value via densitometry using Fuji Image Gauge software (version 4.0; Fujifilm). Furthermore, the proteins were stripped from the blotting membrane after incubation for 15&nbsp;minutes in Restore PLUS Western Blot Stripping Buffer (Thermo Scientific). The expression of each protein was quantified after reaction with the appropriate antibodies and expressed as a ratio to the amount of \u03b2\u2010actin. We compared six respective results with controls without bCII injections in six experiments (control&nbsp;=&nbsp;1.0) and reported the results.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0013\" class=\"sec\">\n<h3 id=\"jcmm14603-sec-0013title\">2.11. RT\u2010qPCR<\/h3>\n<p class=\"p p-first-last\">We performed RT\u2010qPCR to analyse IL\u20106 mRNA expression. We extracted total RNA using TRIzol reagent (Qiagen, GmbH) according to the manufacturer&#8217;s instructions and utilized ready\u2010to\u2010use primer and probe sets from Applied Biosystems (Assay\u2010on\u2010Demand Gene Expression Catalog number Mm00446190m1) for IL\u20106 and glyceraldehyde\u20103\u2010phosphate dehydrogenase (GAPDH). We optimized the primer and probe concentrations for each target gene according to the manufacturer&#8217;s instructions and performed PCR (2&nbsp;minutes at 50\u00b0C, 10&nbsp;minutes at 95\u00b0C, and 45 cycles of 15&nbsp;seconds of denaturation at 95\u00b0C and 60&nbsp;seconds of annealing at 60\u00b0C) using an ABI Prism 7000 Sequence Detection System (Applied Biosystems) and fluorescent TaqMan methodology. We quantified IL\u20106 and GAPDH mRNA levels in triplicate for all experiments and normalized IL\u20106 mRNA expression to GAPDH mRNA expression. Results were expressed relative to the standard sample (1&nbsp;\u00d7&nbsp;standard sample&nbsp;=&nbsp;1.0).<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0014\" class=\"sec sec-last\">\n<h3 id=\"jcmm14603-sec-0014title\">2.12. Statistical analysis<\/h3>\n<p class=\"p p-first-last\">We calculated arithmetic means and standard errors of the means for each data set and applied Student&#8217;s <em>t<\/em> test to compare paired or independent variables. We determined the statistical differences among groups using one\u2010way ANOVA and considered <em>P<\/em>&nbsp;&lt;&nbsp;.05 to be statistically significant.<\/p>\n<\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0015\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0015title\">3.\u2003RESULTS<\/h2>\n<div id=\"jcmm14603-sec-0016\" class=\"sec sec-first\">\n<h3 id=\"jcmm14603-sec-0016title\">3.1. Serum SP\u2010D and pathological analysis of the RA\u2010ILD model<\/h3>\n<p class=\"p p-first\">Serum SP\u2010D levels were significantly increased approximately 10&nbsp;months (40&nbsp;weeks) after the first injection of bCII (Figure <a href=\"#jcmm14603-sup-0001\" rid=\"jcmm14603-sup-0001\" class=\" supplementary-material\">S1<\/a>). Numerous inflammatory cells had infiltrated the perilymphatic stromal area of the D1CC mouse lungs, including the peribronchial (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2A\u2010C)<\/span><\/span><span>2<\/span><\/a>A\u2010C) and perivascular (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2A\u2010G)<\/span><\/span><span>2<\/span><\/a>A\u2010G) connective tissues, featuring a patchy distribution (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2A)<\/span><\/span><span>2<\/span><\/a>A) 10&nbsp;months after the first bCII injection. The infiltrating inflammatory cells in the perivascular area were clearly granulocytes (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2D),<\/span><\/span><span>2<\/span><\/a>D), lymphocytes (B cells and T cells; Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3em;\">Figure2E,F)<\/span><\/span><span>2<\/span><\/a>E,F) and macrophages (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2G).<\/span><\/span><span>2<\/span><\/a>G). Furthermore, inflammatory cells infiltrated the alveolar area surrounding bronchioles, which exhibited pneumocyte hyperplasia and fibrotic changes (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2<\/span><\/span><span>2<\/span><\/a>H,I).<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139785373571952\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g002.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g002.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/JCMM-23-7043-g002.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785373571952\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_jcmm14603-fig-0002\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" rel=\"noopener\">Figure 2<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Histology of lung lesions in D1CC mice 10&nbsp;months after injection with bovine type II collagen (bCII). Paraffin\u2010embedded lung serial sections were stained with haematoxylin and eosin (HE) (A, B, D, H) or elastica Masson\u2010Goldner (EMG) (C, I) or immunostained for B cells (E), T cells (F) or macrophages (G). (A) Low\u2010power view of a lung lesion from a D1CC mouse. Arrows denote the lymphatic distribution of inflammatory changes along with the bronchovascular bundles. (B, C) Active inflammatory lesions in the peribronchial area (white star) as high\u2010magnification images (HE and EMG, respectively) of the area in the black rectangle in (A). The black arrows in (B, C) point to the bronchial epithelium. (D\u2010G) Inflammatory cell\u2010infiltrated lesions in the perivascular area (red stars) in a high\u2010magnification image of the area in the blue rectangle in (A). The inset in (D) shows a high\u2010magnification image of the area in the blue rectangle in (D). Infiltrated inflammatory cells are granulocytes (yellow arrow, inset; D) and B lymphocytes (E), T lymphocytes (F) and macrophages (G), as highlighted by brown staining. (H) Infiltration of inflammatory cells in a patchy distribution in the alveolar area surrounding the bronchi (black arrows). (I) Intraluminal fibrotic change (blue arrow) with inflammatory cells observed in this high\u2010magnification image of the area in the black rectangle in (H). Scale bars, 500 (A, H), 100 (B, C, I) and 50&nbsp;\u00b5m (D\u2010G)<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0017\" class=\"sec sec-last\">\n<h3 id=\"jcmm14603-sec-0017title\">3.2. Analyses of the RA\u2010ILD model with and without H<sub>2<\/sub> treatment<\/h3>\n<p class=\"p p-first\">Up to 8&nbsp;weeks after immunization (Figure <a href=\"#jcmm14603-sup-0002\" rid=\"jcmm14603-sup-0002\" class=\" supplementary-material\">S2<\/a>), we found that D1CC mice developed inflammatory arthritis with redness, swelling and fever in the joints after immunization with bCII as previously reported,<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a> whereas H<sub>2<\/sub> treatment suppressed inflammatory arthritis development in D1CC mice induced by bCII. Ten months after the first bCII injection, we also found an increase in lung density on lung CT images (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure3A,D,J)<\/span><\/span><span>3<\/span><\/a>A,D,J) and increased serum SP\u2010D levels (Figure <a href=\"#jcmm14603-sup-0001\" rid=\"jcmm14603-sup-0001\" class=\" supplementary-material\">S1<\/a> and Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3em;\">Figure3K),<\/span><\/span><span>3<\/span><\/a>K), which were consistent with the histological findings of active alveolitis with pneumocyte hyperplasia (Figures <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -4em;\">(Figures2<\/span><\/span><span>2<\/span><\/a> and <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -1.5em;\">and3B,C,E,F).<\/span><\/span><span>3<\/span><\/a>B,C,E,F). H<sub>2<\/sub> treatment protected against lung damage as evidenced by a reversal of the increases in serum SP\u2010D levels (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure3K)<\/span><\/span><span>3<\/span><\/a>K) and lung density on CT images (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure3D,G,J<\/span><\/span><span>3<\/span><\/a>D,G,J and Figure <a href=\"#jcmm14603-sup-0003\" rid=\"jcmm14603-sup-0003\" class=\" supplementary-material\">S3<\/a>) induced by bCII injection; furthermore, the Ashcroft score (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure3L)<\/span><\/span><span>3<\/span><\/a>L) and soluble collagen levels (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" co-legend-rid=\"lgnd_jcmm14603-fig-0004\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure4F)<\/span><\/span><span>4<\/span><\/a>F) were significantly decreased in DICC mice that consumed H<sub>2<\/sub>\u2010treated water compared with the findings in control mice.<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139785374880016\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g003.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g003.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/JCMM-23-7043-g003.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785374880016\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_jcmm14603-fig-0003\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" rel=\"noopener\">Figure 3<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Bovine type II collagen (bCII)\u2010induced lung injury in D1CC mice with and without H<sub>2<\/sub> treatment. (A, D, G) Micro\u2010computed tomography axial sections showing the lower thoracic areas from control and injected mice 10&nbsp;months after bCII injection. bCII\u2010injected mice displayed a regional increase in the areas of radiopaque lesions (arrows); however, this increase was lower in mice treated with H<sub>2<\/sub>. (B, C, E, F, H, I) Representative lung regions, including a perivascular area from each group 10&nbsp;months after injection (haematoxylin and eosin H&amp;E). (C, F, I) High\u2010magnification images of the respective areas in black rectangles in (B, E, H). Scale bars, 100&nbsp;\u00b5m. (J) Ratios of areas of abnormally high density to whole lung fields were calculated and compared for lungs from non\u2010injected control and injected mice with and without H<sub>2<\/sub> treatment (n&nbsp;=&nbsp;5). (K) Serum surfactant protein D (SP\u2010D) levels of non\u2010injected control and injected mice that consumed control or H<sub>2<\/sub>\u2010rich water (n&nbsp;=&nbsp;9). (L) The severity of lung damage was evaluated using Ashcroft scores (n&nbsp;=&nbsp;6). Data are presented as the mean&nbsp;\u00b1&nbsp;SEM<\/p>\n<\/div>\n<\/div>\n<\/div>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"jcmm14603-fig-0004\" co-legend-rid=\"lgnd_jcmm14603-fig-0004\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139785374873856\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g004.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g004.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/JCMM-23-7043-g004.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785374873856\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_jcmm14603-fig-0004\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" rel=\"noopener\">Figure 4<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), BAX, transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2), interleukin\u20106 (IL\u20106), and soluble collagen levels after bovine type II collagen (bCII) injection with and without H<sub>2<\/sub> treatment. (A\u2010D) Total lung tissue extracts from 10\u2010month\u2010old mice were subjected to Western blotting using antibodies against TNF\u2010\u03b1, BAX, TGF\u2010\u03b2 and \u03b2\u2010actin (total loading control). (A) Representative blots from control and bCII\u2010injected animals without and with H<sub>2<\/sub> treatment obtained from blotting experiments performed on the same days under the same conditions. (B\u2010D) In six experiments similar to those presented in (A), the amounts of each protein were quantified by densitometry and expressed relative to the amount of \u03b2\u2010actin in the same samples. Results are reported relative to those of six non\u2010injected controls (non\u2010injection&nbsp;=&nbsp;1.0). Data are presented as the mean&nbsp;\u00b1&nbsp;SEM. (E) Ratio of IL\u20106 mRNA\/glyceraldehyde\u20103\u2010phosphate dehydrogenase (GAPDH) mRNA in the lungs of bCII\u2010injected mice as analysed using real\u2010time reverse transcription\u2010quantitative polymerase chain reaction (n&nbsp;=&nbsp;6). Each bar represents IL\u20106 mRNA levels normalized to those of GAPDH mRNA, relative to the results from six non\u2010injected controls (non\u2010injection&nbsp;=&nbsp;1.0). Data are presented as the mean&nbsp;\u00b1&nbsp;SEM. (F) Soluble collagen levels in the lungs of non\u2010injected control and injected mice with and without H<sub>2<\/sub> treatment (n&nbsp;=&nbsp;6) as determined using the Sircol assay. Data are presented as the mean&nbsp;\u00b1&nbsp;SEM<\/p>\n<\/div>\n<\/div>\n<\/div>\n<p>Western blotting and RT\u2010qPCR analyses revealed increased lung expression of TNF\u2010\u03b1, BAX, TGF\u2010\u03b2 and IL\u20106 10&nbsp;months following the first bCII injection (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" co-legend-rid=\"lgnd_jcmm14603-fig-0004\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure4A\u2010E).<\/span><\/span><span>4<\/span><\/a>A\u2010E). H<sub>2<\/sub> treatment protected against lung damage by significantly decreasing the magnitudes of these changes in expression (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" co-legend-rid=\"lgnd_jcmm14603-fig-0004\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure4A\u2010E).<\/span><\/span><span>4<\/span><\/a>A\u2010E). Consistent with these observations, immunohistochemical observation revealed that bCII treatment increased TNF\u2010\u03b1 levels in macrophages (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure5A<\/span><\/span><span>5<\/span><\/a>A inset), BAX levels in reactive pneumocytes (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure5C<\/span><\/span><span>5<\/span><\/a>C inset), TGF\u2010\u03b2 levels in fibroblastic cells (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure5E<\/span><\/span><span>5<\/span><\/a>E inset) and IL\u20106 levels in plasmacytoid cells (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure5G<\/span><\/span><span>5<\/span><\/a>G inset) in the lung lesions in DICC mice, whereas H<sub>2<\/sub> treatment reduced these increases (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure5<\/span><\/span><span>5<\/span><\/a>B,D,F,H).<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139785369424544\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g005.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g005.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/JCMM-23-7043-g005.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785369424544\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_jcmm14603-fig-0005\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" rel=\"noopener\">Figure 5<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), BAX, transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2), interleukin\u20106 (IL\u20106), levels in lung lesions after bovine type II collagen (bCII) injection. Ten months after bCII injection, lung sections from each group were immunostained for TNF\u2010\u03b1 (A), BAX (C), TGF\u2010\u03b2 (E) and IL\u20106 (G) from mice without (A, C, E, G) and with (B, D, F, H) H<sub>2<\/sub> treatment. Insets in (A, C, E, G) are high\u2010magnification images of areas in the red rectangles. Positive findings for TNF\u2010\u03b1 (A), BAX (C), TGF\u2010\u03b2 (E) and IL\u20106 (G) were observed in macrophages, pneumocytes, fibroblastic cells and plasmacytoid cells, respectively. Arrows in each inset indicate positive findings. Scale bars, 100 (main images) and 10&nbsp;\u00b5m (insets, high magnification)<\/p>\n<\/div>\n<\/div>\n<\/div>\n<p class=\"p\">Because ROS may be unidentified regulatory factors in RA pathogenesis,<a href=\"#jcmm14603-bib-0001\" rid=\"jcmm14603-bib-0001\" class=\" ref\">1<\/a>, <a href=\"#jcmm14603-bib-0012\" rid=\"jcmm14603-bib-0012\" class=\" ref\">12<\/a> we examined the effect of H<sub>2<\/sub> on oxidative stress in the lungs of mice with RA based on oxidative stress markers, namely LPO levels in the serum and 8\u2010OHdG levels in the lungs. Serum LPO levels were significantly increased in bCII\u2010injected mice compared with the control levels at 10&nbsp;months; however, H<sub>2<\/sub> treatment significantly reversed these increases (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" co-legend-rid=\"lgnd_jcmm14603-fig-0006\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure6E).<\/span><\/span><span>6<\/span><\/a>E). Consistent with these results, the number of 8\u2010OHdG\u2010positive epithelial and inflammatory cells per field of view were significantly increased in bCII\u2010injected mice (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" co-legend-rid=\"lgnd_jcmm14603-fig-0006\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure6B,D)<\/span><\/span><span>6<\/span><\/a>B,D) compared with those in controls (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" co-legend-rid=\"lgnd_jcmm14603-fig-0006\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure6A,D),<\/span><\/span><span>6<\/span><\/a>A,D), and H<sub>2<\/sub> treatment significantly reversed these increases (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" co-legend-rid=\"lgnd_jcmm14603-fig-0006\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure6<\/span><\/span><span>6<\/span><\/a>C,D).<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"jcmm14603-fig-0006\" co-legend-rid=\"lgnd_jcmm14603-fig-0006\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139785367713264\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g006.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is JCMM-23-7043-g006.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/JCMM-23-7043-g006.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139785367713264\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_jcmm14603-fig-0006\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" rel=\"noopener\">Figure 6<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Oxidative stress in lung lesions induced by bovine type II collagen (bCII) injection with and without H<sub>2<\/sub> treatment. (A\u2010C) Ten months after bCII injection, paraffin\u2010embedded lung sections obtained from each group were stained with 8\u2010hydroxydeoxyguanosine (8\u2010OHdG) antibody. The inset in (B) presents a high\u2010magnification image of the area in the red rectangle. Arrows in the inset indicate positive findings. Scale bars, 100 (main image) and 10&nbsp;\u00b5m (inset, high magnification). (D) The number of 8\u2010OHdG\u2010positive cells per field of view (FOV) were counted in areas of the same size in lungs from each group (n&nbsp;=&nbsp;6). (E) Levels of serum lipid peroxide (LPO), a marker of oxidative stress, from non\u2010injected control and injected mice that received H<sub>2<\/sub> treatment or no treatment (n&nbsp;=&nbsp;8). Data are presented as the mean&nbsp;\u00b1&nbsp;SEM<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0018\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0018title\">4.\u2003DISCUSSION<\/h2>\n<p class=\"p p-first\">We previously reported that D1CC transgenic mice aberrantly express major histocompatibility complex class II genes in their joints, developing RA signs such as erosive inflammatory polyarthritis, with anti\u2010cyclic citrullinated peptide antibody production and interstitial pneumonitis.<a href=\"#jcmm14603-bib-0008\" rid=\"jcmm14603-bib-0008\" class=\" ref\">8<\/a> However, we had only presented elastica and Kernechtrot staining histological data for the lungs at 6&nbsp;months following CII injection.<\/p>\n<p>Accordingly, in this study, we confirmed that bCII injections induce lung damage in D1CC mice (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2),<\/span><\/span><span>2<\/span><\/a>), resulting in increased serum SP\u2010D levels (Figure <a href=\"#jcmm14603-sup-0001\" rid=\"jcmm14603-sup-0001\" class=\" supplementary-material\">S1<\/a> and Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3em;\">Figure3K)<\/span><\/span><span>3<\/span><\/a>K) and lung density on CT images (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure3D,G).<\/span><\/span><span>3<\/span><\/a>D,G). Furthermore, we demonstrated that mixed cellular inflammation occurs in a patchy distribution pattern (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2A)<\/span><\/span><span>2<\/span><\/a>A) in these lung lesions, mainly within the perilymphatic stromal region, such as the peribronchial (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2B,C)<\/span><\/span><span>2<\/span><\/a>B,C) and perivascular areas (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2D\u2010G).<\/span><\/span><span>2<\/span><\/a>D\u2010G). We further demonstrated that a fibroinflammatory lesion develops diffusely from the proximal to the distal alveolar areas (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0002\" rid-ob=\"ob-jcmm14603-fig-0002\" co-legend-rid=\"lgnd_jcmm14603-fig-0002\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure2H,I).<\/span><\/span><span>2<\/span><\/a>H,I). The cellular inflammation within the perilymphatic stromal area in this model is similar to a characteristic feature of lung lesions in patients with collagen vascular diseases, including RA.<a href=\"#jcmm14603-bib-0031\" rid=\"jcmm14603-bib-0031\" class=\" ref\">31<\/a>\n<\/p>\n<p>Moreover, we observed increased expression of TNF\u2010\u03b1, IL\u20106, BAX and TGF\u2010\u03b2 in the lungs of bCII\u2010injected mice compared with the findings in the lungs of control mice that consumed normal water without receiving bCII (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" co-legend-rid=\"lgnd_jcmm14603-fig-0004\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure4A).<\/span><\/span><span>4<\/span><\/a>A). This finding is consistent with the pathological increases in the numbers of TNF\u2010\u03b1\u2010positive macrophages, IL\u20106\u2010positive plasmacytoid cells, BAX\u2010positive pneumocytes and TGF\u2010\u03b2\u2010positive fibroblastic cells (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure5A,C,E,G).<\/span><\/span><span>5<\/span><\/a>A,C,E,G). These molecules are all known to be important in the pathophysiology of RA and fibrosis in humans during inflammation, apoptosis and extracellular matrix production. Therefore, this RA\u2010ILD model using D1CC mice is considerably similar to human RA\u2010ILD and is an important animal model of this disorder.<\/p>\n<p>A murine model utilizing bleomycin\u2010induced lung fibrosis is the most commonly used animal model of pulmonary fibrosis, and it recapitulates the general process of wound healing or repair in acute or subacute lung injury. However, it does not represent a model of chronic and progressive pulmonary damage with inflammation and fibrotic remodelling.<a href=\"#jcmm14603-bib-0032\" rid=\"jcmm14603-bib-0032\" class=\" ref\">32<\/a> Our RA\u2010ILD model in D1CC mice manifests chronic and immunologically inflammatory and progressive interstitial pneumonia with increased TNF\u2010\u03b1, IL\u20106 and TGF\u2010\u03b2 levels; thus, it can be considerably important as a model of RA\u2010ILD and chronic progressive interstitial pneumonia in humans, which is valuable for the future evaluation of biomarkers and treatments. We used this model to reveal that serum SP\u2010D is a suitable marker of lung damage in RA\u2010ILD (Figure <a href=\"#jcmm14603-sup-0001\" rid=\"jcmm14603-sup-0001\" class=\" supplementary-material\">S1<\/a> and Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3em;\">Figure3K),<\/span><\/span><span>3<\/span><\/a>K), similar to serum SP\u2010A, SP\u2010D and Krebs von den Lungen\u20106 as markers of idiopathic interstitial pneumonias in humans.<a href=\"#jcmm14603-bib-0033\" rid=\"jcmm14603-bib-0033\" class=\" ref\">33<\/a>\n<\/p>\n<p>ROS may be unidentified regulatory factors in RA pathogenesis.<a href=\"#jcmm14603-bib-0001\" rid=\"jcmm14603-bib-0001\" class=\" ref\">1<\/a>, <a href=\"#jcmm14603-bib-0012\" rid=\"jcmm14603-bib-0012\" class=\" ref\">12<\/a>, <a href=\"#jcmm14603-bib-0013\" rid=\"jcmm14603-bib-0013\" class=\" ref\">13<\/a>, <a href=\"#jcmm14603-bib-0014\" rid=\"jcmm14603-bib-0014\" class=\" ref\">14<\/a> ROS such as \u2022OH, superoxide anions, hydrogen peroxide and hypochlorous acid are reportedly formed in the inflamed joints of patients with RA by nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase and cytochrome P450 monooxygenase, as well as mitochondrial respiratory chain dysfunction, in chondrocytes, activated macrophages and neutrophils.<a href=\"#jcmm14603-bib-0015\" rid=\"jcmm14603-bib-0015\" class=\" ref\">15<\/a>, <a href=\"#jcmm14603-bib-0016\" rid=\"jcmm14603-bib-0016\" class=\" ref\">16<\/a>, <a href=\"#jcmm14603-bib-0017\" rid=\"jcmm14603-bib-0017\" class=\" ref\">17<\/a> Moreover, antioxidant therapy ameliorated arthritis in animal models; for example, \u03b1\u2010tocotrienol exhibited significant antioxidant and anti\u2010inflammatory effects on collagen\u2010induced arthritis in rats,<a href=\"#jcmm14603-bib-0034\" rid=\"jcmm14603-bib-0034\" class=\" ref\">34<\/a> and the transfection of extracellular superoxide dismutase and catalase genes ameliorated antigen\u2010induced arthritis in rats.<a href=\"#jcmm14603-bib-0035\" rid=\"jcmm14603-bib-0035\" class=\" ref\">35<\/a>\n<\/p>\n<p>H<sub>2<\/sub> quenches only harmful ROS, such as \u2022OH and ONOO<sup>\u2212<\/sup>, and it can permeate cell membranes and easily target organelles, including mitochondria and nuclei.<a href=\"#jcmm14603-bib-0018\" rid=\"jcmm14603-bib-0018\" class=\" ref\">18<\/a> Therefore, H<sub>2<\/sub> can be widely used as a medical treatment with good efficacy and safety and few side effects.<\/p>\n<p>In this study, we illustrated that H<sub>2<\/sub> protected against lung damage in an RA\u2010ILD model by decreasing serum SP\u2010D levels and lung density on CT images, as evidenced by histological changes in H<sub>2<\/sub>\u2010treated mice compared with the findings in untreated animals (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0003\" rid-ob=\"ob-jcmm14603-fig-0003\" co-legend-rid=\"lgnd_jcmm14603-fig-0003\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure3D\u2010L).<\/span><\/span><span>3<\/span><\/a>D\u2010L). Consistent with these results, we observed that H<sub>2<\/sub> protects against lung damage by decreasing soluble collagen levels and TNF\u2010\u03b1, IL\u20106, BAX and TGF\u2010\u03b2 expression (Figures <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0004\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0004\" rid-ob=\"ob-jcmm14603-fig-0004\" co-legend-rid=\"lgnd_jcmm14603-fig-0004\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -4em;\">(Figures4<\/span><\/span><span>4<\/span><\/a> and <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0005\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0005\" rid-ob=\"ob-jcmm14603-fig-0005\" co-legend-rid=\"lgnd_jcmm14603-fig-0005\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -1.5em;\">and5).<\/span><\/span><span>5<\/span><\/a>). These inflammatory, apoptotic and extracellular matrix molecules are important in the pathogenesis of RA and fibrosis. In addition, we found that serum LPO levels and 8\u2010OHdG\u2010positive epithelial and inflammatory cell numbers in lung lesions are significantly increased in bCII\u2010injected DICC mice compared with the findings in control mice that consumed normal water without receiving bCII; furthermore, we observed that these increases were significantly reversed by H<sub>2<\/sub> treatment (Figure <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/figure\/jcmm14603-fig-0006\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"jcmm14603-fig-0006\" rid-ob=\"ob-jcmm14603-fig-0006\" co-legend-rid=\"lgnd_jcmm14603-fig-0006\" rel=\"noopener\"><span style=\"position: relative;text-decoration:none;\">\u200b<span class=\"figpopup-sensitive-area\" style=\"left: -3.5em;\">(Figure6<\/span><\/span><span>6<\/span><\/a>).<\/p>\n<p>Together, these results indicate that oxidative stress was induced in the fibrotic lung lesions of the DICC mouse model of RA\u2010ILD, similar to the findings in patients with RA\u2010ILD. H<sub>2<\/sub> treatment can ameliorate this oxidative stress by decreasing serum LPO levels and 8\u2010OHdG\u2010positive cell numbers and suppress inflammation and fibrosis by decreasing the expression of molecules such as TNF\u2010\u03b1, IL\u20106 and TGF\u2010\u03b2 in the lungs.<\/p>\n<p>We previously reported a study using a nephrotoxic mouse model in which the mice consumed H<sub>2<\/sub>\u2010containing water. The H<sub>2<\/sub> levels in the blood approached a concentration of several micromolar within 3&nbsp;minutes of consumption, resulting in decreased oxidative stress.<a href=\"#jcmm14603-bib-0023\" rid=\"jcmm14603-bib-0023\" class=\" ref\">23<\/a> In humans, drinking H<sub>2<\/sub>\u2010rich water rapidly increases exhaled H<sub>2<\/sub> concentrations to a maximal level of approximately 40&nbsp;ppm at 10&nbsp;minutes after ingestion.<a href=\"#jcmm14603-bib-0036\" rid=\"jcmm14603-bib-0036\" class=\" ref\">36<\/a> Therefore, continuous exposure to H<sub>2<\/sub> via H<sub>2<\/sub>\u2010rich water consumption may confer, through blood circulation, protection against the oxidative state that is characteristic of RA\u2010ILD, although H<sub>2<\/sub> acquired by consuming H<sub>2<\/sub>\u2010rich water is believed to exist for a relatively short time and at relatively low concentrations. Ingested H<sub>2<\/sub> can spread immediately to lung cells, where it can reduce toxic ROS levels, because of the lungs&#8217; extensive blood supply and loose anatomical structure. Other studies with animal models reported similar results, that is, continuously drinking H<sub>2<\/sub>\u2010rich water may protect against persistent oxidative damage. These studies include research based on atherosclerosis in apolipoprotein E\u2010knockout mice treated for 6&nbsp;months,<a href=\"#jcmm14603-bib-0037\" rid=\"jcmm14603-bib-0037\" class=\" ref\">37<\/a> chronic allograft nephropathy in rats treated for 5&nbsp;months <a href=\"#jcmm14603-bib-0038\" rid=\"jcmm14603-bib-0038\" class=\" ref\">38<\/a> and non\u2010alcoholic steatohepatitis in mice treated for 8\u201016&nbsp;weeks.<a href=\"#jcmm14603-bib-0025\" rid=\"jcmm14603-bib-0025\" class=\" ref\">25<\/a>, <a href=\"#jcmm14603-bib-0026\" rid=\"jcmm14603-bib-0026\" class=\" ref\">26<\/a>\n<\/p>\n<p>In this study, the RA\u2010ILD model is a chronic lung fibrosis model induced by the immunization of D1CC mice via several type II collagen injections; however, the precise molecular mechanisms underlying the protective effects of H<sub>2<\/sub> remain to be elucidated. There is no satisfactory in vitro cell culture model of RA, although H<sub>2<\/sub> has been reported to inhibit the lipopolysaccharide (LPS)\u2010 and IFN\u2010\u03b3\u2010induced production of nitric oxide in macrophages in vitro by controlling signal transduction. In addition, consuming H<sub>2<\/sub>\u2010rich water for 2&nbsp;weeks ameliorates anti\u2010type II collagen antibody production and LPS\u2010induced arthritis in mice,<a href=\"#jcmm14603-bib-0039\" rid=\"jcmm14603-bib-0039\" class=\" ref\">39<\/a> similar to our observations illustrating that H<sub>2<\/sub> treatment suppressed inflammatory arthritis development in D1CC mice induced by bCII up to 8&nbsp;weeks after immunization (Figure <a href=\"#jcmm14603-sup-0002\" rid=\"jcmm14603-sup-0002\" class=\" supplementary-material\">S2<\/a>). Because reactive nitrogen species such as ONOO<sup>\u2212<\/sup> and reactive nitrogen dioxide mediate tissue damage in patients with RA through nitric oxide\/nitric oxide synthase,<a href=\"#jcmm14603-bib-0040\" rid=\"jcmm14603-bib-0040\" class=\" ref\">40<\/a> the effect of H<sub>2<\/sub> treatment in our model may be associated with the modulation of signal transduction by reactive nitrogen species in addition to the scavenging of ONOO<sup>\u2212<\/sup>, which we previously reported.<a href=\"#jcmm14603-bib-0018\" rid=\"jcmm14603-bib-0018\" class=\" ref\">18<\/a>\n<\/p>\n<p class=\"p p-last\">In conclusion, we reported that the D1CC mouse model of RA\u2010ILD is considerably similar to RA\u2010ILD in humans, and it could be valuable as a model of lung fibrosis, using specific markers such as serum SP\u2010D and CT to detect treatment effects. Furthermore, this model can be used in studies of the treatment and general pathophysiology of chronic interstitial pneumonias in humans. Our study revealed that H<sub>2<\/sub> might protect against RA\u2010ILD by decreasing oxidative stress.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0019\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0019title\">CONFLICT OF INTEREST<\/h2>\n<p class=\"p p-first-last\">The authors confirm that there are no conflicts of interest.<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0020\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0020title\">AUTHOR&#8217;S CONTRIBUTIONS<\/h2>\n<p class=\"p p-first-last\">Yasuhiro Terasaki, Nariaki Kokuho, Hirokazu Urushiyama, Yusuke Kajimoto, Yoko Miura, Motoyo Maruyama and Toshio Akimoto participated in animal treatment and sample collection. Nariaki Kokuho, Mika Terasakt and Satoshi Kanazawa conducted the biochemical and pathological analyses. Yasuhiro Terasaki, Satoshi Kanazawa and Shinobu Kunugi participated in the design of the study and performed the statistical analysis. Yasuhiro Terasaki, Satoshi Kanazawa, Ikuroh Ohsawa, Tsutomu Igarashi and Akira Shimizu conceived the study, participated in its design and coordination and drafted the article. All authors have read and approved the final article.<\/p>\n<\/div>\n<div id=\"sec-a.n.g\" class=\"tsec sec\"><a id=\"supplementary-material-sec\"><\/a><\/p>\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"sec-a.n.gtitle\">Supporting information<\/h2>\n<p><!--\/article\/body\/sec\/--><\/p>\n<div class=\"sec suppmat\" id=\"jcmm14603-sup-0001\">\n<p>&nbsp;<\/p>\n<div class=\"sup-box half_rhythm\" id=\"media-a.n.g.b.b\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/bin\/JCMM-23-7043-s001.tiff\" data-ga-action=\"click_feat_suppl\">Click here for additional data file.<\/a><sup>(1.4M, tiff)<\/sup><\/div>\n<\/div>\n<div class=\"sec suppmat\" id=\"jcmm14603-sup-0002\">\n<p>&nbsp;<\/p>\n<div class=\"sup-box half_rhythm\" id=\"media-a.n.g.c.b\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/bin\/JCMM-23-7043-s002.tiff\" data-ga-action=\"click_feat_suppl\">Click here for additional data file.<\/a><sup>(1.4M, tiff)<\/sup><\/div>\n<\/div>\n<div class=\"sec suppmat\" id=\"jcmm14603-sup-0003\">\n<p>&nbsp;<\/p>\n<div class=\"sup-box half_rhythm\" id=\"media-a.n.g.d.b\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/bin\/JCMM-23-7043-s003.tiff\" data-ga-action=\"click_feat_suppl\">Click here for additional data file.<\/a><sup>(1.4M, tiff)<\/sup><\/div>\n<\/div>\n<\/div>\n<div id=\"jcmm14603-sec-0023\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0023title\">ACKNOWLEDGEMENTS<\/h2>\n<div class=\"sec\">\n<p>The authors thank Ms Arimi Ishikawa and Ms Naomi Kuwahara for contributions to Western blotting and RT\u2010qPCR analyses. This work was supported in part by grants\u2010in\u2010aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The uses of the funding were in the design of the study, the collection, analysis and interpretation of data and in writing the article.<\/p>\n<\/div>\n<\/div>\n<div id=\"notes-a.m.c\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"notes-a.m.ctitle\">Notes<\/h2>\n<p>\n<span class=\"mixed-citation\" id=\"jcmm14603-cit-1001\"><br \/>\nTerasaki Y, Terasaki M, Kanazawa S, et al. <span class=\"ref-title\">Effect of H<sub>2<\/sub> treatment in a mouse model of rheumatoid arthritis\u2010associated interstitial lung disease<\/span>. <span class=\"ref-journal\">J Cell Mol Med<\/span>. 2019;<span class=\"ref-vol\">23<\/span>:7043\u20137053. 10.1111\/jcmm.14603<br \/>\n <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6787460\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/31424157\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] [<a href=\"\/\/doi.org\/10.1111%2Fjcmm.14603\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CCrosslink%7CDOI\">CrossRef<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=J+Cell+Mol+Med&amp;title=Effect+of+H2+treatment+in+a+mouse+model+of+rheumatoid+arthritis\u2010associated+interstitial+lung+disease&amp;volume=23&amp;publication_year=2019&amp;pages=7043-7053&amp;doi=10.1111\/jcmm.14603&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span>\n<\/p>\n<\/div>\n<div id=\"jcmm14603-sec-0022\" class=\"tsec bk-sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-sec-0022title\">DATA AVAILABILITY STATEMENT<\/h2>\n<p><!--\/article\/back\/sec\/--><\/p>\n<p class=\"p p-first-last\">The data that support the findings of this study are available from the corresponding author upon reasonable request.<\/p>\n<\/div>\n<div id=\"jcmm14603-bibl-0001\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"jcmm14603-bibl-0001title\">REFERENCES<\/h2>\n<div class=\"ref-list-sec sec\" id=\"reference-list\">\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0001\">1. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0001\"><br \/>\nFilippin LI, Vercelino R, Marroni NP, Xavier RM. <span class=\"ref-title\">Redox signalling and the inflammatory response in rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Clin Exp Immunol<\/span>. 2008;<span class=\"ref-vol\">152<\/span>(<span class=\"ref-iss\">3<\/span>):415\u2010422. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2453196\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/18422737\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Clin+Exp+Immunol&amp;title=Redox+signalling+and+the+inflammatory+response+in+rheumatoid+arthritis&amp;volume=152&amp;issue=3&amp;publication_year=2008&amp;pages=415-422&amp;pmid=18422737&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0002\">2. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0002\"><br \/>\nDemoruelle MK, Parish MC, Derber LA, et al. <span class=\"ref-title\">Performance of anti\u2010cyclic citrullinated Peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease<\/span>. <span class=\"ref-journal\">Arthritis Rheum<\/span>. 2013;<span class=\"ref-vol\">65<\/span>(<span class=\"ref-iss\">9<\/span>):2243\u20102252. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3776020\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/23686569\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Arthritis+Rheum&amp;title=Performance+of+anti\u2010cyclic+citrullinated+Peptide+assays+differs+in+subjects+at+increased+risk+of+rheumatoid+arthritis+and+subjects+with+established+disease&amp;volume=65&amp;issue=9&amp;publication_year=2013&amp;pages=2243-2252&amp;pmid=23686569&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0003\">3. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0003\"><br \/>\nChang K, Yang S, Kim S, Han K, Park S, Shin J. <span class=\"ref-title\">Smoking and rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Int J Mol Sci<\/span>. 2014;<span class=\"ref-vol\">15<\/span>(<span class=\"ref-iss\">12<\/span>):22279\u201022295. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4284707\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/25479074\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Int+J+Mol+Sci&amp;title=Smoking+and+rheumatoid+arthritis&amp;volume=15&amp;issue=12&amp;publication_year=2014&amp;pages=22279-22295&amp;pmid=25479074&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0004\">4. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0004\"><br \/>\nHitchon CA, El\u2010Gabalawy HS. <span class=\"ref-title\">Oxidation in rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Arthritis Res Ther<\/span>. 2004;<span class=\"ref-vol\">6<\/span>(<span class=\"ref-iss\">6<\/span>):265\u2010278. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1064874\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/15535839\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Arthritis+Res+Ther&amp;title=Oxidation+in+rheumatoid+arthritis&amp;volume=6&amp;issue=6&amp;publication_year=2004&amp;pages=265-278&amp;pmid=15535839&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0005\">5. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0005\"><br \/>\nJohnson C. <span class=\"ref-title\">Recent advances in the pathogenesis, prediction, and management of rheumatoid arthritis\u2010associated interstitial lung disease<\/span>. <span class=\"ref-journal\">Curr Opin Rheumatol<\/span>. 2017;<span class=\"ref-vol\">29<\/span>(<span class=\"ref-iss\">3<\/span>):254\u2010259. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/28207496\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Curr+Opin+Rheumatol&amp;title=Recent+advances+in+the+pathogenesis,+prediction,+and+management+of+rheumatoid+arthritis\u2010associated+interstitial+lung+disease&amp;volume=29&amp;issue=3&amp;publication_year=2017&amp;pages=254-259&amp;pmid=28207496&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0006\">6. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0006\"><br \/>\nKoduri G, Norton S, Young A, et al. <span class=\"ref-title\">Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort<\/span>. <span class=\"ref-journal\">Rheumatology (Oxford)<\/span>. 2010;<span class=\"ref-vol\">49<\/span>(<span class=\"ref-iss\">8<\/span>):1483\u20101489. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/20223814\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Rheumatology+(Oxford)&amp;title=Interstitial+lung+disease+has+a+poor+prognosis+in+rheumatoid+arthritis:+results+from+an+inception+cohort&amp;volume=49&amp;issue=8&amp;publication_year=2010&amp;pages=1483-1489&amp;pmid=20223814&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0007\">7. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0007\"><br \/>\nAscherman DP. <span class=\"ref-title\">Interstitial lung disease in rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Curr Rheumatol Rep<\/span>. 2010;<span class=\"ref-vol\">12<\/span>(<span class=\"ref-iss\">5<\/span>):363\u2010369. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/20628839\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Curr+Rheumatol+Rep&amp;title=Interstitial+lung+disease+in+rheumatoid+arthritis&amp;volume=12&amp;issue=5&amp;publication_year=2010&amp;pages=363-369&amp;pmid=20628839&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0008\">8. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0008\"><br \/>\nKanazawa S, Ota S, Sekine C, et al. <span class=\"ref-title\">Aberrant MHC class II expression in mouse joints leads to arthritis with extraarticular manifestations similar to rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Proc Natl Acad Sci USA<\/span>. 2006;<span class=\"ref-vol\">103<\/span>(<span class=\"ref-iss\">39<\/span>):14465\u201014470. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1599985\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/16980409\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Proc+Natl+Acad+Sci+USA&amp;title=Aberrant+MHC+class+II+expression+in+mouse+joints+leads+to+arthritis+with+extraarticular+manifestations+similar+to+rheumatoid+arthritis&amp;volume=103&amp;issue=39&amp;publication_year=2006&amp;pages=14465-14470&amp;pmid=16980409&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0009\">9. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0009\"><br \/>\nFeldmann M, Maini SR. <span class=\"ref-title\">Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics<\/span>. <span class=\"ref-journal\">Immunol Rev<\/span>. 2008;<span class=\"ref-vol\">223<\/span>:7\u201019. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/18613827\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Immunol+Rev&amp;title=Role+of+cytokines+in+rheumatoid+arthritis:+an+education+in+pathophysiology+and+therapeutics&amp;volume=223&amp;publication_year=2008&amp;pages=7-19&amp;pmid=18613827&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0010\">10. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0010\"><br \/>\nPicchianti Diamanti A, Markovic M, Argento G, et al. <span class=\"ref-title\">Therapeutic management of patients with rheumatoid arthritis and associated interstitial lung disease: case report and literature review<\/span>. <span class=\"ref-journal\">Ther Adv Respir Dis<\/span>. 2017;<span class=\"ref-vol\">11<\/span>(<span class=\"ref-iss\">1<\/span>):64\u201072. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5941974\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/27733490\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Ther+Adv+Respir+Dis&amp;title=Therapeutic+management+of+patients+with+rheumatoid+arthritis+and+associated+interstitial+lung+disease:+case+report+and+literature+review&amp;volume=11&amp;issue=1&amp;publication_year=2017&amp;pages=64-72&amp;pmid=27733490&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0011\">11. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0011\"><br \/>\nIshibashi T, Sato B, Shibata S, et al. <span class=\"ref-title\">Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double\u2010blind, placebo\u2010controlled pilot study<\/span>. <span class=\"ref-journal\">Int Immunopharmacol<\/span>. 2014;<span class=\"ref-vol\">21<\/span>(<span class=\"ref-iss\">2<\/span>):468\u2010473. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/24929023\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Int+Immunopharmacol&amp;title=Therapeutic+efficacy+of+infused+molecular+hydrogen+in+saline+on+rheumatoid+arthritis:+a+randomized,+double\u2010blind,+placebo\u2010controlled+pilot+study&amp;volume=21&amp;issue=2&amp;publication_year=2014&amp;pages=468-473&amp;pmid=24929023&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0012\">12. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0012\"><br \/>\nWinyard PG, Ryan B, Eggleton P, et al. <span class=\"ref-title\">Measurement and meaning of markers of reactive species of oxygen, nitrogen and sulfur in healthy human subjects and patients with inflammatory joint disease<\/span>. <span class=\"ref-journal\">Biochem Soc Trans<\/span>. 2011;<span class=\"ref-vol\">39<\/span>(<span class=\"ref-iss\">5<\/span>):1226\u20101232. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/21936794\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Biochem+Soc+Trans&amp;title=Measurement+and+meaning+of+markers+of+reactive+species+of+oxygen,+nitrogen+and+sulfur+in+healthy+human+subjects+and+patients+with+inflammatory+joint+disease&amp;volume=39&amp;issue=5&amp;publication_year=2011&amp;pages=1226-1232&amp;pmid=21936794&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0013\">13. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0013\"><br \/>\nKageyama Y, Takahashi<br \/>\n M, et al. <span class=\"ref-title\">Reduction of oxidative stress marker levels by anti\u2010TNF\u2010alpha antibody, infliximab, in patients with rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Clin Exp Rheumatol<\/span>. 2008;<span class=\"ref-vol\">26<\/span>(<span class=\"ref-iss\">1<\/span>):73\u201080. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/18328150\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Clin+Exp+Rheumatol&amp;title=Reduction+of+oxidative+stress+marker+levels+by+anti\u2010TNF\u2010alpha+antibody,+infliximab,+in+patients+with+rheumatoid+arthritis&amp;volume=26&amp;issue=1&amp;publication_year=2008&amp;pages=73-80&amp;pmid=18328150&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0014\">14. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0014\"><br \/>\nRall LC, Roubenoff R, Meydani SN, Han SN, Meydani M. <span class=\"ref-title\">Urinary 8\u2010hydroxy\u20102&#8217;\u2010deoxyguanosine (8\u2010OHdG) as a marker of oxidative stress in rheumatoid arthritis and aging: effect of progressive resistance training<\/span>. <span class=\"ref-journal\">J Nutr Biochem<\/span>. 2000;<span class=\"ref-vol\">11<\/span>(<span class=\"ref-iss\">11\u201312<\/span>):581\u2010584. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/11137896\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=J+Nutr+Biochem&amp;title=Urinary+8\u2010hydroxy\u20102'\u2010deoxyguanosine+(8\u2010OHdG)+as+a+marker+of+oxidative+stress+in+rheumatoid+arthritis+and+aging:+effect+of+progressive+resistance+training&amp;volume=11&amp;issue=11\u201312&amp;publication_year=2000&amp;pages=581-584&amp;pmid=11137896&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0015\">15. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0015\"><br \/>\nDatta S, Kundu S, Ghosh P, De S, Ghosh A, Chatterjee M. <span class=\"ref-title\">Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Clin Rheumatol<\/span>. 2014;<span class=\"ref-vol\">33<\/span>(<span class=\"ref-iss\">11<\/span>):1557\u20101564. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/24718487\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Clin+Rheumatol&amp;title=Correlation+of+oxidant+status+with+oxidative+tissue+damage+in+patients+with+rheumatoid+arthritis&amp;volume=33&amp;issue=11&amp;publication_year=2014&amp;pages=1557-1564&amp;pmid=24718487&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0016\">16. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0016\"><br \/>\nKundu S, Ghosh P, Datta S, Ghosh A, Chattopadhyay S, Chatterjee M. <span class=\"ref-title\">Oxidative stress as a potential biomarker for determining disease activity in patients with rheumatoid arthritis<\/span>. <span class=\"ref-journal\">Free Radic Res<\/span>. 2012;<span class=\"ref-vol\">46<\/span>(<span class=\"ref-iss\">12<\/span>):1482\u20101489. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/22998065\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Free+Radic+Res&amp;title=Oxidative+stress+as+a+potential+biomarker+for+determining+disease+activity+in+patients+with+rheumatoid+arthritis&amp;volume=46&amp;issue=12&amp;publication_year=2012&amp;pages=1482-1489&amp;pmid=22998065&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0017\">17. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0017\"><br \/>\nMateen S, Moin S, Zafar A, Khan AQ. <span class=\"ref-title\">Redox signaling in rheumatoid arthritis and the preventive role of polyphenols<\/span>. <span class=\"ref-journal\">Clin Chim Acta<\/span>. 2016;<span class=\"ref-vol\">463<\/span>:4\u201010. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/27720800\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Clin+Chim+Acta&amp;title=Redox+signaling+in+rheumatoid+arthritis+and+the+preventive+role+of+polyphenols&amp;volume=463&amp;publication_year=2016&amp;pages=4-10&amp;pmid=27720800&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0018\">18. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0018\"><br \/>\nOhsawa I, Ishikawa M, Takahashi K, et al. <span class=\"ref-title\">Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals<\/span>. <span class=\"ref-journal\">Nat Med<\/span>. 2007;<span class=\"ref-vol\">13<\/span>(<span class=\"ref-iss\">6<\/span>):688\u2010694. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/17486089\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Nat+Med&amp;title=Hydrogen+acts+as+a+therapeutic+antioxidant+by+selectively+reducing+cytotoxic+oxygen+radicals&amp;volume=13&amp;issue=6&amp;publication_year=2007&amp;pages=688-694&amp;pmid=17486089&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0019\">19. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0019\"><br \/>\nFukuda K, Asoh S, Ishikawa M, Yamamoto Y, Ohsawa I, Ohta S. <span class=\"ref-title\">Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia\/reperfusion through reducing oxidative stress<\/span>. <span class=\"ref-journal\">Biochem Biophys Res Commun<\/span>. 2007;<span class=\"ref-vol\">361<\/span>(<span class=\"ref-iss\">3<\/span>):670\u2010674. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/17673169\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Biochem+Biophys+Res+Commun&amp;title=Inhalation+of+hydrogen+gas+suppresses+hepatic+injury+caused+by+ischemia\/reperfusion+through+reducing+oxidative+stress&amp;volume=361&amp;issue=3&amp;publication_year=2007&amp;pages=670-674&amp;pmid=17673169&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0020\">20. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0020\"><br \/>\nHayashida K, Sano M, Ohsawa I, et al. <span class=\"ref-title\">Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia\u2010reperfusion injury<\/span>. <span class=\"ref-journal\">Biochem Biophys Res Commun<\/span>. 2008;<span class=\"ref-vol\">373<\/span>(<span class=\"ref-iss\">1<\/span>):30\u201035. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/18541148\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Biochem+Biophys+Res+Commun&amp;title=Inhalation+of+hydrogen+gas+reduces+infarct+size+in+the+rat+model+of+myocardial+ischemia\u2010reperfusion+injury&amp;volume=373&amp;issue=1&amp;publication_year=2008&amp;pages=30-35&amp;pmid=18541148&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0021\">21. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0021\"><br \/>\nTerasaki Y, Ohsawa I, Terasaki M, et al. <span class=\"ref-title\">Hydrogen therapy attenuates irradiation\u2010induced lung damage by reducing oxidative stress<\/span>. <span class=\"ref-journal\">Am J Physiol Lung Cell Mol Physiol<\/span>. 2011;<span class=\"ref-vol\">301<\/span>(<span class=\"ref-iss\">4<\/span>):L415\u2010L426. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/21764987\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Am+J+Physiol+Lung+Cell+Mol+Physiol&amp;title=Hydrogen+therapy+attenuates+irradiation\u2010induced+lung+damage+by+reducing+oxidative+stress&amp;volume=301&amp;issue=4&amp;publication_year=2011&amp;pages=L415-L426&amp;pmid=21764987&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0022\">22. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0022\"><br \/>\nKajiyama S, Hasegawa G, Asano M, et al. <span class=\"ref-title\">Supplementation of hydrogen\u2010rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance<\/span>. <span class=\"ref-journal\">Nutr Res<\/span>. 2008;<span class=\"ref-vol\">28<\/span>(<span class=\"ref-iss\">3<\/span>):137\u2010143. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/19083400\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Nutr+Res&amp;title=Supplementation+of+hydrogen\u2010rich+water+improves+lipid+and+glucose+metabolism+in+patients+with+type+2+diabetes+or+impaired+glucose+tolerance&amp;volume=28&amp;issue=3&amp;publication_year=2008&amp;pages=137-143&amp;pmid=19083400&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0023\">23. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0023\"><br \/>\nNakashima\u2010Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. <span class=\"ref-title\">Molecular hydrogen alleviates nephrotoxicity induced by an anti\u2010cancer drug cisplatin without compromising anti\u2010tumor activity in mice<\/span>. <span class=\"ref-journal\">Cancer Chemother Pharmacol<\/span>. 2009;<span class=\"ref-vol\">64<\/span>(<span class=\"ref-iss\">4<\/span>):753\u2010761. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/19148645\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Cancer+Chemother+Pharmacol&amp;title=Molecular+hydrogen+alleviates+nephrotoxicity+induced+by+an+anti\u2010cancer+drug+cisplatin+without+compromising+anti\u2010tumor+activity+in+mice&amp;volume=64&amp;issue=4&amp;publication_year=2009&amp;pages=753-761&amp;pmid=19148645&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0024\">24. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0024\"><br \/>\nTerasaki Y, Suzuki T, Tonaki K, et al. <span class=\"ref-title\">Molecular hydrogen attenuates gefitinib\u2010induced exacerbation of naphthalene\u2010evoked acute lung injury through a reduction in oxidative stress and inflammation<\/span>. <span class=\"ref-journal\">Lab Invest<\/span>. 2019;<span class=\"ref-vol\">99<\/span>(<span class=\"ref-iss\">6<\/span>):793\u2010806. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/30710119\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Lab+Invest&amp;title=Molecular+hydrogen+attenuates+gefitinib\u2010induced+exacerbation+of+naphthalene\u2010evoked+acute+lung+injury+through+a+reduction+in+oxidative+stress+and+inflammation&amp;volume=99&amp;issue=6&amp;publication_year=2019&amp;pages=793-806&amp;pmid=30710119&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0025\">25. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0025\"><br \/>\nTakaki A, Kawai D, Yamamoto K. <span class=\"ref-title\">Multiple hits, including oxidative stress, as pathogenesis and treatment target in non\u2010alcoholic steatohepatitis (NASH)<\/span>. <span class=\"ref-journal\">Int J Mol Sci<\/span>. 2013;<span class=\"ref-vol\">14<\/span>(<span class=\"ref-iss\">10<\/span>):20704\u201020728. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3821639\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/24132155\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Int+J+Mol+Sci&amp;title=Multiple+hits,+including+oxidative+stress,+as+pathogenesis+and+treatment+target+in+non\u2010alcoholic+steatohepatitis+(NASH)&amp;volume=14&amp;issue=10&amp;publication_year=2013&amp;pages=20704-20728&amp;pmid=24132155&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0026\">26. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0026\"><br \/>\nKawai D, Takaki A, Nakatsuka A, et al. <span class=\"ref-title\">Hydrogen\u2010rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice<\/span>. <span class=\"ref-journal\">Hepatology<\/span>. 2012;<span class=\"ref-vol\">56<\/span>(<span class=\"ref-iss\">3<\/span>):912\u2010921. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/22505328\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Hepatology&amp;title=Hydrogen\u2010rich+water+prevents+progression+of+nonalcoholic+steatohepatitis+and+accompanying+hepatocarcinogenesis+in+mice&amp;volume=56&amp;issue=3&amp;publication_year=2012&amp;pages=912-921&amp;pmid=22505328&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0027\">27. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0027\"><br \/>\nFukushi M, Yamashita M, Miyoshi\u2010Akiyama T, Kubo S, Yamamoto K, Kudo K. <span class=\"ref-title\">Laninamivir octanoate and artificial surfactant combination therapy significantly increases survival of mice infected with lethal influenza H1N1 virus<\/span>. <span class=\"ref-journal\">PLoS ONE<\/span>. 2012;<span class=\"ref-vol\">7<\/span>(<span class=\"ref-iss\">8<\/span>):e42419. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3409853\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/22879974\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=PLoS+ONE&amp;title=Laninamivir+octanoate+and+artificial+surfactant+combination+therapy+significantly+increases+survival+of+mice+infected+with+lethal+influenza+H1N1+virus&amp;volume=7&amp;issue=8&amp;publication_year=2012&amp;pages=e42419&amp;pmid=22879974&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0028\">28. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0028\"><br \/>\nNaito C, Yamanaka T. [<span class=\"ref-title\">Lipid peroxides in atherosclerotic diseases (author&#8217;s transl)<\/span>]. <span class=\"ref-journal\">Nihon Ronen Igakkai Zasshi<\/span>. 1978;<span class=\"ref-vol\">15<\/span>(<span class=\"ref-iss\">3<\/span>):187\u2010191. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/671818\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Nihon+Ronen+Igakkai+Zasshi&amp;title=Lipid+peroxides+in+atherosclerotic+diseases+(author's+transl)&amp;volume=15&amp;issue=3&amp;publication_year=1978&amp;pages=187-191&amp;pmid=671818&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0029\">29. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0029\"><br \/>\nAshcroft T, Simpson JM, Timbrell V. <span class=\"ref-title\">Simple method of estimating severity of pulmonary fibrosis on a numerical scale<\/span>. <span class=\"ref-journal\">J Clin Pathol<\/span>. 1988;<span class=\"ref-vol\">41<\/span>(<span class=\"ref-iss\">4<\/span>):467\u2010470. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1141479\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/3366935\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=J+Clin+Pathol&amp;title=Simple+method+of+estimating+severity+of+pulmonary+fibrosis+on+a+numerical+scale&amp;volume=41&amp;issue=4&amp;publication_year=1988&amp;pages=467-470&amp;pmid=3366935&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0030\">30. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0030\"><br \/>\nBrown WR, Isobe Y, Nakane PK. <span class=\"ref-title\">Studies on translocation of immunoglobulins across intestinal epithelium. II. Immunoelectron\u2010microscopic localization of immunoglobulins and secretory component in human intestinal mucosa<\/span>. <span class=\"ref-journal\">Gastroenterology<\/span>. 1976;<span class=\"ref-vol\">71<\/span>(<span class=\"ref-iss\">6<\/span>):985\u2010995. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/992282\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Gastroenterology&amp;title=Studies+on+translocation+of+immunoglobulins+across+intestinal+epithelium.+II.+Immunoelectron\u2010microscopic+localization+of+immunoglobulins+and+secretory+component+in+human+intestinal+mucosa&amp;volume=71&amp;issue=6&amp;publication_year=1976&amp;pages=985-995&amp;pmid=992282&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0031\">31. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0031\"><br \/>\nLeslie KO, Wick MR. <span class=\"ref-journal\">Practical Pulmonary Pathology: A Diagnostic Approach<\/span>. Philadelphia, PA: Saunders; 2011. <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?title=Practical+Pulmonary+Pathology:+A+Diagnostic+Approach&amp;publication_year=2011&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0032\">32. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0032\"><br \/>\nMouratis MA, Aidinis V. <span class=\"ref-title\">Modeling pulmonary fibrosis with bleomycin<\/span>. <span class=\"ref-journal\">Curr Opin Pulm Med<\/span>. 2011;<span class=\"ref-vol\">17<\/span>(<span class=\"ref-iss\">5<\/span>):355\u2010361. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/21832918\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Curr+Opin+Pulm+Med&amp;title=Modeling+pulmonary+fibrosis+with+bleomycin&amp;volume=17&amp;issue=5&amp;publication_year=2011&amp;pages=355-361&amp;pmid=21832918&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0033\">33. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0033\"><br \/>\nHamai K, Iwamoto<br \/>\n H, et al. <span class=\"ref-title\">Comparative study of circulating MMP\u20107, CCL18, KL\u20106, SP\u2010A, and SP\u2010D as disease markers of idiopathic pulmonary fibrosis<\/span>. <span class=\"ref-journal\">Dis Markers<\/span>. 2016;<span class=\"ref-vol\">2016<\/span>:4759040. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4886062\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/27293304\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Dis+Markers&amp;title=Comparative+study+of+circulating+MMP\u20107,+CCL18,+KL\u20106,+SP\u2010A,+and+SP\u2010D+as+disease+markers+of+idiopathic+pulmonary+fibrosis&amp;volume=2016&amp;publication_year=2016&amp;pages=4759040&amp;pmid=27293304&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0034\">34. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0034\"><br \/>\nRadhakrishnan A, Tudawe D, Chakravarthi S, Chiew GS, Haleagrahara N. <span class=\"ref-title\">Effect of gamma\u2010tocotrienol in counteracting oxidative stress and joint damage in collagen\u2010induced arthritis in rats<\/span>. <span class=\"ref-journal\">Exp Ther Med<\/span>. 2014;<span class=\"ref-vol\">7<\/span>(<span class=\"ref-iss\">5<\/span>):1408\u20101414. <span class=\"nowrap\">[<a class=\"int-reflink\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3991526\/\">PMC free article<\/a>]<\/span> [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/24940448\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Exp+Ther+Med&amp;title=Effect+of+gamma\u2010tocotrienol+in+counteracting+oxidative+stress+and+joint+damage+in+collagen\u2010induced+arthritis+in+rats&amp;volume=7&amp;issue=5&amp;publication_year=2014&amp;pages=1408-1414&amp;pmid=24940448&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0035\">35. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0035\"><br \/>\nDai L, Claxson A, Marklund SL, et al. <span class=\"ref-title\">Amelioration of antigen\u2010induced arthritis in rats by transfer of extracellular superoxide dismutase and catalase genes<\/span>. <span class=\"ref-journal\">Gene Ther<\/span>. 2003;<span class=\"ref-vol\">10<\/span>(<span class=\"ref-iss\">7<\/span>):550\u2010558. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/12646860\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Gene+Ther&amp;title=Amelioration+of+antigen\u2010induced+arthritis+in+rats+by+transfer+of+extracellular+superoxide+dismutase+and+catalase+genes&amp;volume=10&amp;issue=7&amp;publication_year=2003&amp;pages=550-558&amp;pmid=12646860&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0036\">36. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0036\"><br \/>\nShimouchi A, Nose K, Shirai M, Kondo T. <span class=\"ref-title\">Estimation of molecular hydrogen consumption in the human whole body after the ingestion of hydrogen\u2010rich water<\/span>. <span class=\"ref-journal\">Adv Exp Med Biol<\/span>. 2012;<span class=\"ref-vol\">737<\/span>:245\u2010250. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/22259109\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Adv+Exp+Med+Biol&amp;title=Estimation+of+molecular+hydrogen+consumption+in+the+human+whole+body+after+the+ingestion+of+hydrogen\u2010rich+water&amp;volume=737&amp;publication_year=2012&amp;pages=245-250&amp;pmid=22259109&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0037\">37. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0037\"><br \/>\nOhsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S. <span class=\"ref-title\">Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice<\/span>. <span class=\"ref-journal\">Biochem Biophys Res Commun<\/span>. 2008;<span class=\"ref-vol\">377<\/span>(<span class=\"ref-iss\">4<\/span>):1195\u20101198. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/18996093\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Biochem+Biophys+Res+Commun&amp;title=Consumption+of+hydrogen+water+prevents+atherosclerosis+in+apolipoprotein+E+knockout+mice&amp;volume=377&amp;issue=4&amp;publication_year=2008&amp;pages=1195-1198&amp;pmid=18996093&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0038\">38. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0038\"><br \/>\nCardinal JS, Zhan J, Wang Y, et al. <span class=\"ref-title\">Oral hydrogen water prevents chronic allograft nephropathy in rats<\/span>. <span class=\"ref-journal\">Kidney Int<\/span>. 2010;<span class=\"ref-vol\">77<\/span>(<span class=\"ref-iss\">2<\/span>):101\u2010109. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/19907413\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Kidney+Int&amp;title=Oral+hydrogen+water+prevents+chronic+allograft+nephropathy+in+rats&amp;volume=77&amp;issue=2&amp;publication_year=2010&amp;pages=101-109&amp;pmid=19907413&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0039\">39. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0039\"><br \/>\nItoh T, Hamada N, Terazawa R, et al. <span class=\"ref-title\">Molecular hydrogen inhibits lipopolysaccharide\/interferon gamma\u2010induced nitric oxide production through modulation of signal transduction in macrophages<\/span>. <span class=\"ref-journal\">Biochem Biophys Res Commun<\/span>. 2011;<span class=\"ref-vol\">411<\/span>(<span class=\"ref-iss\">1<\/span>):143\u2010149. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/21723254\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Biochem+Biophys+Res+Commun&amp;title=Molecular+hydrogen+inhibits+lipopolysaccharide\/interferon+gamma\u2010induced+nitric+oxide+production+through+modulation+of+signal+transduction+in+macrophages&amp;volume=411&amp;issue=1&amp;publication_year=2011&amp;pages=143-149&amp;pmid=21723254&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<div class=\"ref-cit-blk half_rhythm\" id=\"jcmm14603-bib-0040\">40. <span class=\"mixed-citation\" id=\"jcmm14603-cit-0040\"><br \/>\nKhojah HM, Ahmed S, Abdel\u2010Rahman MS, Hamza A\u2010B. <span class=\"ref-title\">Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants<\/span>. <span class=\"ref-journal\">Free Radic Biol Med<\/span>. 2016;<span class=\"ref-vol\">97<\/span>:285\u2010291. [<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/27344969\" ref=\"reftype=pubmed&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Entrez%7CPubMed%7CRecord\">PubMed<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Free+Radic+Biol+Med&amp;title=Reactive+oxygen+and+nitrogen+species+in+patients+with+rheumatoid+arthritis+as+potential+biomarkers+for+disease+activity+and+the+role+of+antioxidants&amp;volume=97&amp;publication_year=2016&amp;pages=285-291&amp;pmid=27344969&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=6787460&amp;issue-id=343604&amp;journal-id=2233&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/div>\n<\/div>\n<\/div>\n<div style=\"display: none; width: 200px; top: -100px; left: -100px;\" aria-live=\"assertive\" aria-hidden=\"true\" class=\"ui-helper-reset ui-ncbipopper-wrapper ui-ncbilinksmenu\">\n<ul id=\"ui-ncbiinpagenav-2\">\n<li><a href=\"#jcmm14603-abs-0001title\">Abstract<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0001title\">1.\u2003INTRODUCTION<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0002title\">2.\u2003MATERIALS AND METHODS<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0015title\">3.\u2003RESULTS<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0018title\">4.\u2003DISCUSSION<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0019title\">CONFLICT OF INTEREST<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0020title\">AUTHOR&#8217;S CONTRIBUTIONS<\/a><\/li>\n<li><a href=\"#sec-a.n.gtitle\">Supporting information<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0023title\">ACKNOWLEDGEMENTS<\/a><\/li>\n<li><a href=\"#notes-a.m.ctitle\">Notes<\/a><\/li>\n<li><a href=\"#jcmm14603-sec-0022title\">DATA AVAILABILITY STATEMENT<\/a><\/li>\n<li><a href=\"#jcmm14603-bibl-0001title\">REFERENCES<\/a><\/li>\n<\/ul>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease<\/p>\n","protected":false},"author":1,"featured_media":17899,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[130],"tags":[],"disease":[852],"body-organ":[1027],"applications":[680],"test_subjects":[1518],"report-topic":[1399],"class_list":["post-27055","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-hydrogen-health","disease-rheumatoid-arthritis-ra-2","body-organ-lung-2","applications-ingestion-2","test_subjects-mouse-2","report-topic-interstitial-lung-disease-2"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.1 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>H2 treatment in RA-associated interstitial lung disease<\/title>\n<meta name=\"description\" content=\"Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"H2 treatment in RA-associated interstitial lung disease\" \/>\n<meta property=\"og:description\" content=\"Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease\" \/>\n<meta property=\"og:url\" content=\"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/\" \/>\n<meta property=\"og:site_name\" content=\"HHO Bulgaria\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/HHOBulgaria\/\" \/>\n<meta property=\"article:published_time\" content=\"2024-01-03T19:41:53+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-01-29T19:10:25+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2023\/12\/Vodorodana-Terapia-ReportsThumb.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1100\" \/>\n\t<meta property=\"og:image:height\" content=\"592\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"5 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/\"},\"author\":{\"name\":\"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#\\\/schema\\\/person\\\/11fc655e42cfb1690bfccd38dc15be88\"},\"headline\":\"H2 treatment in RA-associated interstitial lung disease\",\"datePublished\":\"2024-01-03T19:41:53+00:00\",\"dateModified\":\"2024-01-29T19:10:25+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/\"},\"wordCount\":974,\"publisher\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#organization\"},\"image\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/hho-bulgaria.com\\\/wp-content\\\/uploads\\\/2023\\\/12\\\/Vodorodana-Terapia-ReportsThumb.jpg\",\"articleSection\":[\"Hydrogen Health\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/\",\"url\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/\",\"name\":\"H2 treatment in RA-associated interstitial lung disease\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#primaryimage\"},\"image\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/hho-bulgaria.com\\\/wp-content\\\/uploads\\\/2023\\\/12\\\/Vodorodana-Terapia-ReportsThumb.jpg\",\"datePublished\":\"2024-01-03T19:41:53+00:00\",\"dateModified\":\"2024-01-29T19:10:25+00:00\",\"description\":\"Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease\",\"breadcrumb\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#primaryimage\",\"url\":\"https:\\\/\\\/hho-bulgaria.com\\\/wp-content\\\/uploads\\\/2023\\\/12\\\/Vodorodana-Terapia-ReportsThumb.jpg\",\"contentUrl\":\"https:\\\/\\\/hho-bulgaria.com\\\/wp-content\\\/uploads\\\/2023\\\/12\\\/Vodorodana-Terapia-ReportsThumb.jpg\",\"width\":1100,\"height\":592},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/h2-treatment-in-ra-associated-interstitial-lung-disease\\\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"\u041d\u0430\u0447\u0430\u043b\u043e\",\"item\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"H2 treatment in RA-associated interstitial lung disease\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#website\",\"url\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/\",\"name\":\"HHO Bulgaria\",\"description\":\"\u0413\u0435\u043d\u0435\u0440\u0430\u0442\u043e\u0440 \u043d\u0430 \u0413\u0430\u0437 \u043d\u0430 \u0411\u0440\u0430\u0443\u043d \u0437\u0430 \u0434\u0438\u0437\u0435\u043b\u043e\u0432\u0438 \u0438 \u0431\u0435\u043d\u0437\u0438\u043d\u043e\u0432\u0438 \u0434\u0432\u0438\u0433\u0430\u0442\u0435\u043b\u0438 (\u0432\u043a\u043b\u044e\u0447\u0438\u0442\u0435\u043b\u043d\u043e \u0433\u0430\u0437 \u043f\u0440\u043e\u043f\u0430\u043d-\u0431\u0443\u0442\u0430\u043d \u0438 \u043c\u0435\u0442\u0430\u043d) \u00bb \u0412\u043e\u0434\u043e\u0440\u043e\u0434\u0435\u043d \u0433\u0435\u043d\u0435\u0440\u0430\u0442\u043e\u0440  \u043d\u0430 \u0413\u0430\u0437 \u043d\u0430 \u0411\u0440\u0430\u0443\u043d | HHO \u0433\u0435\u043d\u0435\u0440\u0430\u0442\u043e\u0440, \u043f\u0440\u043e\u0438\u0437\u0432\u0435\u0434\u0435\u043d \u0432 \u0411\u044a\u043b\u0433\u0430\u0440\u0438\u044f\",\"publisher\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#organization\"},\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"},{\"@type\":\"Organization\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#organization\",\"name\":\"HHO Bulgaria\",\"url\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/\",\"logo\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#\\\/schema\\\/logo\\\/image\\\/\",\"url\":\"https:\\\/\\\/hho-bulgaria.com\\\/wp-content\\\/uploads\\\/2022\\\/02\\\/HHOBG-FB-Profile-2.png\",\"contentUrl\":\"https:\\\/\\\/hho-bulgaria.com\\\/wp-content\\\/uploads\\\/2022\\\/02\\\/HHOBG-FB-Profile-2.png\",\"width\":1080,\"height\":1080,\"caption\":\"HHO Bulgaria\"},\"image\":{\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#\\\/schema\\\/logo\\\/image\\\/\"},\"sameAs\":[\"https:\\\/\\\/www.facebook.com\\\/HHOBulgaria\\\/\",\"https:\\\/\\\/www.youtube.com\\\/channel\\\/UC9d5geU7TFrhO2e7MR6IelA\"]},{\"@type\":\"Person\",\"@id\":\"https:\\\/\\\/hho-bulgaria.com\\\/en\\\/#\\\/schema\\\/person\\\/11fc655e42cfb1690bfccd38dc15be88\",\"name\":\"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432\",\"image\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/4995e9b05624f69b6d4e5e58936980feceb66c508ee1e767d105fa5d9ac07802?s=96&d=mm&r=g\",\"url\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/4995e9b05624f69b6d4e5e58936980feceb66c508ee1e767d105fa5d9ac07802?s=96&d=mm&r=g\",\"contentUrl\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/4995e9b05624f69b6d4e5e58936980feceb66c508ee1e767d105fa5d9ac07802?s=96&d=mm&r=g\",\"caption\":\"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432\"},\"sameAs\":[\"https:\\\/\\\/hho-bulgaria.com\"]}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"H2 treatment in RA-associated interstitial lung disease","description":"Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/","og_locale":"en_US","og_type":"article","og_title":"H2 treatment in RA-associated interstitial lung disease","og_description":"Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease","og_url":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/","og_site_name":"HHO Bulgaria","article_publisher":"https:\/\/www.facebook.com\/HHOBulgaria\/","article_published_time":"2024-01-03T19:41:53+00:00","article_modified_time":"2024-01-29T19:10:25+00:00","og_image":[{"width":1100,"height":592,"url":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2023\/12\/Vodorodana-Terapia-ReportsThumb.jpg","type":"image\/jpeg"}],"author":"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432","twitter_card":"summary_large_image","twitter_misc":{"Written by":"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432","Est. reading time":"5 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#article","isPartOf":{"@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/"},"author":{"name":"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432","@id":"https:\/\/hho-bulgaria.com\/en\/#\/schema\/person\/11fc655e42cfb1690bfccd38dc15be88"},"headline":"H2 treatment in RA-associated interstitial lung disease","datePublished":"2024-01-03T19:41:53+00:00","dateModified":"2024-01-29T19:10:25+00:00","mainEntityOfPage":{"@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/"},"wordCount":974,"publisher":{"@id":"https:\/\/hho-bulgaria.com\/en\/#organization"},"image":{"@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#primaryimage"},"thumbnailUrl":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2023\/12\/Vodorodana-Terapia-ReportsThumb.jpg","articleSection":["Hydrogen Health"],"inLanguage":"en-US"},{"@type":"WebPage","@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/","url":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/","name":"H2 treatment in RA-associated interstitial lung disease","isPartOf":{"@id":"https:\/\/hho-bulgaria.com\/en\/#website"},"primaryImageOfPage":{"@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#primaryimage"},"image":{"@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#primaryimage"},"thumbnailUrl":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2023\/12\/Vodorodana-Terapia-ReportsThumb.jpg","datePublished":"2024-01-03T19:41:53+00:00","dateModified":"2024-01-29T19:10:25+00:00","description":"Effect of H 2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung disease","breadcrumb":{"@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/"]}]},{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#primaryimage","url":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2023\/12\/Vodorodana-Terapia-ReportsThumb.jpg","contentUrl":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2023\/12\/Vodorodana-Terapia-ReportsThumb.jpg","width":1100,"height":592},{"@type":"BreadcrumbList","@id":"https:\/\/hho-bulgaria.com\/en\/h2-treatment-in-ra-associated-interstitial-lung-disease\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"\u041d\u0430\u0447\u0430\u043b\u043e","item":"https:\/\/hho-bulgaria.com\/en\/"},{"@type":"ListItem","position":2,"name":"H2 treatment in RA-associated interstitial lung disease"}]},{"@type":"WebSite","@id":"https:\/\/hho-bulgaria.com\/en\/#website","url":"https:\/\/hho-bulgaria.com\/en\/","name":"HHO Bulgaria","description":"\u0413\u0435\u043d\u0435\u0440\u0430\u0442\u043e\u0440 \u043d\u0430 \u0413\u0430\u0437 \u043d\u0430 \u0411\u0440\u0430\u0443\u043d \u0437\u0430 \u0434\u0438\u0437\u0435\u043b\u043e\u0432\u0438 \u0438 \u0431\u0435\u043d\u0437\u0438\u043d\u043e\u0432\u0438 \u0434\u0432\u0438\u0433\u0430\u0442\u0435\u043b\u0438 (\u0432\u043a\u043b\u044e\u0447\u0438\u0442\u0435\u043b\u043d\u043e \u0433\u0430\u0437 \u043f\u0440\u043e\u043f\u0430\u043d-\u0431\u0443\u0442\u0430\u043d \u0438 \u043c\u0435\u0442\u0430\u043d) \u00bb \u0412\u043e\u0434\u043e\u0440\u043e\u0434\u0435\u043d \u0433\u0435\u043d\u0435\u0440\u0430\u0442\u043e\u0440  \u043d\u0430 \u0413\u0430\u0437 \u043d\u0430 \u0411\u0440\u0430\u0443\u043d | HHO \u0433\u0435\u043d\u0435\u0440\u0430\u0442\u043e\u0440, \u043f\u0440\u043e\u0438\u0437\u0432\u0435\u0434\u0435\u043d \u0432 \u0411\u044a\u043b\u0433\u0430\u0440\u0438\u044f","publisher":{"@id":"https:\/\/hho-bulgaria.com\/en\/#organization"},"potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/hho-bulgaria.com\/en\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"},{"@type":"Organization","@id":"https:\/\/hho-bulgaria.com\/en\/#organization","name":"HHO Bulgaria","url":"https:\/\/hho-bulgaria.com\/en\/","logo":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/hho-bulgaria.com\/en\/#\/schema\/logo\/image\/","url":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2022\/02\/HHOBG-FB-Profile-2.png","contentUrl":"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2022\/02\/HHOBG-FB-Profile-2.png","width":1080,"height":1080,"caption":"HHO Bulgaria"},"image":{"@id":"https:\/\/hho-bulgaria.com\/en\/#\/schema\/logo\/image\/"},"sameAs":["https:\/\/www.facebook.com\/HHOBulgaria\/","https:\/\/www.youtube.com\/channel\/UC9d5geU7TFrhO2e7MR6IelA"]},{"@type":"Person","@id":"https:\/\/hho-bulgaria.com\/en\/#\/schema\/person\/11fc655e42cfb1690bfccd38dc15be88","name":"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432","image":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/secure.gravatar.com\/avatar\/4995e9b05624f69b6d4e5e58936980feceb66c508ee1e767d105fa5d9ac07802?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/4995e9b05624f69b6d4e5e58936980feceb66c508ee1e767d105fa5d9ac07802?s=96&d=mm&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/4995e9b05624f69b6d4e5e58936980feceb66c508ee1e767d105fa5d9ac07802?s=96&d=mm&r=g","caption":"\u0418\u0432\u0430\u0439\u043b\u043e \u041c\u043b\u0430\u0434\u0435\u043d\u043e\u0432"},"sameAs":["https:\/\/hho-bulgaria.com"]}]}},"_links":{"self":[{"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/posts\/27055","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/comments?post=27055"}],"version-history":[{"count":0,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/posts\/27055\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/media\/17899"}],"wp:attachment":[{"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/media?parent=27055"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/categories?post=27055"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/tags?post=27055"},{"taxonomy":"disease","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/disease?post=27055"},{"taxonomy":"body-organ","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/body-organ?post=27055"},{"taxonomy":"applications","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/applications?post=27055"},{"taxonomy":"test_subjects","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/test_subjects?post=27055"},{"taxonomy":"report-topic","embeddable":true,"href":"https:\/\/hho-bulgaria.com\/en\/wp-json\/wp\/v2\/report-topic?post=27055"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}