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 51Cr-EDTA. PAF induced a 4-, 25-, and 20-fold increase in 51Cr-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 51Cr-EDTA clearance at each PAF dose and eliminated the dependence of 51Cr-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 51Cr-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 transcapillary fluid and protein fluxes induced by intra-arterial PAF infusion. These agents attenuated the enhanced transvascular fluid and protein filtration by greater than 50% at the low dose but had no effect at the higher doses. We conclude that the PAF-induced increase in mucosal permeability to 51Cr-EDTA is mediated by reactive O2 metabolites produced by resident phagocytic cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Kubes
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P
Department of Physiology, Louisiana State University Medical Center, Shreveport 71130.
Arfors
K E
KE
Granger
D N
DN
D000818:Animals; D002374:Catalase / Q000494:pharmacology*; D002415:Cats; D003676:Deferoxamine / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D007082:Ileum / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology*
D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D002374:Catalase; D009195:Peroxidase; D013482:Superoxide Dismutase; D003676:Deferoxamine