• Tingting Di, Yue Yang, Congli Fu, Zixiao Zhang, Chu Qin, Xiaoyan Sai, Jiaxin Liu, Caixia Hu, Mingfeng Zheng, Yan Wu, and Tao Bian.
• Departments of Respiratory Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, P.R. China.
• Eur. J. Clin. Invest. 2021 Apr 1; 51 (4): e13425.

BackgroundMyofibroblast differentiation and extracellular matrix (ECM) deposition are observed in chronic obstructive pulmonary disease (COPD). However, the mechanisms of regulation of myofibroblast differentiation remain unclear.Materials And MethodsWe detected let-7 levels in peripheral lung tissues, serum and primary bronchial epithelial cells of COPD patients and cigarette smoke (CS)-exposed mice. IL-6 mRNA was explored in lung tissues of COPD patients and CS-exposed mice. IL-6 protein was detected in cell supernatant from primary epithelial cells by ELISA. We confirmed the regulatory effect of let-7 on IL-6 by luciferase reporter assay. Western blotting assay was used to determine the expression of α-SMA, E-cadherin and collagen I. In vitro, cell study was performed to demonstrate the role of let-7 in myofibroblast differentiation and ECM deposition.ResultsLow expression of let-7 was observed in COPD patients, CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. Increased IL-6 was found in COPD patients, CS-exposed mice and CSE-treated HBE cells. Let-7 targets and silences IL-6 protein coding genes through binding to 3' untranslated region (UTR) of IL-6. Normal or CSE-treated HBE cells were co-cultured with human embryonic lung fibroblasts (MRC-5 cells). Reduction of let-7 in HBE cells caused myofibroblast differentiation and ECM deposition, while increase of let-7 mimics decreased myofibroblast differentiation phenotype and ECM deposition.ConclusionWe demonstrate that CS reduced let-7 expression in COPD and, further, identify let-7 as a regulator of myofibroblast differentiation through the regulation of IL-6, which has potential value for diagnosis and treatment of COPD.© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

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