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 med iator implicated in necrotizing enterocolitis. Regulation of PAF acety lhydrolase (AH), the enzyme degrading PAF, is poorly understood. In th is study we found that administration of a dose of PAF (1.5 mu g/kg, i .v), which does not cause gross intestinal injury, increased plasma an d intestinal PAF-AH in the rat. Cycloheximide (CHX, 5 mg/kg, i.v.) red uced 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 P AF and CHX was ameliorated by posttreatment with WEB2170 (a PAF antago nist), indicating a role of endogenous PAF in mediating injury. Both W EB2170 and anti-TNF antibody reduced PAF-induced AH activity in intest inal 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 mainta in 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 inte stinal AH; the former probably mediating the intestinal injury by PAF; and 5) reactive oxygen species may mediate the injurious effect of PA F plus CHX, but do not contribute to the regulation of AH by PAF.