Improvement of normothermic rat liver ischemia/reperfusion by muramyl dipeptide

Normothermic ischemia and reperfusion (I/R) of the liver remains a major problem after liver surgery and transplantation. Activation of Kupffer cells (KCs) after normothermic I/R is responsible for a massive release of various monokines such as tumor necrosis factor alpha (TNF-alpha) and a decrease in phagocytic activity. Muramyl dipeptide (MDP) is an immunostimulant that increases phagocytic activity of KCs. The aim of this study was to demonstrate that MDP pretreatment might protect the liver against I/R injury by a modification of KC functions. Rats were divided into three groups: group 1, control, Ringer's lactate administration; group 2, MDP (N-acetyl-muramyl-d-alanyl-d-isoglutamine) treatment; group 3, sham-operated control animals. MDP (500 microg/250 g) was injected intravenously 5 min before the induction of 90 min ischemia. Survival rates were compared and serum activities of TNF-alpha, aspartate aminotransferase, and alanine aminotransferase were assessed in the blood collected from the suprahepatic vena cava. Histology of the liver and KC activity were assessed 6 and 9 h after the end of ischemia, respectively. MDP treatment significantly increased 7-day survival (86.6%) compared with nontreated rats (40%, P < 0.001). Serum activities of TNF-alpha and aminotransferases were significantly decreased after MDP treatment, whereas phagocytic capacity of KCs was partially restored. The extent of liver necrosis was decreased after MDP administration. A significant difference was observed for other histological parameters studied, except for steatosis. Our findings have demonstrated that MDP is able to protect the liver from ischemic insult by modulation of KC activity (TNF-alpha release and phagocytic capacity). Control of macrophage activity may offer a new strategy to reduce ischemic injury of the liver.