REACTIVE OXIDANTS MEDIATE TNF-ALPHA-INDUCED LEUKOCYTE ADHESION TO RATMESENTERIC VENULAR ENDOTHELIUM

We investigated the role of reactive oxygen metabolites (ROMs) as pote ntial mediators of tumor necrosis factor-alpha (TNF-alpha)-stimulated neutrophil adhesion to rat mesenteric venules in vivo, using intravita l microscopy and fixed whole mount preparations of mesentery. Intraper itoneal injection of TNF-alpha significantly increased leukocyte rolli ng, adhesion, and emigration in a dose- and time-dependent manner. Leu kocyte adhesion and emigration, but not rolling, were significantly at tenuated by prior intravenous administration of monoclonal anti-interc ellular adhesion molecule-1 (ICAM-1). Rolling leukocyte flux was signi ficantly attenuated by intravenous preadministration of superoxide dis mutase (SOD), catalase, or both. Only catalase or SOD plus catalase si gnificantly inhibited leukocyte adhesion. Catalase alone inhibited emi gration. Moreover, postadhesive treatment with catalase but not SOD, 4 h after TNF-alpha administration reduced the flux of rolling (but not adherent) leukocytes that had previously increased in response to TNF -alpha. Intragastric allopurinol (50 mg/kg at 3 and 18 h before TNF-al pha administration) or 3 wk of a tungsten-enriched diet substantially inhibited xanthine oxidase activity but had no significant effects on the above parameters of neutrophil dynamics. In parallel experiments u sing fixed whole mount preparations of the mesoappendix stained specif ically for neutrophil esterase, neutrophil adhesion 2 h after TNF-alph a administration was also inhibited by continuous intravenous administ ration of catalase but not by SOD, intragastric allopurinol, or tungst en diet. These findings suggest that ROMs, apparently not from xanthin e oxidase, are important mediators of TNF-alpha-induced upregulation o f neutrophil adhesion in rat mesenteric venules.