2000 Fiscal Year Final Research Report Summary
Protecting mechanism of hepatocyte growth factor against liver fibrosis and cirrhosis.
| Project/Area Number |
09671345
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Digestive surgery
|
|---|
| Research Institution | Kansai Medical University |
|---|
Principal Investigator |
KWON A-hon Kansai Medical University, First Department of Surgery, Associate Professor, 医学部, 助教授 (70225605)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MATSUI Yoichi Kansai Medical University, First Department of Surgery, Assistant Professor, 医学部, 助手 (60278637)
|
|---|
| Project Period (FY) |
1997 – 2000
|
| Keywords | hepatocyte growth factor / liver cirrhosis / ischemia and reperfusion / heat shock protein / nitric oxide |
|---|
| Research Abstract |
1) Stimulation of liver regeneration and function after partial hepatectomy in cirrhotic rats by continuous infusion of recombinant human hepatocyte growth factor.
We performed 45% hepatectomy in rats with cirrhosis induced by thioacetamide, and administered recombinant human hepatocyte growth factor (HGF). HGF stimulated an increase in the wet weight of the remnant liver compared with untreated control rats. The proliferating cell nuclear antigen labeling index showed that this increase resulted from the stimulation of DNA synthesis. Serum levels of liver enzymes increased after hepatectomy, but returned to the prehepatectomy level more rapidly in rhHGF-treated rats than in controls. rhHGF increased hepatic protein synthesis above prehepatectomy levels and also markedly increased the serum levels of hepatic lipid metabolites. (Journal of Hepatology, 27, 1997)
2) Hepatocyte growth factor stimulates synthesis of lipids and secretion of lipoproteins in rat hepatocytes.
Isolated cells were c
… More
ultured in the presence or absence of rhHGF for 2 days. During the first 12 hours, rhHGF transiently inhibited the release of lipids. [3H]-glycerol experiment with the transcriptional and translational inhibitors revealed that rhHGF stimulated de novo synthesis of lipids by affecting activities of lipid metabolic gene. [35S]-Methionine experiment also revealed de novo synthesis of apolipoprotein B by rhHGF.Genistein, a tyrosine kinase inhibitor, blocked the secretion of VLDL, as well as synthesis of lipids and apolipoprotein B stimulated by rhHGF.(Hepatology 25, 1997)
3) Recombinant human hepatocyte growth factor protects the liver against hepatic ischemia and reperfusion injury in rats.
Rats were subjected to total or segmental hepatic ischemia by occluding the hepatic artery, portal vein, and bile duct with a microvascular clip. Rats were treated with four intravenous injections of recombinant human HGF.None of the eight animals in the control group were alive 12 h after total hepatic WI/Rp. Seven of eight animals in the rhHGF-treated group were alive more than 2 days after the reperfusion. In the model of segmental hepatic ischemia, rhHGF inhibited the increase in cytokine-induced neutrophil chemoattractant in serum. The number of neutrophils infiltrating the liver was significantly lower in the rhHGF-treated group than in the control group. rhHGF prevented increases in the activity of serum alanine transaminase and in hepatic necrosis. Experiments with proliferating cell nuclear antigen staining demonstrated that hepatocyte proliferation markedly increased in rhHGF-treated rats as compared with controls. (Journal of Surgical Research, 92, 2000)
4) Hypoxia and heat inhibit inducible nitric oxide synthase gene expression by different mechanisms in rat hepatocytes.
we found that hypoxia and heat markedly inhibited the induction of nitric oxide production stimulated by IL-1beta in rat cultured hepatocytes. Both treatments also abolished the induction of iNOS protein and mRNA.However, hypoxia could not prevent either degradation of an inhibitory protein (IkappaBalpha) of nuclear factor-kappaB (NF-kappaB) or translocation of NF-kappaB to the nucleus, whereas heat inhibited both of the IkappaBalpha degradation and NF-kappaB translocation. Transfection experiments with iNOS promoter construct revealed that hypoxia as well as heat significantly inhibited the transactivation of iNOS gene. Further, a hypoxia-response element located in the promoter was not involved in the inhibition of iNOS induction by hypoxia. (Hepatology, 32. 2000) Less
|
