Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation.
Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation.
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DOI：
10.1152/ajplung.00206.2011
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发表时间：
2012-07
期刊：
影响因子：
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通讯作者：
Kristin Westphalen;Eiji Monma;M. Islam;J. Bhattacharya
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文献类型：
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作者：
Kristin Westphalen;Eiji Monma;M. Islam;J. Bhattacharya
尽管胃酸误吸会导致快速肺部炎症和急性肺损伤，但其引发机制尚不清楚。为了确定肺泡上皮对酸的反应，我们通过荧光显微镜观察了离体肺的活肺泡，然后我们向肺泡显微注射了 pH 为 1.5 的 HCl。显微注射导致顶端肺泡膜立即但短暂地形成分子尺度的孔，导致细胞溶质染料的损失。然而，膜很快重新密封。尽管连续注射 HCl，但没有细胞损伤，也没有进一步的染料损失。与此同时，邻近肺泡周围微血管内皮细胞中的活性氧（ROS）以Ca（2+）依赖性方式增加。相比之下，在肺泡内注射聚乙二醇（PEG）过氧化氢酶的野生型小鼠、过度表达肺泡过氧化氢酶的小鼠或缺乏功能性 NADPH 氧化酶（Nox2）的小鼠中，ROS 没有增加。总之，我们的研究结果表明存在一种不寻常的促炎机制，其中肺泡与酸的接触导致膜孔的形成。该作用虽然短暂，但足以诱导Ca(2+) 进入肺泡上皮和Nox2 依赖性H(2)O(2) 释放。这些反应将肺泡 H(2)O(2) 释放确定为导致酸诱导的肺部炎症的信号机制，并表明肺泡内 PEG-过氧化氢酶可能对酸诱导的肺损伤具有治疗作用。
Although gastric acid aspiration causes rapid lung inflammation and acute lung injury, the initiating mechanisms are not known. To determine alveolar epithelial responses to acid, we viewed live alveoli of the isolated lung by fluorescence microscopy, then we microinjected the alveoli with HCl at pH of 1.5. The microinjection caused an immediate but transient formation of molecule-scale pores in the apical alveolar membrane, resulting in loss of cytosolic dye. However, the membrane rapidly resealed. There was no cell damage and no further dye loss despite continuous HCl injection. Concomitantly, reactive oxygen species (ROS) increased in the adjacent perialveolar microvascular endothelium in a Ca(2+)-dependent manner. By contrast, ROS did not increase in wild-type mice in which we gave intra-alveolar injections of polyethylene glycol (PEG)-catalase, in mice overexpressing alveolar catalase, or in mice lacking functional NADPH oxidase (Nox2). Together, our findings indicate the presence of an unusual proinflammatory mechanism in which alveolar contact with acid caused membrane pore formation. The effect, although transient, was nevertheless sufficient to induce Ca(2+) entry and Nox2-dependent H(2)O(2) release from the alveolar epithelium. These responses identify alveolar H(2)O(2) release as the signaling mechanism responsible for lung inflammation induced by acid and suggest that intra-alveolar PEG-catalase might be therapeutic in acid-induced lung injury.