Endotoxin and Hypoxia-Induced Intestinal Necrosis in Rats: The Role of Platelet Activating Factor

Abstract

ABSTRACT. 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 mglkg), 3) hypoxia alone (5% 04, 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 f 5.6% baseline versus 101 f 3.9% control), metabolic acidosis (pH 7.05, base deficit 24 mEq/L), hemoconcentration, decreased superior mesenteric artery blood flow (2.2 f 0.3 mL/min versus 5.8 f 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. (Pediatr Res 31: 428-434,1992) Abbreviations PAF, platelet activating factor LPS, lipopolysaccharide, endotoxin WBC, white blood cell count TNF, tumor necrosis factor NEC, necrotizing enterocolitis SMA, superior mesenteric artery NEC is a common gastrointestinal disease of premature infants that has a high incidence of morbidity and mortality (1). Alto the development of the disease (2, 3). We have previously shown that intravascular administration of PAF (PAF-acether), an endogenous phospholipid inflammatory mediator, produces intestinal injury in an animal model (4). In addition, it is known that endotoxin (LPS)-induced shock and intestinal injury can be prevented by PAF receptor antagonists (5, 6). Because we have recently reported increased plasma PAF concentrations in newborns afflicted with NEC (7), it is possible that, in addition to causing experimental intestinal injury, PAF is an important endogenous mediator of the human disease.Additional factors related to PAF metabolism may play a role in the development of intestinal injury. PAF is rapidly degraded to the inactive metabolite lysoPAF by acetylhydrolase (8), a 43-kD acid-labile enzyme critical to PAF regulation. We have shown that serum acetylhydrolase is decreased in NEC patients compared with controls (7) and that newborn infants have lower acetylhydrolase activity than older children and adults (9). Because the majority of NEC cases occur in the neonatal period, suppressed PAF degradation may contribut...

Hematologic Abnormalities in Severe Neonatal Necrotizing Enterocolitis: 25 Years Later

“…Platelet activating factor (PAF) is implicated in the gastrointestinal pathology of NEC. [9][10][11][12] PAF is an inflammatory, phospholipid cytokine contributing to the bowel necrosis seen in experimental NEC. 9 Compared to adults, neonatal gastrointestinal tissue has a relatively greater capacity for producing PAF.…”

“…14,15 In rats, experimental NEC is prevented by concurrent administration of exogenous PAF-acetylhydrolase 11 or PAF receptor antagonists. 9,10 Although PAF universally stimulates platelet activation, no rat or human studies reported simultaneous PAF and peripheral platelet counts. However, experimental LPS administration to human volunteers results in a rapid fall in platelet counts.…”

A simple presurgical necrotizing enterocolitis-mortality scoring system

“…5 However, the value of CRP measurement for therapeutic decision making or assessment of prognosis remains uncertain. Other analyses that have been described in infants with NEC include procalcitonin, interleukins and platelet-activating factor, 6,7 but their clinical usefulness has not been established.…”

Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

“…[8][9][10][11][12] Although the hepatic effects of PAF are not completely understood, it has been documented that intravascular administration of PAF can induce an ischemic bowel necrosis similar to that observed in neonatal necrotizing enterocolitis and that PAF mediates the development of endotoxin-and hypoxiainduced intestinal necrosis in rats. [13][14][15] In contrast, recombinant PAF-AH prevented the development of ischemia-elicited necrosis of the duodenum, jejunum, and ileum after injection of PAF into rat descending aorta. 16,17 PAF and PAF-AH are implicated in the pathogenesis of liver and inflammatory bowel diseases in humans including patients with cirrhosis of the liver and Crohn' s disease.…”