Depressed Liver Regeneration After Partial Hepatectomy of Germ–Free, Athymic and Lipopolysaccharide–Resistant Mice

Abstract

A hypothesis has been proposed by this laboratory that endogenous gut–derived lipopolysaccharide is responsible for systemic endotoxemia in animals with acute liver injury particularly after partial (67%) hepatectomy. Systemic lipopolysaccharide and possibly fibrin aggregates or tissue debris then elicit release of cytokines from phagocytizing macrophages and/or monocytes that may be essential for normal liver regeneration. To test this hypothesis liver regeneration was assessed in germ–free euthymic mice that lack the gram–negative bacterial source of lipopolysaccharide, as well as being deficient in lymphoid tissue and relatively resistant to endotoxin. To complement the germ–free animals, conventional athymic nude BALB/c mice and conventional lipopolysaccharide–resistant C3H/HeJ mice were also examined. Liver regeneration, quantified by [3 H] thymidine incorporation into hepatic DNA after partial hepatectomy was performed on mice anesthetized with ether, was significantly depressed in germ–free euthymic and conventional athymic BALB/c mice and delayed in conventional lipopolysaccharide–resistant C3H/HeJ mice, as compared with conventional control BALB/c and C3H/HeN animals. Pretreatment of conventional euthymic control mice with lipopolysaccharide 24 hr before surgery significantly stimulated hepatic DNA synthesis after 67% liver resection. Germ–free euthymic, conventional athymic, and conventional lipopolysaccharide–resistant mice pretreated with endotoxin did not manifest significant stimulation of liver regeneration. Evidence is reviewed that cytokine release in response to endotoxin was depressed in germ–free euthymic, conventional athymic, and conventional lipopolysaccharide–resistant mice as compared with conventional euthymic controls. The inability to release cytokines in response to gut–derived endotoxin in the three murine strains studied or the paucity of endogenous lipopolysaccharide in germ–free animals may explain the significant depression or delay of liver regeneration as compared with conventional euthymic control mice.(HEPATOLOGY 1990;11:916–922.).