Inhibition of angiotensin II and calpain attenuates pleural fibrosis
Inhibition of angiotensin II and calpain attenuates pleural fibrosis
复制标题
抑制血管紧张素 II 和钙蛋白酶可减轻胸膜纤维化。
DOI：
10.1016/j.pupt.2017.10.012
复制
发表时间：
2018-02-01
影响因子：
3.2
通讯作者：
Ma, Wan-Li
中科院分区：
文献类型：
--
作者：
Song, Lin-Jie;Xiang, Fei;Ma, Wan-Li
胸膜纤维化与各种炎症过程有关，如结核性胸膜炎和细菌性脓胸。目前尚无理想的治疗方法来减轻胸膜纤维化。一些促纤维化介质通过炎症过程诱导纤维化，提示阻断这些介质可能预防胸膜纤维化。本研究以MET-5A人胸膜间皮细胞系(PMC)作为体外纤维化模型，胸膜内注射博莱霉素碳颗粒作为体内小鼠胸膜纤维化模型。观察Calain基因敲除小鼠、Calain抑制剂(CalPeptin)和血管紧张素II 1型受体(AT(1)R)拮抗剂(氯沙坦)对实验性胸膜纤维化的预防作用。我们发现博莱霉素和碳颗粒可以诱导培养的PMCs中钙蛋白酶的激活。这一体外反应与I型胶原合成增加有关，并可被Calain抑制剂或AT1R拮抗剂阻断。在博莱霉素和碳颗粒诱导的小鼠模型中，钙蛋白酶基因或钙肽蛋白或氯沙坦治疗可预防胸膜纤维化。我们的研究结果表明，Ang II信号和钙蛋白酶激活诱导了I型胶原的合成，并促进了胸膜纤维化的纤维化改变。因此，抑制血管紧张素转换酶II和钙蛋白酶可能成为治疗胸膜纤维化的新策略。
Pleural fibrosis is associated with various inflammatory processes such as tuberculous pleurisy and bacterial empyema. There is currently no ideal therapeutic to attenuate pleural fibrosis. Some pro-fibrogenic mediators induce fibrosis through inflammatory processes, suggesting that blockage of these mediators might prevent pleural fibrosis. The MeT-5A human pleural mesothelial cell line (PMC) was used in this study as an in vitro model of fibrosis; and intra-pleural injection of bleomycin with carbon particles was used as an in vivo mouse model of pleural fibrosis. Calpain knockout mice, calpain inhibitor (calpeptin), and angiotensin (Ang) II type 1 receptor (AT(1)R) antagonist (losartan) were evaluated in prevention of experimental pleural fibrosis. We found that bleomycin and carbon particles induced calpain activation in cultured PMCs. This in vitro response was associated with increased collagen-I synthesis, and was blocked by calpain inhibitor or AT1R antagonist. Calpain genetic or treatment with calpeptin or losartan prevented pleural fibrosis in a mouse model induced by bleomycin and carbon particles. Our findings indicate that Ang II signaling and calpain activation induce collagen-I synthesis and contribute to fibrotic alterations in pleural fibrosis. Inhibition of Ang II and calpain might therefore be a novel strategy in treatment of pleural fibrosis.