Journal of Gastroenterology and Hepatology (2000) 15 (Suppl.) D20–D25 the idea that Kupffer cells of patients with alcoholic liver disease are activated, because TNF-a is produced exclusively by the monocyte–macrophage lineage, which is mostly made up of Kupffer cells. 4 Third, Kupffer cells, which contain Ca 2+ channels, 5 are acti- vated by Ca 2+ , 6 and chronic ethanol treatment makes Ca 2+ channels in Kupffer cells easier to open. 7 It has recently been demonstrated that the calcium channel blocker nimodipine reduced the amount of alcohol- induced liver damage in the Tsukamoto–French model, suggesting that calcium channels play an important role in Kupffer cell activation. 8 Collectively, these observa- KUPFFER CELLS ARE INVOLVED IN ALCOHOL-INDUCED LIVER INJURY Several observations support the hypothesis that Kupffer cells are involved in liver injury caused by alcohol. First, alcohol has been reported to affect Kupffer cell functions, such as phagocytosis and cytokine production, 1,2 Second, the increased serum tumour necrosis factor-a (TNF-a) concentrations in alcoholics reported by Stahnke et al. 3 are consistent with HEPATOLOGY: MICROCIRCULATION AND PATHOGENESIS OF ALCOHOLIC LIVER INJURY Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury 1 NOBUYUKI ENOMOTO,* † KENICHI IKEJIMA,* † BLAIR U BRADFORD,* CHANTAL A RIVERA,* HIROSHI KONO,* MORITAKA GOTO,* SHUNHEI YAMASHINA,* PETER SCHEMMER,* TSUNEO KITAMURA, † HIROSUMI OIDE, † YOSHIYUKI TAKEI, † MIYOKO HIROSE, † HIDETAKE SHIMIZU, † AKIHISA MIYAZAKI, † DAVID A BRENNER, ‡ NOBUHIRO SATO † AND RONALD G THURMAN* *Laboratory of Hepatobiology and Toxicology, Department of Pharmacology and ‡ Division of Digestive Disease and Nutrition, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA and † Department of Gastroenterology, Juntendo University, Bunkyo-ku,Tokyo, Japan Abstract The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially been characterized. For example, it is known that chronic ethanol ingestion increases hepatotoxicity and produces fatty liver, hepatitis and cirrhosis. However, acute ethanol consumption reduces endotoxin hepatotoxicity. It now appears that Kupffer cells participate in several aspects of these phenomena. Previously, most studies on the effects of alcohol on liver function have focused chiefly on the hepatocyte. Recently, attention has been directed towards the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxins (lipopolysac- charides) via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol-induced liver injury. Here we will review new evidence for the pro- posal that Kupffer cells and endotoxins play a pivotal role in hepatotoxicity following alcohol exposure, based on studies using the continuous intragastric enteral feeding model developed by Tsukamoto and French and an acute model developed by us. © 2000 Blackwell Science Asia Pty Ltd Key words: CD14, intracellular calcium, lipopolysaccharide, tumour necrosis factor-a. Correspondence: Dr N Sato, Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-ku,Tokyo 113- 8421, Japan. Email: nsato@med.juntendo.ac.jp Accepted for publication 29 November 1999. 1 This study was performed in the Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina.