Inhibition of the ERK1/2-ubiquitous calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro
Inhibition of the ERK1/2-ubiquitous calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro
复制标题
抑制 ERK1/2 普遍存在的钙蛋白酶途径可减轻体内和体外实验性肺纤维化
DOI：
10.1016/j.yexcr.2020.111886
复制
发表时间：
2020
影响因子：
3.7
通讯作者：
Cheng Zhenshun
中科院分区：
文献类型：
--
作者：
Zou Menglin;Zhang Guqin;Zou Jingfeng;Liu Yuan;Liu Bing;Hu Xingxing;Cheng Zhenshun
特发性肺纤维化（IPF）是一种预后不良的纤维化肺部疾病。据报道，上皮-间质转化（EMT）在IPF中发挥重要作用。调节EMT和肿瘤发生的细胞外信号调节激酶1和2（ERK 1/2）级联与IPF的发病机制有关。钙蛋白酶是一种钙离子依赖性半胱氨酸蛋白酶，可介导包括上皮细胞标志物E-钙粘蛋白在内的多种特异性底物的受控蛋白水解，参与器官纤维化。钙蛋白酶家族的钙蛋白酶-1和钙蛋白酶-2是普遍存在的钙蛋白酶。ERK 1/2信号通路在肿瘤发生发展中刺激普遍存在的钙蛋白酶活性，但ERK 1/2信号通路是否介导肺纤维化中普遍存在的钙蛋白酶活性尚不清楚。在这里，我们研究是否抑制ERK 1/2信号和普遍存在的钙蛋白酶减弱实验性肺纤维化，并检查潜在的机制。我们的研究结果表明，抑制ERK 1/2信号和普遍存在的钙蛋白酶都减弱博莱霉素（BLM）诱导的小鼠肺纤维化。抑制ERK 1/2信号通路可下调钙蛋白酶-1和钙蛋白酶-2在体内和体外的表达。我们检测到IPF患者中E-钙粘蛋白表达减少，钙蛋白酶-1表达增加。抑制ERK 1/ 2信号和普遍存在的钙蛋白酶都抑制EMT在体内和体外的发展。我们的研究表明，抑制ERK 1/2-普遍存在的钙蛋白酶途径保护肺纤维化从BLM，可能通过抑制EMT。因此，靶向普遍存在的钙蛋白酶可能是减轻IPF的潜在策略。
Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in IPF. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) cascade, which regulates EMT and oncogenesis, has been implicated in the pathogenesis of IPF. Calpains, Ca2+-dependent cysteine proteinases that mediate controlled proteolysis of many specific substrates including epithelial cell marker E-cadherin, participate in organ fibrosis. Calpain-1 and calpain-2 of calpain family are ubiquitous calpains. ERK1/2 signaling stimulates the ubiquitous calpains activity in cancer development, but whether ERK1/2 signaling mediates the ubiquitous calpains activity in pulmonary fibrosis is unknown. Here we investigated whether inhibition of ERK1/2 signaling and the ubiquitous calpains attenuated experimental pulmonary fibrosis and examined the potential mechanism. Our results showed that inhibition of ERK1/2 signaling and the ubiquitous calpains both attenuated bleomycin (BLM)-induced lung fibrosis in mice. Inhibition of ERK1/2 signaling downregulated the expression of calpain-1 and calpain-2 in vivo and in vitro. We detected decreased E-cadherin expression and increased calpain-1 expression in IPF patients. Inhibition of ERK1/ 2 signaling and the ubiquitous calpains both suppressed the development of EMT in vivo and in vitro. Our study indicated that inhibition of the ERK1/2-ubiquitous calpains pathway protected pulmonary fibrosis from BLM, possibly via inhibition of EMT. Therefore, targeting ubiquitous calpains may be a potential strategy to attenuate IPF.