Perturbation of endothelial junction proteins by Staphylococcus aureus α-toxin:: inhibition of endothelial gap formation by adrenomedullin
Perturbation of endothelial junction proteins by Staphylococcus aureus α-toxin:: inhibition of endothelial gap formation by adrenomedullin
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DOI：
10.1007/s00418-006-0174-5
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发表时间：
2006-09-01
影响因子：
2.3
通讯作者：
Hippenstiel, Stefan
中科院分区：
文献类型：
--
作者：
Hocke, Andreas C.;Temmesfeld-Wollbrueck, Bettina;Hippenstiel, Stefan
内皮细胞高渗透性是炎症反应的标志，在严重感染中导致组织损伤。内皮细胞-细胞粘附的丧失导致细胞间隙的形成，允许细胞旁流体流动。虽然金黄色葡萄球菌α毒素对葡萄球菌病有重要作用，但其诱导内皮细胞高通透性的机制尚不清楚。本研究证明，在离体大鼠回肠灌注模型中，大量应用金黄色葡萄球菌α毒素后，内源性肽肾上腺髓质素（ADM）抑制了毛细血管内皮-钙粘蛋白（VE-cadherin）的停止。在体外，α毒素暴露诱导人培养的脐静脉内皮细胞VE-cadherin和occludin的免疫反应性丧失。同样，ADM阻断了细胞间α -毒素相关连接蛋白的消失。此外，α毒素应用后，环AMP升高可稳定内皮屏障功能。虽然内皮α毒素暴露后没有发现RhoA活化，但抑制Rho激酶和肌球蛋白轻链激酶可阻断VE-cadherin和occludin免疫反应性的丧失以及细胞间隙的形成。总之，内皮间免疫染色显示的内皮连接完整性稳定可能是稳定严重金黄色葡萄球菌感染内皮屏障功能的一种有趣方法。
Endothelial hyperpermeability is a hallmark of an inflammatory reaction and contributes to tissue damage in severe infections. Loss of endothelial cell-cell adhesion leads to intercellular gap formation allowing paracellular fluid flux. Although Staphylococcus aureus alpha-toxin significantly contributed to staphylococci disease, little is known about its mechanism of endothelial hyperpermeability induction. Here, we demonstrate that in a model of isolated perfused rat ileum discontinuation of capillary vascular-endothelial-cadherin (VE-cadherin) was observed after bolus application of S. aureus alpha-toxin being inhibited by the endogenous peptide adrenomedullin (ADM). In vitro, alpha-toxin exposure induced loss of immunoreactivity of VE-cadherin and occludin in human cultured umbilical vein endothelial cells. Likewise, ADM blocked alpha-toxin-related junctional protein disappearance from intercellular sites. Additionally, cyclic AMP elevation was shown to stabilize endothelial barrier function after alpha-toxin application. Although no RhoA activation was noted after endothelial alpha-toxin exposure, inhibition of Rho kinase and myosin light chain kinase blocked loss of immunoreactivity of VE-cadherin and occludin as well as intercellular gap formation. In summary, stabilization of endothelial junctional integrity as indicated by interendothelial immunostaining might be an interesting approach to stabilize endothelial barrier function in severe S. aureus infections.