Pirfenidone and nintedanib attenuate pulmonary fibrosis in mice by inhibiting the expression of JAK2

作者全名：Yang, Yan; Wang, Xinmeng; Zhang, Jie

作者地址：[Yang, Yan; Wang, Xinmeng] Chongqing Med Univ, Dept Geriatr, Chongqing, Peoples R China; [Zhang, Jie] Chongqing Gen Hosp, Dept Geriatr, 118,Xingguang Ave, Chongqing 401147, Peoples R China

通信作者：Zhang, J (通讯作者)，Chongqing Gen Hosp, Dept Geriatr, 118,Xingguang Ave, Chongqing 401147, Peoples R China.

来源：JOURNAL OF THORACIC DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001223132200001

JCR分区：Q3

影响因子：2.1

年份：2024

卷号：16

期号：2

开始页：1128

结束页：1140

文献类型：Article

关键词：Pirfenidone; nintedanib; pulmonary fibrosis; JAK2; transforming growth factor-0 (TGF-01)

摘要：Background: Pirfenidone and nintedanib were approved by the Food and Drug Administration (FDA) for the treatment of idiopathic pulmonary fibrosis (IPF). These two drugs can slow the progression of the disease, but the specific mechanisms are not fully understood. In the current study, bleomycin (BLM) induced pulmonary fibrosis in mice was accompanied by high p-JAK2 expression in lung tissue, mainly in the nucleus. The expression of p-JAK2 significantly decreased after intragastric administration of pirfenidone and nintedanib. p-JAK2 is reportedly expressed mainly in the cytoplasm and exerts its effect by activating downstream p-STAT3 in the nucleus. Methods: In vivo experiments, pulmonary fibrosis was induced in mice with BLM and then treated with pirfenidone and nintedanib. The levels of transforming growth factor -0 (TGF-01), SP -A, SP -D and KL-6 in serum were measured by enzyme -linked immunosorbent assay (ELISA). Pathological staining was performed to assess lung fibrosis in mice, Western blot was performed to detect the expression levels of relevant proteins, and immunofluorescence was performed to observe the fluorescence expression of p-JAK2. In cellular experiments, MLE12 was stimulated with TGF-01 and intervened with TGF-01 receptor inhibitor and si-JAK2, pirfenidone and nintedanib, respectively, and the related protein expression levels were detected by Western blot. Results: In both in vivo and in vitro experiments, pirfenidone and nintedanib were found to attenuate the expression of lung fibrosis markers by inhibiting the expression of JAK2, which may reduce the entry of p-JAK2 into the nucleus by downregulating JAK2 phosphorylation through inhibition of the TGF-0 receptor. In contrast, inhibition of JAK2 expression greatly reduced the expression of TGF-0 receptor and a -smooth muscles actin (a myofibroblast activation marker). Conclusions: In both in vivo and in vitro experiments, the present study demonstrated that TGF-01 promotes JAK2 phosphorylation through a non -classical pathway, and conversely, inhibition of JAK2 expression affects the TGF-01 signalling pathway. Therefore, we speculate that TGF-01 and JAK2 signaling pathways interact with each other and participate in fibrosis.

基金机构：　

基金资助正文：