Role of nitric oxide and peroxynitrite in gut barrier failure
Role of nitric oxide and peroxynitrite in gut barrier failure
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DOI：
10.1007/s00268-002-4056-2
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发表时间：
2002-07-01
影响因子：
2.6
通讯作者：
Ford, HR
中科院分区：
文献类型：
--
作者：
Potoka, DA;Nadler, EP;Ford, HR
细菌易位（BT）可能是一个正常的生理过程，是重要的粘膜抗原采样在肠道。然而，生理性损伤如内毒素血症。失血性休克或坏死性小肠结肠炎（NEC）可能导致病理性BT，从而有助于医院感染的发病机制。其机制可能涉及肠绒毛顶端的肠上皮细胞凋亡加速，至少是短暂的。在绒毛尖端的“裸露区域”，细菌可以附着并穿过上皮。有证据表明，持续上调的诱导型一氧化氮合酶（NOS-2）共定位与肠细胞凋亡和免疫反应3-硝基酪氨酸。过氧亚硝酸盐（ONOO-）的足迹，它是一种由一氧化氮（NO）与超氧化物反应形成的强效氧化剂。我们认为绒毛顶端的裸露区域是由肠上皮细胞凋亡引起的，这些细胞从隐窝底部迁移到绒毛顶端并脱落到肠腔中。这些裸露的区域以及BT的程度可能是肠上皮细胞增殖和凋亡之间不平衡的结果。我们推测，正常的肠上皮细胞凋亡介导的半胱天冬酶级联反应，而肠上皮细胞的增殖和分化的隐窝可能是由酪氨酸激酶依赖的信号通路。NO及其代谢产物ONOO-的过量产生可能会影响这些细胞通路的浴。因此，在炎症状态下持续的NO产生和ONOO-形成可能不同地加速绒毛顶端的细胞凋亡和/或抑制隐窝基部的增殖，导致绒毛顶端的挤出区扩大和加速BT。
Bacterial translocation (BT) may be a normal physiologic process that is important for mucosal antigen sampling in the gut. However, physiologic insults such as endotoxemia. hemorrhagic shock. or necrotizing enterocolitis (NEC) may lead to pathologic BT and thus contribute to the pathogenesis of nosocomial infection. The mechanism may involve accelerated enterocyte apoptosis at the intestinal villus apex resulting, at least transiently. in a "bare area" at the villus tip where bacteria can attach and traverse the epithelium. Evidence suggests that sustained upregulation of the inducible isoform of nitric oxide synthase (NOS-2) co-localizes with enterocyte apoptosis and immunoreactivity to 3-nitrotyrosine. the footprint of peroxynitrite (ONOO-), a potent oxidant formed by the reaction of nitric oxide (NO) with superoxide. We propose that the bare area at the villus apex is caused by apoptosis of enterocytes that have migrated from the base of the crypts to the villus apex and are shed into the intestinal lumen. These bare areas, and thus the degree of BT, may be the result of an imbalance between enterocyte proliferation and apoptosis. We postulate that normal enterocyte apoptosis is mediated by the caspase cascade, whereas enterocyte proliferation and differentiation in the crypt may be regulated by tyrosine kinase-dependent signaling pathways. Bath of these cellular pathways may be influenced by overproduction of NO and its metabolite ONOO-. Therefore, sustained NO production and ONOO- formation occurring in inflammatory states may differentially accelerate apoptosis in the villas apex and/or inhibit proliferation at the base of the crypts resulting in expanded extrusion zones at the villus tip and accelerated BT.