Exercise training ameliorates bleomycin-induced epithelial mesenchymal transition and lung fibrosis through restoration of H2S synthesis
Exercise training ameliorates bleomycin-induced epithelial mesenchymal transition and lung fibrosis through restoration of H2S synthesis
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运动训练通过恢复 H2S 合成改善博莱霉素诱导的上皮间质转化和肺纤维化
DOI：
10.1111/apha.13177
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发表时间：
2019-02-01
影响因子：
6.3
通讯作者：
Zhu, Xiao-Yan
中科院分区：
文献类型：
--
作者：
Du, Shu-Fang;Wang, Xiu-Li;Zhu, Xiao-Yan
目的临床试验显示运动训练对肺纤维化的有益作用。本研究旨在探讨运动训练的预防性干预是否通过调节内源性硫化氢（H2S）的产生来减轻肺纤维化。方法将ICR小鼠分为对照组、博来霉素组、运动组和博来霉素+运动组。跑步机运动从第一天开始，持续4周。第15天给予单次气管内剂量博来霉素（3mg /kg）。将ICR小鼠分为对照组、博莱霉素组、H2S组和博莱霉素+ H2S组。H2S供体NaHS （28 μ mol/kg）腹腔注射，每天1次，连续2周。结果博来霉素处理小鼠肺组织中胶原沉积、羟脯氨酸、I型胶原、转化生长因子(TGF)- β 1、Smad2/Smad3/低密度脂蛋白受体相关蛋白(lfp -6)/糖原合酶激酶-3 β (GSK-3 β)磷酸化和Smad4/ β -catenin表达均升高（P < 0.01），运动训练可减轻这种升高（P GSK-3 β: P < 0.05）。博莱霉素诱导的肺纤维化与α -平滑肌肌动蛋白（α - sma）升高、E-cadherin表达降低相关（P < 0.01）。双免疫荧光染色显示E-cadherin/ α - sma共定位，表明上皮-间质转化（epithelial-mesenchymal transition， EMT）形成，运动训练改善了EMT的形成。此外，运动训练恢复了博莱霉素诱导的肺组织胱硫氨酸- β -合成酶（CBS）和胱硫氨酸- γ -裂解酶（CSE）表达下调以及H2S生成（P < 0.01）。NaHS治疗可减弱博莱霉素诱导的tgf - β 1生成、LRP-6/ β -连环蛋白信号激活、EMT和肺纤维化（P P < 0.05）。结论运动训练可恢复博莱霉素诱导的肺CBS/CSE表达下调，从而促进H2S生成增加，抑制tgf - β 1/Smad和LRP-6/ β -catenin信号通路、EMT和肺纤维化。
Aims Clinical trials have shown the beneficial effects of exercise training against pulmonary fibrosis. This study aimed to investigate whether prophylactic intervention with exercise training attenuates lung fibrosis via modulating endogenous hydrogen sulphde (H2S) generation. Methods First, ICR mice were allocated to Control, Bleomycin, Exercise, and Bleomycin + Exercise groups. Treadmill exercise began on day 1 and continued for 4 weeks. A single intratracheal dose of bleomycin (3 mg/kg) was administered on day 15. Second, ICR mice were allocated to Control, Bleomycin, H2S, and Bleomycin + H2S groups. H2S donor NaHS (28 mu mol/kg) was intraperitoneally injected once daily for 2 weeks. Results Bleomycin-treated mice exhibited increased levels of collagen deposition, hydroxyproline, collagen I, transforming growth factor (TGF)-beta 1, Smad2/Smad3/low-density lipoprotein receptor-related proteins (LRP-6)/glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylation, and Smad4/beta-catenin expression in lung tissues (P < 0.01), which was alleviated by exercise training (P GSK-3 beta: P < 0.05). Bleomycin-induced lung fibrosis was associated with increased alpha smooth muscle actin (alpha-SMA) and decreased E-cadherin expression (P < 0.01). Double immunofluorescence staining showed the co-localization of E-cadherin/alpha-SMA, indicating epithelial-mesenchymal transition (EMT) formation, which was ameliorated by exercise training. Moreover, exercise training restored bleomycin-induced downregulation of cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) expression, as well as H2S generation in lung tissue (P < 0.01). NaHS treatment attenuated bleomycin-induced TGF-beta 1 production, activation of LRP-6/beta-catenin signalling, EMT and lung fibrosis (P P < 0.05). Conclusion Exercise training restores bleomycin-induced downregulation of pulmonary CBS/CSE expression, thus contributing to the increased H2S generation and suppression of TGF-beta 1/Smad and LRP-6/beta-catenin signalling pathways, EMT and lung fibrosis.