OXIDANT STRESS AND CYTOKINES IN ENDOTOXIN INDUCED INJURY IN SHEEP

急性肺损伤，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，相关死亡率为0-60%。脓毒症综合征 是引起ARDS和革兰氏阴性细菌的最常见诱因 是败血症综合征最常见的病因。有毒的细胞壁 革兰氏阴性细菌的成分，内毒素，也称为 众所周知，脂多糖是急性肺损伤的有力触发因素。 目前对脓毒症所致肺损伤的治疗是支持性的，因为 病理生理机制是不确定的，实验治疗方法如 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内源性快速产生 衍生的炎症介质。其中一种炎性细胞因子， 肿瘤坏死因子α(TNFpha)刺激细胞释放 血管活性化合物，如内皮素和花生四烯酸 代谢产物血栓素和前列环素，并导致粘连和 中性粒细胞的激活。TNFa还通过以下方式显著改变氧化还原状态 促进活性氧化剂物种的精细化。大量数据 现在表明细胞内和细胞外的氧化还原发生了变化 脓毒症综合征和急性肺损伤期间的状态，即 产生过多的活性氧或无法解毒 细胞内活性氧的正常水平。中心是 调节氧化还原状态的是谷胱甘肽(GSH)和 谷胱甘肽氧化还原循环。在这一系列事件中，肿瘤坏死因子诱导的 中性粒细胞到内皮细胞表面和中性粒细胞的激活是关键 对于PMN衍生的氧化剂的产生，因此干预以阻断 TnFa的作用，阻断中性粒细胞黏附，增强谷胱甘肽 在内毒素诱导的致病机制研究中，防御措施是合理的 急性肺损伤，值得考虑作为潜在的人类治疗方法 如果这些研究被证明是成功的。

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.