Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation
Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation
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DOI：
10.1084/jem.186.11.1831
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发表时间：
1997-12-01
影响因子：
15.3
通讯作者：
Kolesnick, R
中科院分区：
文献类型：
--
作者：
HaimovitzFriedman, A;CordonCardo, C;Kolesnick, R
内毒素休克综合征的特征是全身炎症、多器官损害、循环衰竭和死亡。全身释放肿瘤坏死因子和其他细胞因子被认为是这一过程的中介。然而，主要的组织靶点仍未确定。目前的研究提供了内毒素休克是播散性内皮细胞凋亡的证据。C57BL/6小鼠注射脂多糖(LPS)及其可能的效应因子TNF-α，6h后可诱导肠、肺、脂肪和胸腺内皮细胞发生凋亡，导致非内皮组织损伤。注射脂多糖或肿瘤坏死因子-α后1h内，组织产生促凋亡的脂质神经酰胺。肿瘤坏死因子结合蛋白可以阻止内毒素诱导的死亡，阻止内毒素诱导的神经酰胺生成和内皮细胞凋亡，这表明全身肿瘤坏死因子是这两种反应所必需的。酸性鞘磷脂酶基因敲除的小鼠表现出正常的血清肿瘤坏死因子-α的增加，以响应内毒素，但保护内皮细胞凋亡和动物死亡，明确了神经酰胺在介导内毒素反应中的作用。此外，静脉注射碱性成纤维细胞生长因子作为内皮细胞的血管内存活因子，可阻止内毒素诱导的神经酰胺升高、内皮细胞凋亡和动物死亡，但不影响内毒素诱导的血清肿瘤坏死因子-α的升高。这些研究表明，内毒素诱导了一种弥漫性的内皮细胞凋亡，由肿瘤坏死因子和神经酰胺的产生依次介导，并提示这一级联反应在内毒素综合征的演变中是强制性的。
The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death. Systemic release of tumor necrosis factor (TNF)-alpha and other cytokines purportedly mediates this process. However, the primary tissue target remains unidentified. The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis. Injection of lipopolysaccharide (LPS), and its putative effector TNF-alpha, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage. LPS or TNF-alpha injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide. TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses. Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-alpha in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response. Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha. These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.