EFFECTS OF THE ARACHIDONATE 5-LIPOXYGENASE SYNTHESIS INHIBITOR A-64077 IN INTESTINAL ISCHEMIA-REPERFUSION INJURY

This study was designed to characterize the role of arachidonate 5-lip oxygenase metabolism during experimental intestinal ischemia-reperfusi on (I/R) injury. Canines were subjected to 3 hr of intestinal ischemia followed by 1 hr of normobaric reperfusion. Intestinal mucosal leukot riene B-4 and leukotriene C-4 synthesis tripled after ischemia and isc hemia-reperfusion, relative to nonischemic intestinal mucosa. The flux of fluid and protein from the capillary to the lumen also increased 3 -fold after I/R. The selective 5-lipoxygenase synthesis inhibitor A-64 077 (Ziluten, 5 mg/kg, p.o.) abolished I/R-induced leukotriene synthes is and reduced transluminal protein flux (50%) but did not influence t he lumenal accumulation of fluid after I/R. In animals treated with th e leukotriene synthesis inhibitor, intestinal vascular resistance sign ificantly declined during the imposed ischemia period and after 60 min of reperfusion. Mucosal myeloperoxidase activity, a biochemical marke r for tissue neutrophils, rose significantly after I/R, and these incr eases were prevented with the 5-lipoxygenase synthesis inhibitor. In o ther experiments, the lipoxygenase inhibitor nondihydroguaretic acid p roduced similar results to those of A64077. In an attempt to determine the source of mucosal leukotrienes during intestinal I/R, we imposed in vitro ischemia and reperfusion on normal mucosal tissue in a blood- free environment. Mucosal tissue was incubated in Krebs buffer under o xygen for 3 hr to simulate the control condition, under nitrogen for 3 hr to simulate ischemia and under nitrogen for 2 hr followed by oxyge n for 1 hr to simulate I/R. These experiments indicate that in vitro i schemia and I/R in a blood-free system result in enhanced leukotriene synthesis by intestinal mucosa of the same magnitude that was measured in the in vivo I/R experiments. Tissue myeloperoxidase activity in th is in vitro setting was not altered by ischemia and reperfusion. In co nclusion, this investigation suggests that aberrant arachidonate 5-lip oxygenase metabolism in ischemic intestinal tissue contributes to the microvascular/mucosal epithelial barrier dysfunction, vasoconstriction and polymorphonuclear infiltration that characteristically occur afte r reperfusion. The 5-lipoxygenase metabolites may be derived from the intestinal parenchyma and not solely from circulating cellular element s at reperfusion.