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 [3H] 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

“…Our data from the TLR4 KO mice are particularly surprising in light of published data demonstrating a delay in liver regeneration in C3H/HeJ mice, an inbred strain of mice with a point mutation in Tlr4 (i.e., Tlr4 P712H ) (15,16). Our findings, which are consistent with recent studies by Seki et al (58), suggest that a point mutation in TLR4 has more profound effects on liver regeneration than the loss of the entire receptor.…”

“…Although the importance of leukocytes in liver regeneration (53) is accepted, the impact of a proposed difference in composition of liver leukocytes in C3H/HeJ mice on liver regeneration is unknown. Clearly, any of these hypothetical possibilities would need in vivo experimentation to understand the potency of the mutant TLR4 allele in liver regeneration (15,16). In any case, the data presented here strongly suggest that TLR2 and TLR4 are not involved in the initiation of liver regeneration.…”

“…Rats in which LPS has been depleted by antibiotic administration or other methods display impaired hepatocyte DNA synthesis following PH (14). Liver regeneration is also delayed in athymic nucli mice and C3H/HeJ mice, a naturally occurring strain that is hyporesponsive to LPS (15,16). Hepatocyte DNA synthesis is enhanced if these animals receive LPS 24 h before surgery (15,17).…”

“…Liver regeneration is also delayed in athymic nucli mice and C3H/HeJ mice, a naturally occurring strain that is hyporesponsive to LPS (15,16). Hepatocyte DNA synthesis is enhanced if these animals receive LPS 24 h before surgery (15,17). In addition, Webber et al (18) demonstrated that LPS primes hepatocytes for growth factor-induced replication in nonoperated rats.…”

Contribution of Toll‐like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration†

“…Potentially, our findings provide new insights into liver regeneration incidentally induced by various stresses, such as microbes, drugs, trauma, or surgical maneuvers. [38][39][40] Intestine-derived lipopolysaccharide (LPS) has been considered to be an initiator of the liver regeneration, 41 but our current findings clearly show that LPS is not essential for induction of liver regeneration (Fig. 5).…”