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
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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; .
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- Received July 5, 2021.
- Accepted August 19, 2021.
- Copyright ©The authors 2021
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