{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:50:01Z","timestamp":1788871801624,"version":"build-2803163510"},"reference-count":40,"publisher":"European Respiratory Society (ERS)","issue":"4","license":[{"start":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T00:00:00Z","timestamp":1630540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["JP 26461470, 23591444, 17K09982, and 17K16055"],"award-info":[{"award-number":["JP 26461470, 23591444, 17K09982, and 17K16055"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008883","name":"Nagoya City University","doi-asserted-by":"publisher","award":["Grant Number 1943005"],"award-info":[{"award-number":["Grant Number 1943005"]}],"id":[{"id":"10.13039\/501100008883","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["ERJ Open Res"],"accepted":{"date-parts":[[2021,8,19]]},"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:p>Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is relevant for the prognosis in patients with RA. Nintedanib, which inhibits both receptor and non-receptor type tyrosine kinases, is an antifibrotic drug for the treatment of progressive fibrosing ILDs, such as idiopathic pulmonary fibrosis and systemic sclerosis-associated interstitial lung disease. Little is known about the effects of nintedanib on RA-ILD. We examined the characteristics of a novel induced RA-ILD (iRA-ILD) mouse model and the effects of nintedanib on the model.<\/jats:p><jats:p>D1CC\u00d7D1BC mice are highly susceptible to arthritogenic antigens, such as bovine type II collagen, resulting in severe inflammatory arthritis. ILD develops after joint inflammation is alleviated. Serum surfactant protein D levels were monitored as an ILD marker. Nintedanib was orally administered to iRA-ILD mice for 2\u2005months.<\/jats:p><jats:p>The iRA-ILD model showed similar symptoms to those in patients with RA-ILD. The histopathological features of pulmonary disorder resembled nonspecific interstitial pneumonia, but with metaplastic epithelium. Histopathological analysis revealed that in addition to reducing fibrosis, nintedanib suppressed M2 macrophage polarisation and hyperplasia of Type 2 alveolar epithelial cells. The metaplastic epithelium acquired invasiveness because of the expression of E-cadherin, MMP7,<jats:italic>Tgf-<\/jats:italic>\u03b2,<jats:italic>Col1a1<\/jats:italic>,<jats:italic>Padi2<\/jats:italic>and<jats:italic>Padi4<\/jats:italic>. Moreover, citrullinated peptides were detected in these invasive epithelial cells as well as in the bronchiolar epithelium. Administration of nintedanib reduced the expression of Pad4 and citrullinated peptides and eliminated invasive epithelial cells.<\/jats:p><jats:p>The broad inhibitory effects of nintedanib on tyrosine kinases may contribute to the overall improvement in RA-ILD, including epithelial abnormalities associated with progressive lung fibrosis.<\/jats:p>","DOI":"10.1183\/23120541.00345-2021","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T11:40:21Z","timestamp":1630582821000},"page":"00345-2021","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model"],"prefix":"10.1183","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-8018","authenticated-orcid":false,"given":"Yoko","family":"Miura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8538-1150","authenticated-orcid":false,"given":"Hirotsugu","family":"Ohkubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4947-4760","authenticated-orcid":false,"given":"Akio","family":"Niimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0690-0993","authenticated-orcid":false,"given":"Satoshi","family":"Kanazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2021,9,2]]},"reference":[{"key":"2024101711211302000_7.4.00345-2021.1","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2007.59"},{"key":"2024101711211302000_7.4.00345-2021.2","first-page":"280","article-title":"Rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis: shared mechanistic and phenotypic traits suggest overlapping disease mechanisms","volume":"67","author":"Paulin","year":"2015","journal-title":"Rev Invest Clin"},{"key":"2024101711211302000_7.4.00345-2021.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201004-0622OC"},{"key":"2024101711211302000_7.4.00345-2021.4","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kel202"},{"key":"2024101711211302000_7.4.00345-2021.5","doi-asserted-by":"publisher","DOI":"10.3109\/01902148.2011.636139"},{"key":"2024101711211302000_7.4.00345-2021.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606450103"},{"key":"2024101711211302000_7.4.00345-2021.7","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10132"},{"key":"2024101711211302000_7.4.00345-2021.8","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14603"},{"key":"2024101711211302000_7.4.00345-2021.9","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101059"},{"key":"2024101711211302000_7.4.00345-2021.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2018.05.004"},{"key":"2024101711211302000_7.4.00345-2021.11","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/art.38904","article-title":"Biomarkers of rheumatoid arthritis-associated interstitial lung disease","volume":"67","author":"Chen","year":"2015","journal-title":"Arthritis Rheum"},{"key":"2024101711211302000_7.4.00345-2021.12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39104"},{"key":"2024101711211302000_7.4.00345-2021.13","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201807-1255ST"},{"key":"2024101711211302000_7.4.00345-2021.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605669103"},{"key":"2024101711211302000_7.4.00345-2021.15","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200601-003TK"},{"key":"2024101711211302000_7.4.00345-2021.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1308362110"},{"key":"2024101711211302000_7.4.00345-2021.17","first-page":"3087","article-title":"PADI4-mediated epithelial\u2013mesenchymal transition in lung cancer cells","volume":"19","author":"Liu","year":"2019","journal-title":"Mol Med Rep"},{"key":"2024101711211302000_7.4.00345-2021.18","doi-asserted-by":"publisher","DOI":"10.1002\/mc.20169"},{"key":"2024101711211302000_7.4.00345-2021.19","doi-asserted-by":"crossref","unstructured":"Mutua V , Gershwin LJ . 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