Endotoxin and hypoxia-induced intestinal necrosis in rats: the role of platelet activating factor.
We have previously shown that intravascular platelet activating factor (PAF) causes ischemic bowel necrosis in rats morphologically similar to neonatal necrotizing enterocolitis (NEC). Because endotoxin (LPS) and hypoxia are risk factors for NEC, we studied their effect on PAF metabolism and the development of intestinal injury. Young male Sprague-Dawley rats were anesthetized with pentobarbital and divided into six experimental groups: 1) control, 2) LPS alone (2 mg/kg), 3) hypoxia alone (5% O2), 4) LPS+hypoxia, 5) WEB 2086 (PAF antagonist)+LPS+hypoxia, and 6) SRI 63-441 (PAF antagonist)+LPS+hypoxia. Evaluations included blood pressure recording, superior mesenteric artery blood flow, arterial blood gas, white blood cell count, hematocrit, plasma PAF, plasma acetylhydrolase, plasma tumor necrosis factor, intestinal perfusion, and intestinal injury at 3 h. We found that LPS+hypoxia synergistically contributed to hypotension (mean blood pressure 27 +/- 5.6% baseline versus 101 +/- 3.9% control), metabolic acidosis (pH 7.05, base deficit 24 mEq/L), hemoconcentration, decreased superior mesenteric artery blood flow (2.2 +/- 0.3 mL/min versus 5.8 +/- 0.2 mL/min control), and intestinal injury. The morbidities resulting from LPS+hypoxia were partially or completely prevented by PAF antagonists. In addition, animals treated with LPS+hypoxia had neutropenia, elevated plasma acetylhydrolase, and elevated plasma TNF. These results suggest that endogenous PAF may contribute to LPS+hypoxia-induced intestinal hypoperfusion and necrosis.
Caplan
M S
MS
Department of Pediatrics, Evanston Hospital, Illinois 60201.
Kelly
A
A
Hsueh
W
W
D000818:Animals; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000097:blood / Q000209:etiology* / Q000473:pathology; D000860:Hypoxia / Q000097:blood / Q000473:pathology; D007422:Intestines / Q000098:blood supply / Q000293:injuries / Q000473:pathology*; D008070:Lipopolysaccharides; D008297:Male; D010972:Platelet Activating Factor / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains
D008070:Lipopolysaccharides; D010972:Platelet Activating Factor