Hypoxia causes ischemic bowel necrosis in rats: the role of platelet-activating factor (PAF-acether).
We have previously shown that injection of platelet-activating factor causes necrotizing enterocolitis in the rat and that platelet-activating factor is an endogenous mediator in lipopolysaccharide-induced bowel necrosis. Because hypoxia is a known predisposing factor for neonatal necrotizing enterocolitis, we investigated the effect of hypoxia on platelet-activating factor formation and intestinal necrosis. Young male Sprague-Dawley rats were made severely hypoxic by placing them in a 100% N2 chamber for 2 minutes; moderate hypoxia was accomplished using 10% O2 for 15 or 30 minutes. To evaluate the role of platelet-activating factor on intestinal perfusion and injury, two platelet-activating factor antagonists, SRI 63-441 and WEB 2086, were injected 10 minutes before the hypoxic exposure. We found that plasma platelet-activating factor levels were significantly elevated after 2 minutes of severe hypoxia (13.8 +/- 2.9 ng/mL vs. control 2.1 +/- 0.8 ng/mL) and after 30 minutes of moderate hypoxia (41.1 +/- 11.7 ng/mL). This increase in platelet-activating factor level was not caused by decreased degradation, because neither plasma nor intestinal platelet-activating factor acetylhydrolase was decreased in the hypoxic rats. (Intestinal acetylhydrolase activity was actually increased). Intestinal perfusion was markedly decreased at 30 minutes in hypoxic animals. In contrast, all platelet-activating factor antagonist-treated animals had normal intestinal perfusion. Histological examination of affected bowel from hypoxic animals showed early intestinal necrosis which was completely prevented by pretreatment with SRI 63-441 and WEB 2086. Because 30 minutes of hypoxia also resulted in metabolic acidosis, we further investigated if acidosis alone could induce platelet-activating factor release and bowel injury. We found that acidosis alone resulted in moderate increase of plasma platelet-activating factor but did not produce bowel injury. We conclude that platelet-activating factor plays a central role in mediating hypoxia-induced intestinal necrosis. Acidosis may enhance the effect of hypoxia on platelet-activating factor production.
Department of Pathology, Children's Memorial Hospital, Chicago, Illinois.
M S
MS
Caplan
X M
XM
Sun
W
W
Hsueh
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004761:Enterocolitis, Pseudomembranous / Q000209:etiology* / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D007421:Intestine, Small / Q000473:pathology; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011806:Quinolinium Compounds / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D010972:Platelet Activating Factor; D011806:Quinolinium Compounds; D014230:Triazoles; C050531:SRI 63-441; C052518:WEB 2086