Abstract
The gut and the neutrophil (PMN) have been emphasized to play mechanistic roles in the development of adult respiratory distress syndrome and multiple organ failure. Reactive oxygen metabolites and various lipid mediators have been implicated as key players in these pathophysiology. We have previously shown that gut ischemia/reperfusion (I/R) provokes neutrophil-mediated lung injury. We hypothesized in this study that gut I/R produces lung injury via a mechanism which involves xanthine oxidase (XO) and phospholipase A2 (PLA2). Methods: Sprague-Dawley rats were divided into five groups. 1) Normal rats, 2) I/R group: Rats were subjected to 45min of superior mesenteric artery (SMA) occlusion, 3) Sham-laparotomy group (Lap): Rats underwent the same procedures except SMA occlusion, 4) XO-inactivated I/R group (Tung+I/R): Rats were fed tungsten enriched, molybdenum depleted diet for three weeks to inactivate XO before SMA clamp, 5) PLA2-inactivated I/R group (Quin+I/R): Rats were pretreated with a PLA2 inhibitor, quinacrine (10mg/kg, IV), prior to the induction of gut Ischemia. Six hr after reperfusion, circulating PMN priming was determined by the difference in superoxide generation with and without the activating stimulus, N-formyl-Met-Leu-Phe (fMLP). Pulmonary PMN sequestration was quantitated by myeloperoxidase (MPO) activity, while lung endothelial permeability was assessed by 125I albumin lung/blood ratio. Results: Gut I/R markedly enhanced PMN superoxide production in the presence of fMLP, increased pulmonary MPO activities, and provoked 125I albumin lung leak. Although the Tung+I/R and Quin+I/R groups did not alter I/R-induced pulmonary MPO activities, these groups attenuated gut I/R-induced circulating PMN priming and abrogated gut I/R-induced lung injury. Conclusion: These data suggest that both XO and PLA2 activation are proximal steps in the pathogenesis of lung injury following splanchnic hypoperfusion.
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