Zhang Ping, Wang Jiaxin, Luo Weiren, Yuan Jifan, Cui Chunhong, Guo Ling, Wu Chuanyue
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Academy for Advanced Interdisciplinary Studies and Department of Biology, Southern University of Science and Technology, Shenzhen, China.
Department of Pathology, Cancer Research Institute, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Diseases, Shenzhen, China; and.
Am J Respir Cell Mol Biol. 2021 Jul;65(1):54-69. doi: 10.1165/rcmb.2020-0320OC.
Pulmonary fibrosis is a progressive and fatal lung disease characterized by activation of lung fibroblasts and excessive deposition of collagen matrix. We show here that the concentrations of kindlin-2 and its binding partner PYCR1, a key enzyme for proline synthesis, are significantly increased in the lung tissues of human patients with pulmonary fibrosis. Treatment of human lung fibroblasts with TGF-β1 markedly increased the expression of kindlin-2 and PYCR1, resulting in increased kindlin-2 mitochondrial translocation, formation of the kindlin-2-PYCR1 complex, and proline synthesis. The concentrations of the kindlin-2-PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone or nintedanib, two clinically approved therapeutic drugs for pulmonary fibrosis. Furthermore, depletion of kindlin-2 alone was sufficient to suppress TGF-β1-induced increases of PYCR1 expression, proline synthesis, and fibroblast activation. Finally, using a bleomycin mouse model of pulmonary fibrosis, we show that ablation of kindlin-2 effectively reduced the concentrations of PYCR1, proline, and collagen matrix and alleviate the progression of pulmonary fibrosis . Our results suggest that kindlin-2 is a key promoter of lung fibroblast activation, collagen matrix synthesis, and pulmonary fibrosis, underscoring the therapeutic potential of targeting the kindlin-2 signaling pathway for control of this deadly lung disease.
肺纤维化是一种进行性致命性肺部疾病，其特征为肺成纤维细胞活化和胶原基质过度沉积。我们在此表明，在人类肺纤维化患者的肺组织中，黏着斑蛋白2（kindlin-2）及其结合伴侣PYCR1（脯氨酸合成的关键酶）的浓度显著升高。用转化生长因子-β1（TGF-β1）处理人肺成纤维细胞可显著增加黏着斑蛋白2和PYCR1的表达，导致黏着斑蛋白2向线粒体转位增加、黏着斑蛋白2-PYCR1复合物形成以及脯氨酸合成增加。对于吡非尼酮或尼达尼布（两种临床上已批准用于治疗肺纤维化的药物），黏着斑蛋白2-PYCR1复合物浓度和脯氨酸合成显著降低。此外，单独敲除黏着斑蛋白2足以抑制TGF-β1诱导的PYCR1表达增加、脯氨酸合成及成纤维细胞活化。最后，利用博来霉素诱导的肺纤维化小鼠模型，我们表明敲除黏着斑蛋白2可有效降低PYCR1、脯氨酸和胶原基质的浓度，并减轻肺纤维化的进展。我们的结果表明，黏着斑蛋白2是肺成纤维细胞活化、胶原基质合成和肺纤维化的关键促进因子，这突出了靶向黏着斑蛋白-2信号通路治疗这种致命性肺部疾病的潜力。
