Platelet-activating factor (PAF) up-regulates plasma and tissue PAF-acetylhydrolase activity in the rat: effect of cycloheximide

Pediatr Res. 1997 Nov;42(5):597-603. doi: 10.1203/00006450-199711000-00008.

Abstract

Platelet-activating factor (PAF) is a proinflammatory phospholipid mediator implicated in necrotizing enterocolitis. Regulation of PAF-acetylhydrolase (AH), the enzyme degrading PAF, is poorly understood. In this study we found that administration of a dose of PAF (1.5 microg/kg, i.v.), which does not cause gross intestinal injury, increased plasma and intestinal PAF-AH in the rat. Cycloheximide (CHX, 5 mg/kg, i.v.) reduced the activity of plasma (but not intestinal tissue) AH in control, as well as in PAF-injected rats, and aggravated systemic inflammation and tissue injury in the latter. The intestinal necrosis induced by PAF and CHX was ameliorated by posttreatment with WEB2170 (a PAF antagonist), indicating a role of endogenous PAF in mediating injury. Both WEB2170 and anti-TNF antibody reduced PAF-induced AH activity in intestinal tissue, but not in the plasma. Allopurinol largely prevented the injury induced by PAF and CHX, but had no effect on the up-regulation of AH. We conclude: 1) de novo protein synthesis is required to maintain physiologic AH level in the plasma; 2) PAF up-regulates plasma and intestinal AH activity; 3) CHX enhances the injurious effect of PAF; 4) endogenous PAF and TNF also play a role in the up-regulation of intestinal AH; the former probably mediating the intestinal injury by PAF; and 5) reactive oxygen species may mediate the injurious effect of PAF plus CHX, but do not contribute to the regulation of AH by PAF.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Animals
  • Cycloheximide / pharmacology*
  • Intestinal Mucosa / metabolism*
  • Intestines / pathology
  • Male
  • Necrosis
  • Phospholipases A / blood*
  • Platelet Activating Factor / physiology*
  • Protein Biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Up-Regulation

Substances

  • Platelet Activating Factor
  • Reactive Oxygen Species
  • Cycloheximide
  • Phospholipases A
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase