Survival of TNF toxicity: Dependence on caspases and NO
Survival of TNF toxicity: Dependence on caspases and NO
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DOI：
10.1016/j.abb.2007.01.021
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发表时间：
2007-06-15
影响因子：
3.9
通讯作者：
Brouckaert, Peter
中科院分区：
文献类型：
--
作者：
Cauwels, Anje;Brouckaert, Peter
肿瘤坏死因子是一种内源性促炎细胞因子，与类风湿性关节炎和感染性休克等病理过程有关。它最初是作为一种具有非凡抗肿瘤活性的因子被发现的，但它的休克诱导特性仍然阻止了它在癌症中的全身应用。临床试验显示，低血压是肿瘤坏死因子毒性的主要剂量限制因素。当给小鼠注射肿瘤坏死因子时，会引发一种致命的休克综合征，其中心血管衰竭是由一氧化氮(NO)集中指挥的。然而，在动物模型和感染性休克患者中抑制一氧化氮合酶(NOS)并不能改善甚至加重预后，提示NO具有二价作用。在败血症、内毒素血症或肿瘤坏死因子治疗的动物中，以及在败血症患者中，已经描述了淋巴细胞和肠道细胞的凋亡。在这篇综述中，我们描述了我们最近关于NO和caspase在肿瘤坏死因子诱导的小鼠休克中的作用的研究。综上所述，我们发现在肿瘤坏死因子休克过程中，NO和caspase都可能发挥着意想不到的双重作用。虽然过量的NO产生会导致致命的低血压，但它也具有重要的抗氧化功能，保护器官免受氧化应激和脂质过氧化的影响。此外，我们的结果还表明，caspase也可能在氧化应激中发挥重要的内源性负反馈作用。(C)2007 Elsevier Inc.保留所有权利。
Tumor necrosis factor (TNF) is an endogenous pro-inflammatory cytokine, implicated in pathologies such as rheumatoid arthritis and septic shock. It was originally discovered as a factor with extraordinary antitumor activity, but its shock-inducing properties still prevent its systemic use in cancer. Clinical trials revealed hypotension as the major dose-limiting factor of TNF toxicity. When administered to mice, TNF provokes a lethal shock syndrome, where cardiovascular collapse is centrally orchestrated by nitric oxide (NO). Nevertheless, NO synthase (NOS) inhibition in animal models and septic shock patients could not improve and even aggravated outcome, suggesting a bivalent role for NO. Lymphocyte and enterocyte apoptosis has been described in septic, endotoxemic, or TNF-treated animals, as well as in septic patients. In this review, we describe our recent studies on the role of NO and caspases in TNF-induced shock in mice. In summary, we have found that both NO and caspases may exert unexpected and dual functions during TNF shock. Whereas excessive NO production provokes lethal hypotension, it also has an important anti-oxidant function, protecting organs from oxidative stress and lipid peroxidation. In addition, our results also indicate that caspases may exert an important endogenous negative feedback on oxidative stress as well. (C) 2007 Elsevier Inc. All rights reserved.