Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability
Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability
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DOI：
10.2353/ajpath.2007.060583
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发表时间：
2007-03-01
影响因子：
6
通讯作者：
Popoff, Michel R.
中科院分区：
文献类型：
--
作者：
Geny, Blandine;Khun, Huot;Popoff, Michel R.
当腹腔注射到瑞士小鼠中时，索氏梭菌致命毒素再现了在自然感染后在人类和动物中观察到的致命中毒性休克综合征。该动物模型用于研究致死性毒素诱导的死亡机制。组织学和生物化学分析确定肺和心脏是致命毒素的优先靶器官。由于肺血管通透性增加导致胸腔内大量血液外渗，导致严重变化，如动物脱水、血细胞比容增加、缺氧，最终导致心肺衰竭。电镜观察表明，致死毒素引起的肺血管通透性增加是由于肺内皮细胞的改变所致。免疫组织化学分析表明，VE-钙粘蛋白，参与细胞间粘附连接的蛋白质，在肺内皮细胞中从膜重新分布到胞质溶胶。没有观察到可能参与中毒性休克综合征的致死性毒素诱导的炎症的主要体征。致死毒素的主要作用是小GTP酶的葡萄糖基化依赖性失活，特别是Rac，其参与肺中体内发生的肌动蛋白聚合，导致E-钙粘蛋白连接不稳定。我们得出的结论是，对致命毒素最敏感的细胞是肺血管内皮细胞，中毒后其粘附连接发生了改变。
When intraperitoneally injected into Swiss mice, clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication.