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Acute lung injury characterized by increased microvascular permeability Is one feature of multiple-organ system failure and the adult respiratory distress syndrome. Intestinal ischemia–reperfusion injury has been linked to this type of acute lung injury. The purpose of these experiments was to examine the pathogenic mediators that link the two processes, with particular emphasis on the roles of endotoxln and tumor necrosis factor α (TNFα). Previously described characteristics of the acute lung Injury in this rat model of Intestinal ischemia-reperfusion include pulmonary neutrophil sequestration, depletion of lung tissue ATP, alveolar endotnelial cell disruption, and increased microvascular permeability. Plasma levels of TNF In the systemic circulation of sham-operated animals and those with intestinal ischemlc injury less than 60 minutes In duration were very low or undetectable. Intestinal ischemia for 120 minutes was associated with TNF elevation to 1.19 ± 0.50 U/mL. Reperfusion for periods of 15 and 30 minutes generated 5− to 10-fold Increases In circulating TNF levels (6.61 ± 3.11 U/mL, p > 0.05 and 10.41 ± 5.41 U/mL, p.= 0.004 compared to sham); however this increase in circulating TNF was transient and largely cleared within 60 minutes after Initiating reperfusion. Portal vein endotoxln levels were found to increase significantly before the appearance of TNF in systemic plasma, suggesting that gut-derived endotoxin may Induce TNF release from hepatic macrophages into the systemic circulation. Antl-TNF antibody attenuated the increase in pulmonary microvascular permeability In this preparation but did not prevent pulmonary, neutrophil sequestration. These observations suggest that endotoxin and TNF have pathogenic roles in this acute lung Injury, but that mechanisms of adherence of neutrophils to endotnelial cells Independent of TNF may be Involved. The accumulation of neutrophils in the lung but the prevention of a vascular permeability increase in the presence of antibody to TNF may imply an in vivo role for TNF in the process of neutrophil activation. These studies provide additional evidence of the Importance of the endogenous inflammatory mediators in the development of systemic injury in response to local tissue Injury.