PLATELET-ACTIVATING-FACTOR - THE EFFECTOR OF PROTEIN-RICH PLASMA EXTRAVASATION AND NITRIC-OXIDE SYNTHASE INDUCTION IN RAT IMMUNE-COMPLEX PERITONITIS

1 The involvement of platelet-activating factor (PAF) in immune comple x-induced/polymorphonuclear-mediated tissue injury was studied by use of a reverse passive Arthus (RPA) model in the peritoneal cavity of ra ts. 2 Extravasation of protein-rich plasma, accumulation of polymorpho nuclear leukocytes (PMN), and the production of nitric oxide (NO) by r esident peritoneal mononuclear phagocytes were assayed. 3 Treatment of rats with either UR-12460 or BE-823, two compounds which possess diff erent chemical structures, but elicit the same antagonistic effect on the PAF receptor, abrogated protein-rich plasma extravasation. In cont rast, they did not show any effect on the accumulation of PMN. 4 Inhib ition of NO production with both N-G-mono methyl-L-arginine and N-G-ni tro-L-arginine failed to prevent protein-rich plasma extravasation. 5 The production of NO by peritoneal adherent cells following RPA was me asured in cells maintained for 2 to 28 h in culture, and it was signif icantly increased in cells removed as early as 15 min after RPA induct ion, as compared to controls. 6 Addition of 10 nM PAF to the culture m edium reduced the generation of NO by peritoneal cells from RPA rats, whereas this mediator enhanced NO production in cells from naive contr ol animals. 7 Treatment with either UR-12460 or BE-823 prior to the in duction of RPA produced an almost complete inhibition of NO production . 8 Assay of nitric oxide synthase activity in cell homogenates from p eritoneal cells showed that the activity was due to the inducible form of the enzyme. 9 Study by Northen blotting of mRNA coding for the ind ucible NO synthase (iNOS) showed transcription at 6 and 18 h after the induction of RPA, which was inhibited in UR-12460-treated rats. 1 10 These data indicate that PAF is the main mediator of the early plasma leakage observed in RPA, and also that PAF is implicated in the trigge ring of long-term changes via induction of specific genes, as judged f rom its ability to promote the expression of iNOS.