Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model
Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model
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DOI：
10.1183/23120541.00345-2021
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发表时间：
2021-10-01
影响因子：
4.6
通讯作者：
Kanazawa, Satoshi
中科院分区：
文献类型：
--
作者：
Miura, Yoko;Ohkubo, Hirotsugu;Kanazawa, Satoshi
风湿性关节炎相关间质性肺病（RA-ILD）与RA患者的预后相关。抑制受体型和非受体型酪氨酸激酶的尼莫地平是一种抗纤维化药物，用于治疗进行性纤维化ILD，如特发性肺纤维化和系统性硬化症相关的间质性肺病。关于尼达尼布对RA-ILD的影响知之甚少。我们研究了一种新型诱导RA-ILD（iRA-ILD）小鼠模型的特征以及尼达尼布对该模型的影响。D1CCxD 1BC小鼠对致关节炎抗原（如牛H型胶原蛋白）高度敏感，导致严重的炎性关节炎。ILD在关节炎症缓解后发生。监测血清表面活性蛋白D水平作为ILD标志物。iRA-ILD小鼠经口给药2个月，iRA-ILD模型表现出与RA-ILD患者相似的症状。肺部病变的组织病理学特征类似非特异性间质性肺炎，但上皮化生。组织学分析显示，除了减少纤维化外，尼达尼布还抑制了M2巨噬细胞极化和2型肺泡上皮细胞增生。化生上皮由于E-cadherin、MMP 7、Tgf-β、Col 1a 1、Padi 2和Padi 4的表达而获得侵袭性。此外，在这些侵袭性上皮细胞以及细支气管上皮中检测到瓜氨酸化肽。尼达尼布给药可降低Pad 4和瓜氨酸化肽的表达，并消除侵袭性上皮细胞。尼达尼布对酪氨酸激酶的广泛抑制作用可能有助于RA-ILD的总体改善，包括与进行性肺纤维化相关的上皮异常。
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.D1CCxD1BC mice are highly susceptible to arthritogenic antigens, such as bovine type H 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 months.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, Tgf-beta, 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.