Vol. 281, Issue 3, 1264-1271, 1997

Platelet-Activating Factor Contributes to Immune Cell and Oxidant-Mediated Intestinal Secretion^1,2

Thomas A. Hinterleitner³ , John D. Valentich, Jih-Ho Cha, Peter Will, Ann Welton and Don W. Powell

Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (T.A.H., J.H.C., D.W.P.); Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas (J.D.V., D.W.P.); Hoffman-La Roche, Inc., Nutley, New Jersey (A.W.); and Pharmaceuticals Studies Program, Fairleigh Dickinson University, Teaneck, New Jersey (P.W.)

The sensitivity of the Ussing-chambered rat colon to stimulation of Cl secretion (as measured by the change in short-circuit current) by exogenous platelet-activating factor (PAF) was increased significantly by washing the colon in vitro with Ringer's solution containing fatty acid-free albumin. When the wash solution was extracted with chloroform/methanol and the lipid extract was added back to Ussing-chambered colons, inhibition of PAF-stimulated short-circuit current was observed, whereas short-circuit current responses to bradykinin or vasoactive intestinal peptide were not affected. Hypoxia appears to be an important trigger for the down-regulation of the PAF response. These data suggest that hypoxia releases PAF or an endogenous lipid PAF inhibitor that desensitizes PAF receptors on colonic epithelial or mucosal cells. The short-circuit current response of rabbit colon to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by any PAF antagonist devoid of cyclooxygenase inhibitory activity but was strongly inhibited by indomethacin. In contrast, anti-IgE- or H₂O₂-stimulated short-circuit current in rat colon was inhibited by specific PAF antagonists, and this inhibition was additive with indomethacin. Both anti-IgE and H₂O₂ significantly increased PAF production by rat colon. These data suggest that PAF plays an important role in oxidant (H₂O₂)- and anti-IgE-mediated colonic Cl secretion but not in Cl secretion mediated by formyl-methionyl-leucyl-phenylalanine-stimulated phagocytes.