EFFECT OF A PLATELET-ACTIVATING-FACTOR ANTAGONIST ON PANCREATITIS-ASSOCIATED GUT BARRIER DYSFUNCTION IN RATS

Platelet-activating factor (PAF) may play a critical and primary role in the pathogenesis of acute pancreatitis and pancreatitis-associated distant organ injury. The present study evaluated the effect of a PAF antagonist, lexipafant (an idin-1-ylmethyl)-benzenesulphonyl]-amino}pe ntanoic acid ethyl ester, BB-882; British Biotech Ltd.), on the potent ial prevention of gut barrier dysfunction, by measuring gut origin sep sis, bidirectional permeability of the intestinal barrier, and pancrea tic capillary endothelial barrier integrity, in acute pancreatitis ind uced by intraductal infusion of 5% sodium taurodeoxycholate. Pancreati c endothelial permeability significantly increased in animals with acu te pancreatitis, whereas pretreatment with lexipafant had a preventive effect (p < 0.05 vs. pancreatitis with saline). Similarly, alteration s noted in hematocrit and plasma levels of lipase and calcium were cou nteracted by the PAF antagonist. It also prevented the increase in alb umin leakage from blood to the mucosal interstitium and from blood to the intestinal lumen in acute pancreatitis. Albumin passage from the g ut lumen to blood in animals with pancreatitis pretreated with saline increased from 3 h and on, and lexipafant prevented alterations in muc osal epithelial permeability. Bacterial translocation was commonly see n in pancreatitis, whereas only a few positive cultures were observed in pancreatitis animals given lexipafant. Microthrombosis in intestina l villi seemed less frequent after lexipafant pretreatment. We conclud e that (a) PAF may play a role in the pathogenesis of pancreatitis-ass ociated intestional dysfunction, (b) PAF may be involved in the develo pment of distant organ dysfunction by triggering endothelial barrier d ysfunction, and (c) PAF antagonists may provide potential agents for p reventing pancreatitis-associated gut barrier dysfunction.