Heme oxygenase‐1 serves as an important effector in the postischemic anti‐inflammatory phenotype induced by antecedent ethanol ingestion

Abstract

Since the catalytic products of heme oxygenase-1 (HO-1) activity exert powerful anti-adhesive and anti-oxidant properties, we postulated that ethanol (EtOH)-induced HO-1 expression serves as an effector of the postischemic anti-inflammatory effects of this preconditioning stimulus. EtOH was administered to C57BL/6 mice by gavage at a dose that produced a peak plasma concentration of 45 mg/dl 30 min after ingestion. I/R was induced 24 hr later followed by assessment of leukocyte- and platelet-endothelial interactions, HO-1 activity (bilirubin assay), and HO-1 expression (Western). I/R induced significant leukocyte and platelet adhesion, effects that were abolished by antecedent EtOH. Treatment with a HO-1 inhibitor (SnPP-IX) during I/R prevented the beneficial effects of EtOH-PC. Alternatively, upregulation of HO-1 with hemin mimicked the effects of antecedent EtOH. Although jejunal HO-1 expression was not increased 24 hr after EtOH consumption, HO-1 activity was increased during I/R. Pharmacologic inhibition studies indicated that EtOH-induced increases in HO-1 activity occur by an adenosine A2-receptor/eNOS-dependent mechanism. The latter results are confirmed in WT mice and in eNOS-/- mice. Taken together, our data indicate that HO-1 functions as an effector of EtOH-PC. Our work also suggests that a novel class of agents, HO-1 inducers, may represent a new avenue for therapeutic intervention in I/R. Supported by DK 43785.