Binge drinking disturbs hepatic microcirculation after transplantation: prevention with free radical scavengers.
Disturbances in hepatic microcirculation increase graft injury and failure; therefore, this study evaluates the effects of ethanol on microcirculation after liver transplantation. Donor rats were given one dose of ethanol (5 g/kg) by gavage 20 h before explantation, and grafts were stored in University of Wisconsin solution for 24 h before implantation. Acute ethanol treatment decreased 7-day survival of grafts from about 90 to 30%, increased transaminase release nearly 4-fold, and decreased bile production by 60%. Moreover, portal pressure increased significantly and liver surface oxygen tension decreased about 50%, indicating that ethanol disturbs hepatic microcirculation. Pimonidazole, a 2-nitroimidazole hypoxia marker, was given i.v. to recipients 30 min after implantation, and grafts were harvested 1 h later. Ethanol increased hepatic pimonidazole binding about 3-fold, indicating that ethanol led to hypoxia in fatty grafts. Ethanol also significantly increased free radicals in bile. Catechin (30 mg/kg i.v. upon reperfusion), a free radical scavenger, and Carolina Rinse solution, which contains several agents that inhibit free radical formation, minimized disturbances in microcirculation and prevented pimonidazole adduct formation significantly. These treatments also blunted increases in transaminase release and improved survival of fatty grafts. Destruction of Kupffer cells with GdCl(3) (20 mg/kg i.v. 24 h before explantation) or inhibition of formation of leukotrienes with MK-886 (50 microM in University of Wisconsin or rinse solution) also minimized hypoxia and improved survival after transplantation. Taken together, these results demonstrate that ethanol disturbs hepatic microcirculation, leading to graft hypoxia after transplantation, most likely by activating Kupffer cells and increasing free radical production.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, Research Triangle Park, North Carolina, USA.
Z
Z
Zhong
G E
GE
Arteel
H D
HD
Connor
P
P
Schemmer
S C
SC
Chou
J A
JA
Raleigh
R P
RP
Mason
J J
JJ
Lemasters
R G
RG
Thurman
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002392:Catechin / Q000494:pharmacology; D000431:Ethanol / Q000506:poisoning*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D005682:Gadolinium / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D000860:Hypoxia / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008102:Liver Circulation / Q000187:drug effects*; D008111:Liver Function Tests; D016031:Liver Transplantation; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D014280:Triglycerides / Q000378:metabolism
D016166:Free Radical Scavengers; D005609:Free Radicals; D014280:Triglycerides; D000431:Ethanol; D002392:Catechin; D005682:Gadolinium; D001219:Aspartate Aminotransferases; C038958:gadolinium chloride