ROLE OF PLATELET-ACTIVATING-FACTOR IN ACUTE-PANCREATITIS INDUCED BY LIPOPOLYSACCHARIDES IN RABBITS

In the present study we demonstrated that a single injection of endoto xin (lipopolysaccharides, E. Coli 0111-B4) into the superior pancreati coduodenal artery of rabbits induced a dose-dependent acute necrotizin g pancreatitis. The lesions observed by light microscopy were signific ant for 10 mu g lipopolysaccharides and were maximal for 20 mu g. Afte r 24 h the main findings were edema, acinar cell vacuolisation, polymo rphonuclear neutrophil infiltration and tissue necrosis. The pancreati c lesions developed strictly in the area supplied by the artery inject ed with lipopolysaccharides, without significant intestinal involvemen t. Since platelet-activating factor -O-hexadecyl-2-acetyl-sn-glycero-3 -phosphocholine, PAF; 50-500 ng), a phospholipid mediator of endotoxin -induced inflammation and shock, was previously shown to cause an acut e necrotizing pancreatitis in rabbits, the role of PAF in the developm ent of acute pancreatitis induced by lipopolysaccharides was studied b y evaluating: (1) the synergism between doses of lipopolysaccharides ( 5-10 mu g), which produced a mild tissue injury, and doses of PAF (10 ng) not producing, per se, any significant injury, and (2) the effect of three structurally unrelated PAF receptor antagonists. The results obtained demonstrated that 10 ng of PAF significantly potentiated panc reatic tissue damage induced by 10 mu g of lipopolysaccharides. Moreov er, PAF receptor blockade resulted in complete prevention of the sever e pancreatitis caused by 20 mu g lipopolysaccharides with -furanyl]met hoxy-phosphinyl-oxy]ethyl]-quinolinium hydroxide, SRI 63675 and in a s ignificant reduction of the incidence and the extension of tissue inju ry with rbamoyloxy)-propyl-2-(3-thiazolio)-ethylphosphate, CV 3988 and 9-dihydro-1-methyl-8-(4-morpholinyl-carbonyl)-4H,7 H-cyclopentyl[4,5] thieno[3,2-f Pi 1,2,4]-triazolo-[4,3-alpha Pi 1,4]diazepine, WEB 2170. These observations suggest a crucial role of PAF in the pathogenesis of pancreatic tissue damage induced by lipopolysaccharides.