背景:JAK抑制剂用于治疗类风湿性关节炎(RA),但是它们是否可以用于治疗肺纤维化,一种常见的类风湿性关节炎关节外疾病,还有待澄清。
方法:一种jak2抑制剂,CEP33779(CEP),对RA相关间质性肺病的大鼠模型给药,观察关节肿胀和肺纤维化的改善程度。用TGF-β1刺激HFL1细胞以观察p-JAK2的表达。然后,将不同浓度的相关基因抑制剂(JAK2,TGFβ-R1/2和p-STAT3)或沉默子(STAT3,JAK2)施用于HFL1细胞,并检测相关蛋白的表达水平,以探索潜在的作用机制。
结果:CEP不仅减轻了大鼠关节肿胀和炎症的程度,而且改善了肺功能,抑制促炎因子IL-1β和IL-6,减轻肺部炎症和胶原沉积,减轻肺纤维化。CEP降低TGFβ-R2,p-SMAD的表达水平,大鼠肺组织中的p-STAT3和ECM蛋白。TGF-β1诱导HFL1细胞高表达p-JAK2,在48h表达最明显。抑制JAK2或STAT3后,p-STAT3,p-SMAD3和ECM相关蛋白的水平显着降低。
结论:JAK2抑制剂可能是一种重要的新型免疫治疗药物,可以改善RA症状,同时延缓或阻断相关肺纤维化疾病的发展。其机制可能与通过抑制JAK2/STAT信号通路下调p-STAT3蛋白有关,影响SMAD3的磷酸化。
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-β1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGFβ-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-1β and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGFβ-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-β1 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.
CONCLUSIONS: 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.