Cyclic Stretch-Induced Oxidative Stress Increases Pulmonary Alveolar Epithelial Permeability
Cyclic Stretch-Induced Oxidative Stress Increases Pulmonary Alveolar Epithelial Permeability
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DOI：
10.1165/rcmb.2012-0252oc
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发表时间：
2013-07-01
影响因子：
6.4
通讯作者：
Margulies, Susan S.
中科院分区：
文献类型：
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作者：
Davidovich, Nurit;DiPaolo, Brian C.;Margulies, Susan S.
高潮气量机械通气与肺泡溢流有关。了解循环拉伸引起的肺泡上皮通透性增加的机制对于设计急性肺损伤的预防措施可能很重要。在这项工作中，我们评估了循环拉伸是否会导致 I 型肺泡上皮细胞中活性氧的产生，从而通过激活 NF-κ B 和细胞外信号调节激酶 (ERK) 来增加单层通透性。我们以 12%、25% 和 37% 的表面积变化 (Delta SA) 循环拉伸 I 型大鼠原代肺泡上皮细胞 10 至 120 分钟。在 37% Delta SA 拉伸 10 至 120 分钟的细胞中，检测到高水平的活性氧、超氧化物和 NO。外源性超氧化物和 NO 刺激会增加未拉伸细胞的上皮通透性，而 NF-κ B 抑制剂 MG132 可以预防这种情况。超氧化物清除剂 Tironand MG132 降低了循环拉伸引起的渗透性增加。此外，在机械通气条件下，钛试剂对体内肺通透性具有显着的保护作用。循环拉伸增加了 NF-kappa B 信号通路的激活，而 ERK 抑制剂 U0126 则显着降低了该信号通路的激活。总而言之，我们的体外和体内数据证明了通透性对拉伸和通气引起的超氧化物产生的敏感性，表明使用抗氧化剂可能有助于预防和治疗呼吸机引起的肺损伤。
Mechanical ventilation with high tidal volumes has been associated with pulmonary alveolar flooding. Understanding the mechanisms underlying cyclic stretch-induced increases in alveolar epithelial permeability may be important in designing preventive measures for acute lung injury. In this work, we assessed whether cyclic stretch leads to the generation of reactive oxygen species in type I-like alveolar epithelial cells, which increase monolayer permeability via activation of NF-kappa B and extracellular signal-regulated kinase (ERK). We cyclically stretched type I-like rat primary alveolar epithelial cells at magnitudes of 12, 25, and 37% change in surface area (Delta SA) for 10 to 120 minutes. High levels of reactive oxygen species and of superoxide and NO specifically were detected in cells stretched at 37% Delta SA for 10 to 120 minutes. Exogenous superoxide and NO stimulation increased epithelial permeability in unstretched cells, which was preventable by the NF-kappa B inhibitor MG132. The cyclic stretch-induced increase in permeability was decreased by the superoxide scavenger tironand by MG132. Furthermore, tiron had a dramatic protective effect on in vivo lung permeability under mechanical ventilation conditions. Cyclic stretch increased the activation of the NF-kappa B signaling pathway, which was significantly decreased with the ERK inhibitor U0126. Altogether, our in vitro and in vivo data demonstrate the sensitivity of permeability to stretch-and ventilation-induced superoxide production, suggesting that using antioxidants may be helpful in the prevention and treatment of ventilator-induced lung injury.