OXIDANT STRESS AND CYTOKINES IN ENDOTOXIN INDUCED INJURY IN SHEEP

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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.