Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability
Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability
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DOI：
10.1152/ajplung.00350.2007
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发表时间：
2008-04-01
影响因子：
4.9
通讯作者：
Catravas, John D.
中科院分区：
文献类型：
--
作者：
Chatterjee, Anuran;Snead, Connie;Catravas, John D.
内皮通透性增高导致血管渗漏是脓毒症及其所致肺损伤的重要后果。我们之前曾报道，热休克蛋白(HSP)90抑制剂预处理可改善脓毒症所致肺损伤小鼠的肺屏障功能障碍。我们现在研究HSP90抑制剂对内毒素介导的内皮高通透性的影响，这反映在牛肺动脉内皮细胞(BPAEC)跨内皮电阻(TER)的变化上。经内毒素处理的细胞TER、pp60(Src)活性、粘着斑蛋白Paxlin的磷酸化程度呈浓度依赖性下降，黏附连接蛋白、血管内皮细胞钙粘附素和β-连环素的表达减少。HSP90抑制剂自由基酚可阻止TER的下降，维持VE-钙粘蛋白和β-连环素的表达，抑制pp60Src的激活和Paxlin的磷酸化。同样，当内毒素激活的中性粒细胞诱导BPAEC高通透性时，中性粒细胞和/或内皮细胞用自由基预处理可对抗激活的中性粒细胞诱导的TER下降。腹腔注射内毒素12h后，小鼠肺组织中Paxlin磷酸化水平升高，β-连环素和VE-钙粘附素表达降低，而预先注射自由基的小鼠肺组织中β-连环素和VE-钙粘附素的表达减弱。这些结果表明，HSP90在脓毒症相关的内皮屏障功能障碍中起重要作用。
Endothelial hyperpermeability leading to vascular leak is an important consequence of sepsis and sepsis-induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis-induced lung injury. We now examine the effects of hsp90 inhibitors on LPS-mediated endothelial hyperpermeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary arterial endothelial cells (BPAEC). Vehicle-pretreated cells exposed to endotoxin exhibited a concentration-dependent decrease in TER, activation of pp60(Src), phosphorylation of the focal adhesion protein paxillin, and reduced expression of the adherens junction proteins, vascular endothelial (VE)-cadherin and beta-catenin. Pretreatment with the hsp90 inhibitor, radicicol, prevented the decrease in TER, maintained VE-cadherin and beta-catenin expression, and inhibited activation of pp60Src and phosphorylation of paxillin. Similarly, when BPAEC hyperpermeability was induced by endotoxin-activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil-induced decrease in TER. Increased paxillin phosphorylation and decreased expression of beta-catenin and VE-cadherin were also observed in mouse lungs 12 h after intraperitoneal endotoxin and attenuated in mice pretreated with radicicol. These results suggest that hsp90 plays an important role in sepsis-associated endothelial barrier dysfunction.