Protective role of nitric oxide in the TNFα-mediated hepatic microvascular inflammatory response following acute ethanol ingestion

Abstract

Gut-drived endotoxin is thought to be involved in the pathogenesis of alcoholic liver disease. Nitric oxide (NO) has a protective function in attenuating hepatic injury elicited by endotoxin and is suspected to play a role in the hepatic microvascular responses induced following alcohol ingestion. As a result, the role of NO and the possible involvement of TNFα in these hepatic microcirculatory responses were investigated in mice using established in vivo microscopic methods. The livers were examined 3 h after acute ethanol (1 g/kg b.w.) ingestion alone or in combined with inhibition of NO synthesis by intravenous N G-monomethyl- l-arginine (L-NMMA) injection. Portal venous blood pressure and ethanol concentrations also were measured. Acute ethanol ingestion alone elicited 2-fold increase in leukocyte adherence (WBC) to the sinusoid lining but without alteration in blood flow when compared with maltose-dextrin treated controls. In contrast, in mice treated with the combination of L-NMMA and ethanol, WBC was increased an additional 3-fold above animals treated with ethanol alone. This was accompanied by a significant reduction in sinusoidal blood flow, no significant changes in portal blood pressure or concentrations of ethanol. Simultaneous administration of l-arginine eliminated these microcirculatory disturbances. Pretreatment with anti-mouse TNFα serum neutralized the microvascular responses elicited by the combined treatment of ethanol and L-NMMA. The results demonstrate that inhibition of NO production leads to hepatic microcirculatory dysfunction in response to a small dose of acute ethanol ingestion which by itself is scarcely stimulatory and that anti-TNFα neutralizes these responses. Thus, the results suggest that NO plays a significant role in stabilizing the TNFα mediated hepatic microvascular inflammatory responses elicited following acute ethanol ingestion.