Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress role of bilirubin generated by the enzyme

This study aimed to examine whether an elevated activity of heme oxygenase (HO)-1 in the tissue attenuates endothelial cell-leukocyte interactions mic rovessels in vivo. When rats were pretreated with an intraperitoneal inject ion of hemin, an HO-1 inducer, mesenteric tissues, including their microves sels, displayed a marked induction of HO-1 concurrent with an increase in p lasma concentrations of bilirubin-IX alpha, the product of HO-catalyzed deg radation of protoheme IX. In these rats, oxidative stress such as superfusi on with H2O2 and ischemia-reperfusion of the tissues neither induced rollin g nor exhibited adherent responses of leukocytes in venules. In contrast, t he oxidative stresses evoked marked rolling and adhesion of leukocytes in t he control rats without HO-1 induction. The HO-1 induction also downregulat ed leukocyte adhesion elicited by other pro-oxidant stimuli such as N-omega -nitro-L-arginine methyl ester, The decreases in the oxidant-elicited leuko cyte adhesive responses under HO-1-inducing conditions were restored by per fusion with zinc protoporphyrin-IX, an HO inhibitor, but not with copper pr otoporphyrin-IX, which did not inhibit the enzyme. Furthermore, the effects of zinc protoporphyrin-M were repressed by superfusion with bilirubin or b iliverdin at the micromolar level, but not by the same concentration of car bon monoxide, another product of HO. These results indicate that induction of the HO-1 activity serves as a potential stratagem to prevent oxidant-ind uced microvascular leukocyte adhesion through the action of bilirubin, a pr oduct of HO reaction.