Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2
Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2
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DOI：
10.1038/ni914
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发表时间：
2003-04-01
影响因子：
30.5
通讯作者：
Brouckaert, P
中科院分区：
文献类型：
--
作者：
Cauwels, A;Janssen, B;Brouckaert, P
失调的凋亡性细胞死亡导致许多病理状况，包括脓毒症，提示半胱天冬酶抑制以阻断凋亡可能具有有用的治疗应用。由于细胞因子肿瘤坏死因子（TNF，也称为TNF-α）是促凋亡和促炎症的，并参与脓毒性休克，我们测试了半胱天冬酶抑制是否会减轻TNF诱导的体内毒性。蛋白酶抑制剂zVAD-favor的一般半胱天冬酶抑制通过增强氧化应激和线粒体损伤而加剧TNF毒性，导致超急性血流动力学崩溃、肾衰竭和死亡。因此，TNF毒性的存活取决于半胱天冬酶依赖性过程。我们的研究结果表明，caspase独立的，ROS介导的途径在小鼠致死性TNF诱导的休克反应的病理生理相关性。此外，TNF毒性的存活似乎需要对过量活性氧（ROS）形成和磷脂酶A2活化的半胱天冬酶依赖性保护反馈。
Dysregulated apoptotic cell death contributes to many pathological conditions, including sepsis, prompting the suggestion that caspase inhibition to block apoptosis could have useful therapeutic applications. Because the cytokine tumor necrosis factor (TNF, also known as TNF-alpha) is both proapoptotic and pro-inflammatory and is involved in septic shock, we tested whether caspase inhibition would alleviate TNF-induced toxicity in vivo. General caspase inhibition by the protease inhibitor zVAD-fmk exacerbated TNF toxicity by enhancing oxidative stress and mitochondrial damage, resulting in hyperacute hemodynamic collapse, kidney failure and death. Thus, survival of TNF toxicity depends on caspase-dependent processes. Our results demonstrated the pathophysiological relevance of caspase-independent, ROS-mediated pathways in response to lethal TNF-induced shock in mice. In addition, survival of TNF toxicity seemed to require a caspase-dependent protective feedback on excessive reactive oxygen species (ROS) formation and phospholipase A2 activation.