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首页> 外文期刊>Thorax: The Journal of the British Thoracic Society >Fas activation alters tight junction proteins in acute lung injury
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Fas activation alters tight junction proteins in acute lung injury

机译：FAS激活改变急性肺损伤的紧密结蛋白

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Background:The acute respiratory distress syndrome (ARDS) is characterized by protein-rich oedema in the alveolar spaces, a feature in which Fas-mediated apoptosis of the alveolar epithelium has been involved. Objective:To determine whether Fas activation increases protein permeability by mechanisms involving disruption of the paracellular tight junction (TJ) proteins in the pulmonary alveoli. Methods: Protein permeability and the expression of TJ proteins were assessed in vivo in wild-type and Fas-deficient lpr mice 16 hours after the intratracheal instillation of recombinant human soluble Fas ligand (rh-sFasL), and at different time points in vitro in human pulmonary alveolar epithelial cells (HPAEpiC) exposed to rh-sFasL Results:Activation of the Fas pathway increased protein permeability in mouse lungs and altered the expression of the TJ proteins occludin and zonula occludens-1 in the alveolar-capillary membrane in vivo and in human alveolar epithelial cell monolayers in vitro. Blockade of caspase-3, but not inhibition of tyrosine kinase dependent pathways, prevented the alterations in TJ protein expression and permeability induced by the Fas/FasL system in human alveolar cell monolayers in vitro. We also observed that both the Fas-induced increase of protein permeability and disruption of TJ proteins occurred before cell death could be detected in the cell monolayers in vitro. Conclusion:Targeting caspase pathways could prevent the disruption of TJs and reduce the formation of lung oedema in the early stages of ARDS.
机译：背景：急性呼吸窘迫综合征（ARDS）的特征在于肺泡空间中富含蛋白质的水肿，该特征在其中涉及肺泡上皮的Fas介导的凋亡。目的：判断FAS激活是否通过涉及肺肺泡中的肺细胞紧密结（TJ）蛋白的破坏的机制增加蛋白质渗透性。方法：在野生型和Fas缺陷的LPR小鼠中，在重组人可溶性Fas配体（RH-SFASL）的腹腔滴注后16小时，在野生型和Fas缺陷的LPR小鼠中评估蛋白质渗透性和TJ蛋白的表达，在体外的不同时间点暴露于RH-SFASL结果的人肺肺泡上皮细胞（HPAEPIC）：激活FAS途径增加了小鼠肺部的蛋白质渗透性，并改变了在体内肺泡 - 毛细血管膜中的TJ蛋白闭塞蛋白和Zonula occludens-1的表达。体外人肺泡上皮细胞单层。封闭胱天蛋白酶-3，但不能抑制酪氨酸激酶依赖性途径，防止了在体外人肺泡细胞单层中的Fas / FasL系统诱导的TJ蛋白表达和渗透性的改变。我们还观察到，在体外在细胞单层中检测到细胞死亡之前，可以在细胞死亡中发生Fas诱导的蛋白质渗透性和TJ蛋白的破坏。结论：靶向胱天蛋白酶途径可以防止TJ的破坏并减少ARDS早期阶段肺水肿的形成。

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