Platelet-activating factor (PAF) up-regulates plasma and tissue PAF-acetylhydrolase activity in the rat: effect of cycloheximide.
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.
Wang
H
H
Department of Pathology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Tan
X D
XD
Qu
X W
XW
Chang
H
H
Remick
D G
DG
Gonzalez-Crussi
F
F
Hsueh
W
W
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D008297:Male; D009336:Necrosis; D010741:Phospholipases A / Q000097:blood*; D010972:Platelet Activating Factor / Q000502:physiology*; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
D010972:Platelet Activating Factor; D017382:Reactive Oxygen Species; D003513:Cycloheximide; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase