JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation

作者全名：Wei, Yimei; Wang, Dandan; Wu, Juan; Zhang, Jie

作者地址：[Wei, Yimei] Chongqing Med Univ, Dept Geriatr, Chongqing 400010, Peoples R China; [Wei, Yimei; Wang, Dandan; Wu, Juan; Zhang, Jie] Chongqing Gen Hosp, Dept Geriatr, Chongqing, Peoples R China; [Wang, Dandan] Southwest Med Univ, Dept Pulm, Dept Resp & Crit Care Med, Luzhou, Peoples R China

通信作者：Zhang, J (通讯作者)，Chongqing Gen Hosp, Dept Geriatr, Chongqing, Peoples R China.

来源：INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001214176300001

JCR分区：Q2

影响因子：2.4

年份：2024

卷号：27

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：CEP33779; JAK2; pulmonary fibrosis; rheumatoid arthritis; TGF-beta

摘要：Background: JAK inhibitors are well known for the treatment of rheumatoid arthritis (RA), but whether they can be used to treat pulmonary fibrosis, a common extra-articular disease of RA, remains to be clarified. Methods: A jak2 inhibitor, CEP33779 (CEP), was administered to a rat model of RA-associated interstitial lung disease to observe the degree of improvement in both joint swelling and pulmonary fibrosis. HFL1 cells were stimulated with TGF-beta 1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGF beta-R1/2, and p-STAT3) or silencers (STAT3, JAK2) were administered to HFL1 cells, and the expression levels of related proteins were detected to explore the underlying mechanisms of action. Results: CEP not only reduced the degree of joint swelling and inflammation in rats but also improved lung function, inhibited the pro-inflammatory factors IL-1 beta and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGF beta-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-beta 1 induced HFL1 cells to highly express p-JAK2, with the most pronounced expression at 48 h. The levels of p-STAT3, p-SMAD3, and ECM-related proteins were significantly reduced after inhibition of either JAK2 or STAT3. Conclusion: JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3.

基金机构：The Chongqing Clinical Research Center for Geriatric Diseases

基金资助正文：Thanks to Dr. Lulu Xu and Dr. Shuyun Wang of the Department of Geriatrics at Chongqing General Hospital for their help with the experiment.