成纤维细胞活化增殖在百草枯(PQ)中毒后肺纤维化形成中起重要作用。前期研究应用KCa3.1 阻断剂后肺组织中活化成纤维细胞数减少、成纤维细胞中TGF-β1诱导JNK活化减少。国外研究报道KCa3.1活化引起细胞内钙平衡失调，诱发内质网应激(ERS)，而ERS又参与JNK信号通路的调节。因此分析在PQ中毒后，KCa3.1活化可能通过Ca2+内流，诱导ERS，参与TGF-β1激活JNK信号通路，导致成纤维细胞活化增殖。本项目拟通过体内体外中毒模型：①用阻断剂、激动剂、siRNA和基因转染技术，调节KCa3.1表达和状态，检测成纤维细胞表型和细胞增殖变化、肺活化成纤维细胞数和细胞外基质蛋白表达、肺纤维化程度；②应用ERS抑制剂，观察肺成纤维细胞内Ca2+浓度、ERS标志蛋白、JNK信号通路基因和蛋白。探讨PQ中毒后 KCa3.1介导肺成纤维细胞活化增殖的作用机制，为临床治疗提供新思路和干预靶点。

Paraquat poisoning could result in extensive pulmonary fibrosis, thus affecting the prognosis of patients. Fibroblasts have been showed to be majority source of collagen and contribute to pulmonary fibrosis in both physiologic and pathologic settings. We found that, by blocking the Ca2+-activated K+ channel (KCa3.1), both the number of fibroblasts in the lungs and the extent of pulmonary fibrosis were attenuated in the rat model of paraquat (PQ) poisoning. And TRAM34, the blocker of KCa3.1, inhibited the TGF-β1-mediated increase in p-JNK expression. Previous studies have demonstrated that KCa3.1 regulates K+ efflux, increasing the driving force for Ca2+ entry through hyperpolarization of the plasma membrane. Intracellular Ca2+ imbalance can impact and disturb proper functioning of the endoplasmic reticulum, resulting in endoplasmic reticulum stress (ERS). It was reported that ERS contribute to the mediation of JNK pathway. We postulated that the fibroblasts was activated by KCa3.1 channels which contributed to the TGF-β1-mediated JNK pathway via ERS after Ca2+ influx in PQ induced pulmonary fibrosis. We will investigate the role of KCa3.1 in the activation and proliferation of fibroblasts by means of administrating KCa3.1 channel blockers and openers, as well as RNA interference both in vitro and in vivo. The goal of this study is to investigate the role of ion channel in the development of PQ-induced pulmonary fibrosis, which may be a potential therapeutic target.