Role of non-parenchymal liver cells in ischaemia-reperfusion liver injury: protective effects of muramyl dipeptide

Abstract

It has been suggested that non-parenchymal liver cells play a central role after ischaemia and reperfusion of the liver. Male Lewis rats were subjected to 90 min of warm liver ischaemia. Four groups were constituted: group 1, no treatment; group 2, muramyl dipeptide treatment, activation of Kupffer cells; group 3, dextran sulphate injection, Kupffer cell blockade; and group 4, gadolinium chloride administration, Kupffer cell blockade. Dextran sulphate (4 mg/100 g) and gadolinium chloride (GdCl2, 0.7 mg/100 g) were given intravenously on day 2. MDP was injected intravenously (500 mg/250 g) 24 h before and 10 min after the intervention. Mortality rates were assessed and serum transaminases, histology of the liver and Kupffer cell phagocytic activity were evaluated 6 h after the end of ischaemia. MDP treatment significantly (P < 0.001) reduced mortality (30%) in comparison with the non-treated group (60%). The mortality rate was significantly higher in the dextran sulphate-treated (80%) and gadolinium chloride-treated (90%) groups in comparison with group 1. A significant reduction in transaminase levels was observed after MDP treatment, while blockade of Kupffer cells resulted in higher serum transaminase levels. The extent of necrosis and congestion was improved by MDP administration, while disruption of the vascular and sinusoidal integrity of the liver and extensive areas of necrosis were observed in dextran sulphate and gadolinium chloride-treated rats. Sheep red blood cell 51Cr liver uptake was deeply depressed 6 h after the end of ischaemia in group 1 (10 +/- 1.2%/g tissue). MDP injection restored the Kupffer cell activity (30.6 +/- 3.22%/g tissue) while dextran sulphate and gadolinium chloride administration markedly decreased SRBC 51Cr liver uptake. Our findings demonstrate that MDP in able to protect the liver from ischaemic insult while blockade of Kupffer cells was deleterious in rats subjected to liver ischaemia.

Improvement of Normothermic Rat Liver Ischemia/Reperfusion by Muramyl Dipeptide

“…Several studies have shown that Kupffer cells in the cold-stored liver appear to be activated [3,5,6] and that inhibition of Kupffer cell function contributes to the prevention of reperfusion injury [5,27]. Pathomechanisms associated with warm I/R, as in our experimental model, seem to differ from those after cold I/R in liver transplantation, since increased phagocytic activity of KCs was reported after cold storage, transplantation, and reperfusion of rat liver [7], and since reduced phagocytic activity of Kupffer cells was reported after warm liver I/R [11][12][13][14]. Depression of the phagocytic activity of Kupffer cells may have important consequences for postischemic liver viability [13,15] and may contribute to systemic endotoxinemia and death [28,29].…”

“…In hypothermic I/R, activation of Kupffer cells is responsible for a massive release of monokines such as tumor necrosis factor ␣ (TNF-␣) and interleukin-1 (IL-1) [4,5] and an increase in phagocytic activity [6,7]. In normothermic I/R, several studies [8 -10] have demonstrated a massive release of TNF-␣, whereas phagocytic activity of KCs was decreased [11][12][13][14], which might contribute to systemic endotoxemia and death. Several studies have shown that modulation of macrophage activity may modify hepatic injuries after I/R [15,16].…”

“…Particularly the phagocytic activity of KCs was increased after MDP treatment [19,20]. This led us to hypothesize that treatment with MDP before normothermic liver I/R may improve animal survival after normothermic I/R modifying KC activation [11]. The aim of the present study was to demonstrate the protective role of MDP JOURNAL OF SURGICAL RESEARCH 80, 339 -344 (1998) on normothermic I/R and to clarify the effects of MDP on the different functions of KCs.…”

Protein Kinase Activation by Warm and Cold Hypoxia–Reoxygenation in Primary–Cultured Rat Hepatocytes-Jnk1/Sapk1 Involvement in Apoptosis

“…10,11,12,13 In addition, activated Kupffer cells may release eicosanoids and monokines (IL-1, IL-6, TNF-␣, TNF-␤). 14,15 In hepatocytes, reoxygenation may trigger a mitochondrial respiratory chain-dependent production of OFR, 3,16 which requires molecular oxygen and NADPH to generate O 2 .Ϫ anions. 3,10,11 These OFR could be involved in apoptosis, which leads to postoperative dysfunction and even to graft rejection.…”

Allogeneic Liver Transplantation and Subsequent Syngeneic Hepatocyte Transplantation in a Rat Model: Proof of Concept for in vivo Tissue Engineering

“…Literature on the transplantation of nonparenchymal cell fractions is scarce, but a positive influence of nonparenchymal cells in coculture systems with hepatocytes has been described [Miyazawa et al, 2005]. Additionally, stellate cells, sinusoidal endothelial cells and Kupffer cells are known to influence the proliferation of hepatocytes [Malik et al, 2002] and seem to positively influence oval cell-driven hepatic regeneration [Gugenheim and Crafa, 1994;Zhang et al, 2009]. When reducing immunosuppression later on, the transplanted cells would have the clear advantage of being syngeneic to the organ recipient.…”