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Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model

Yoko Miura, Hirotsugu Ohkubo, Akio Niimi, Satoshi Kanazawa
ERJ Open Research 2021; DOI: 10.1183/23120541.00345-2021
Yoko Miura
1Department of Neurodevelopmental Disorder Genetics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Hirotsugu Ohkubo
2Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Akio Niimi
2Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Satoshi Kanazawa
1Department of Neurodevelopmental Disorder Genetics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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  • ORCID record for Satoshi Kanazawa
  • For correspondence: kanas@med.nagoya-cu.ac.jp
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Abstract

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.

D1CC×D1BC mice are highly susceptible to arthritogenic antigens, such as bovine type II collagen, resulting in severe inflammatory arthritis. ILD develops after joint inflammation alleviates. Serum surfactant protein D levels were monitored as an ILD marker. Nintedanib was orally administered to iRA-ILD mice for two months.

The iRA-ILD model showed similar symptoms as 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 polarization and hyperplasia of type 2 alveolar epithelial cells. The metaplastic epithelium acquired invasiveness because of the expression of E-cadherin, MMP7, Tgf-β, Col1a1, Padi2, and Padi4. 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.

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.

Footnotes

This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Miura has nothing to disclose.

Conflict of interest: Dr. Ohkubo reports grants from Boehringer Ingelheim, outside the submitted work;.

Conflict of interest: Dr. Niimi has nothing to disclose.

Conflict of interest: Dr. Kanazawa reports grants from Boehringer Ingelheim, personal fees from T. Furuya, outside the submitted work; .

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received July 5, 2021.
  • Accepted August 19, 2021.
  • Copyright ©The authors 2021
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model
Yoko Miura, Hirotsugu Ohkubo, Akio Niimi, Satoshi Kanazawa
ERJ Open Research Jan 2021, 00345-2021; DOI: 10.1183/23120541.00345-2021

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Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model
Yoko Miura, Hirotsugu Ohkubo, Akio Niimi, Satoshi Kanazawa
ERJ Open Research Jan 2021, 00345-2021; DOI: 10.1183/23120541.00345-2021
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