Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition
Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition
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DOI：
10.1097/ccm.0b013e31822f09d7
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发表时间：
2012-02-01
影响因子：
8.8
通讯作者：
Slutsky, Arthur S.
中科院分区：
文献类型：
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作者：
Cabrera-Benitez, Nuria E.;Parotto, Matteo;Slutsky, Arthur S.
目的：许多机械通气的急性呼吸窘迫综合征患者出现肺纤维化。机械通气性应激可通过多种机制(如肺泡上皮损伤、生物创伤等)解释肺纤维化的发生。本研究旨在验证机械通气在肺纤维化发病机制中起重要作用的假设。方法：C57BL/6小鼠随机分为4组：健康对照组、单纯盐酸吸入组、24小时后溶媒对照组和24小时后吸酸组、机械通气组(吸气峰压22 cm H2O、呼气末正压2 cm H2O 2 h)。这些动物在酸吸入后被监测了长达15天。为了探讨机械应激对肺纤维化形成的直接影响，将人肺上皮细胞(BEAS-2B)暴露在机械牵张中长达48小时。测量和主要结果：机械通气后肺力学受损与肺组织羟脯氨酸含量增加以及转化生长因子-β、β-连环素和间质标志物(α-平滑肌肌动蛋白和波形蛋白)在基因和蛋白水平的表达增加有关。上皮标志物细胞角蛋白-8、E-钙粘蛋白和前表面活性蛋白B的表达减少。肺组织学显示纤维化形成和潜在的上皮-间充质转化。体外直接机械拉伸BEAS-2B细胞可导致类似的纤维化和上皮-间充质转化。结论：机械应激可诱导肺纤维化，上皮-间充质转化在介导呼吸机诱导的肺纤维化中可能起重要作用。(CRET CARE Med 2012；40：510-517)
Objectives: Many mechanically ventilated patients with acute respiratory distress syndrome develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a number of mechanisms (e. g., damage the alveolar epithelium, biotrauma). The objective of this study was t test the hypothesis that mechanical ventilation plays an important role in the pathogenesis of lung fibrosis.Methods: C57BL/6 mice were randomized into four groups: healthy controls; hydrochloric acid aspiration alone; vehicle control solution followed 24 hrs later by mechanical ventilation (peak inspiratory pressure 22 cm H2O and positive end-expiratory pressure 2 cm H2O for 2 hrs); and acid aspiration followed 24 hrs later by mechanical ventilation. The animals were monitored for up to 15 days after acid aspiration. To explore the direct effects of mechanical stress on lung fibrotic formation, human lung epithelial cells (BEAS-2B) were exposed to mechanical stretch for up to 48 hrs.Measurement and Main Results: Impaired lung mechanics after mechanical ventilation was associated with increased lung hydroxyproline content, and increased expression of transforming growth factor-beta, beta-catenin, and mesenchymal markers (alpha-smooth muscle actin and vimentin) at both the gene and protein levels. Expression of epithelial markers including cytokeratin-8, E-cadherin, and prosurfactant protein B decreased. Lung histology demonstrated fibrosis formation and potential epithelia-mesenchymal transition. In vitro direct mechanical stretch of BEAS-2B cells resulted in similar fibrotic and epithelia-mesenchymal transition formation.Conclusions: Mechanical stress induces lung fibrosis, and epithelia-mesenchymal transition may play an important role in mediating the ventilator-induced lung fibrosis. (Crit Care Med 2012; 40:510-517)