OXIDANT STRESS AND CYTOKINES IN ENDOTOXIN INDUCED INJURY IN SHEEP

急性肺损伤，在其最极端的形式被称为成人 呼吸窘迫综合征（ARDS），影响超过15万人 每年发生一次，相关死亡率为0- 60%。 败血症综合征 是导致急性呼吸窘迫综合征和革兰氏阴性菌的最常见诱因 是脓毒症最常见的病因。 有毒细胞壁 革兰氏阴性细菌的成分，内毒素，也称为 已知脂多糖是急性肺损伤的有效触发剂。 目前脓毒症诱导的肺损伤的治疗是支持性的，因为 病理生理机制是不确定的， 作为内毒素抗体，纳洛酮和皮质类固醇没有改善 结果。 内毒素几乎没有直接毒性，但主要通过 导致单核细胞和巨噬细胞的快速内源性产生 衍生的炎症介质。 其中一种炎性细胞因子， 肿瘤坏死因子α（TNF α），刺激释放 血管活性化合物如内皮素和花生四烯酸 代谢物血栓素和前列环素，并引起粘附， 激活中性粒细胞。 TNFa还通过以下方式剧烈改变氧化还原状态： 促进活性氧化剂物质的加工。 实质数据 现在表明细胞内和细胞外的氧化还原 脓毒症综合征和急性肺损伤期间的状态，即，要么 过量产生活性氧或无法解毒 细胞内活性氧的正常水平。 的核心 氧化还原状态的调节是谷胱甘肽（GSH）和酶的氧化还原状态。 GSH氧化还原循环。 在这一系列的事件中，TNF诱导的粘附， 中性粒细胞粘附于内皮表面，中性粒细胞活化是关键 对于PMN衍生的氧化剂产生，因此干预阻断 TNF α的作用，阻断中性粒细胞粘附，并增加谷胱甘肽 防御是合理的，在调查LPS诱导的发病机制， 急性肺损伤，值得考虑作为潜在的人类治疗方法 如果这些研究成功的话。

Acute lung injury, in its most extreme form known as the Adult Respiratory Distress Syndrome (ARDS), affects more than 150,000 people annually and carries an associated mortality of 0-60%. Sepsis syndrome is the most common predisposing cause of ARDS and gram-negative bacteria are the most frequent etiology of sepsis syndrome. The toxic cell wall component of gram-negative bacterial, endotoxin, also known as lipopolysaccharide is known to be a potent trigger of acute lung injury. Current therapy for sepsis induced lung injury is supportive since the pathophysiologic mechanisms are uncertain and experimental therapies such as endotoxin antibodies, naloxone and corticosteroids have not improved outcome. Endotoxin has little direct toxicity but acts predominately by causing the rapid endogenous production of monocyte and macrophage derived inflammatory mediators. One of these inflammatory cytokines, tumor necrosis factor alpha (TNFalpha), stimulates the release of vasoactive compounds such as endothelin and the arachidonic acid metabolites thromboxane and prostacyclin, and causes adherence and activation of neutrophils. TNFa also acutely alters the redox state by promoting the elaboration of reactive oxidant species. Substantial data now indicate there are alterations of intra- and extracellular redox state during sepsis syndrome and acute lung injury, i.e., either excessive production of reactive oxygen species or inability to detoxify normal levels of intracellular reactive oxygen species. Central to the regulation of the redox state is glutathione (GSH) and the enzymes of the GSH redox cycle. In this chain of events, TNF-induced adherence of neutrophils to endothelial surfaces and neutrophil activation is critical for PMN derived oxidant generation and hence interventions to block TNFa's action, block neutrophil adherence, and augment glutathione defenses are rational in investigating the pathogenesis of LPS-induced acute lung injury and deserve consideration as potential human treatments if these studies prove successful.