MEDIATORS OF ISCHEMIA-REPERFUSION INJURY OF RAT LUNG

In rats, we characterized the mediators of lung reperfusion injury aft er ischemia. Animals underwent left lung ischemia. After 90 minutes of ischemia, reperfusion for up to 4 hours was evaluated. Lung injury, a s determined by vascular leakage of serum albumin, increased in ischem ic-reperfused animals when compared with time-matched sham controls. I njury was biphasic, peaking at 30 minutes and 4 hours of reperfusion. The late but not the early phase of reperfusion injury is known to be neutrophil dependent. Bronchoalveolar lavage of ischemic-reperfused lu ngs at 30 minutes and 4 hours of reperfusion demonstrated increased pr esence of serum albumin, indicative of damage to the normal vascular/a irway barrier. Lung mRNA for rat monocyte chemoattractant protein-1 an d tumor necrosis factor-alpha peaked very early (between 0.5 and 1.0 h our) during the reperfusion process. Development of injury was associa ted with a decline in serum complement activity and progressive intrap ulmonary sequestration of neutrophils. Administration of superoxide di smutase before reperfusion resulted in reduction of injury at 30 minut es of reperfusion. Complement depletion decreased injury at both 30 mi nutes and 4 hours of reperfusion. Requirements for tumor necrosis fact or-alpha, interferon-gamma, and monocyte chemoattractant protein-1 for early injury were shown whereas only tumor necrosis factor-alpha was involved at 4 hours. We propose that acute (30-minute) lung injury is determined in large part by products of activated lung macrophages whe reas the delayed (4-hour) injury is mediated by products of activated and recruited neutrophils.