PLATELET-ACTIVATING FACTOR-INDUCED MUCOSAL DYSFUNCTION - ROLE OF OXIDANTS AND GRANULOCYTES

We tested the possibility that platelet-activating factor (PAF) exerts some of its actions on the microvascular and mucosal membranes by stimulating the production of reactive O2 metabolites. Two series of experiments were performed using autoperfused segments of cat ileum pretreated with human recombinant superoxide dismutase (hSOD), catalase (H2O2 scavenger), or deferoxamine (an iron chelator). In the first series, we examined the effects of PAF infusion on mucosal permeability (blood-to-lumen clearance) to Cr-51-EDTA. PAF induced a 4-, 25-, and 20-fold increase in Cr-51-EDTA clearance at 4, 20, and 40 ng/min, respectively, and the increase was positively correlated with luminal fluid flux. hSOD, catalase, and deferoxamine reduced the Cr-51-EDTA clearance at each PAF dose and eliminated the dependence of Cr-51-EDTA clearance on transmucosal fluid flux. To determine whether mucosal granulocytes were the source of the reactive O2 metabolites, the mucosa was depleted of myeloperoxidase-positive cells using an antibody against the leukocyte integrin CD11/CD18. Mucosal granulocyte depletion resulted in a greatly reduced clearance of Cr-51-EDTA, suggesting that resident granulocytes may be the source of the reactive O2 metabolites. In a second series of studies, we examined the influence of hSOD, catalase, and deferoxamine on the increased trans-capillary fluid and protein fluxes induced by intra-arterial PAF infusion. These agents attenuated the enhanced transvascular fluid and protein filtration by > 50% at the low dose but had no effect at the higher doses. We conclude that the PAF-induced increase in mucosal permeability to Cr-51-EDTA is mediated by reactive O2 metabolites produced by resident phagocytic cells. The increase in mucosal permeability can be attenuated by hSOD, catalase, or deferoxamine independent of changes in the transmucosal fluid flux. Reactive O2 metabolites contribute to the vascular fluid and protein leakage induced by low, but not by high, doses of PAF.