|Budget Amount *help
¥3,400,000 (Direct Cost : ¥3,400,000)
Fiscal Year 1998 : ¥300,000 (Direct Cost : ¥300,000)
Fiscal Year 1997 : ¥3,100,000 (Direct Cost : ¥3,100,000)
1 : Hepatic regeneration after hepatectomy and endotoxin administration
Postoperative infection inhibits liver regeneration after hepatectomy. To elucidate this inhibition, we analyzed growth rates of hepatocyte and signals between Kupffer cells and hepatocyte using rat 70% hepatectomy model with or without endotoxin (ET) administration. In this rat postoperative infection model, we administered ET (1 mg/kg) one day after hepatectomy. To evaluate hepatocyte growth rate, PCNA (proliferative core nuclear antigen) staining was performed in liver specimens obtained at 3 and 7 postoperative days. The percentages of PCNA positive cells were 27% and 17% in the rats with only hepatectomy whereas those were 16% and 10 % in 1 mg/kg ET-administered rats, respectively. Thus, ET administration inhibited liver regeneration after hepatectomy.
2. Molecular analysis for signalings of hepatic regeneration
Using the same hepatectomy model rats with low dose ET (30 mug/kg)and high dose ET (1 mg/kg)-administe
red rats, we measured HGF (hepatocyte growth factor) mRNA and c-met mRNA expressions in the liver specimens obtained 3,6,12,24,48 and 72 hours after hepatectomy. in the rats with only hepatectomy, HGF expression increased 12-24 hours after hepatectomy and c-met expression simultaneously increased. In the low dose ET administered rats, the expression levels of HGF and c-met were higher than those in the rats without ET-administration. On the other hand, in the high dose ET administered rats, peak of HGF expression was delayed and unlikely to cooperate with c-met expression.
These data suggested that low dose administration of ET after hepatectomy stimulated hepatic regeneration after hepatectomy, whereas its high dose administration inhibited. ET administration stimulated inflammatory cytokines by Kupffer cells. The overproduction of inflammatory cytokines due to postoperative severe infection might disarrange signal transduction for hepatocyte growth, which causes the delay of liver regeneration and increases the death rates of these rats model. Less