Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Exp Cell Res. 2020 Jun 1;391(1):111886. doi: 10.1016/j.yexcr.2020.111886. Epub 2020 Feb 1.
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, Ca-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.
特发性肺纤维化（IPF）是一种预后不良的肺纤维化疾病。上皮-间充质转化（EMT）已被报道在 IPF 中发挥重要作用。细胞外信号调节激酶 1 和 2（ERK1/2）级联反应，调节 EMT 和致癌作用，与 IPF 的发病机制有关。钙蛋白酶，Ca 依赖性半胱氨酸蛋白酶，可介导包括上皮细胞标志物 E-钙粘蛋白在内的许多特定底物的可控蛋白水解，参与器官纤维化。钙蛋白酶家族中的钙蛋白酶-1 和钙蛋白酶-2 是普遍存在的钙蛋白酶。ERK1/2 信号在癌症发展中刺激普遍存在的钙蛋白酶活性，但 ERK1/2 信号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，我们研究了抑制 ERK1/2 信号和普遍存在的钙蛋白酶是否能减轻实验性肺纤维化，并研究了潜在的机制。我们的结果表明，抑制 ERK1/2 信号和普遍存在的钙蛋白酶都能减轻博来霉素（BLM）诱导的小鼠肺纤维化。抑制 ERK1/2 信号在体内和体外均下调钙蛋白酶-1 和钙蛋白酶-2 的表达。我们在 IPF 患者中检测到 E-钙粘蛋白表达降低和钙蛋白酶-1 表达增加。抑制 ERK1/2 信号和普遍存在的钙蛋白酶都能抑制 EMT 的发生。我们的研究表明，抑制 ERK1/2-普遍存在的钙蛋白酶途径可防止 BLM 引起的肺纤维化，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 的一种潜在策略。
