| Project/Area Number |
14571204
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
TOMIKAWA Morimasa (2003) KYUSHU UNIVERSITY, GRADUATE SCHOOL OF MEDICAL SCIENCES, RESEARCH ASSOCIATE, 大学病院, 助手 (60325454)
赤星 朋比古 (2002) 九州大学, 大学院・医学研究院, 助手 (20336019)
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| Co-Investigator(Kenkyū-buntansha) |
HASHIZUME Makoto KYUSHU UNIVERSITY, GRADUATE SCHOOL OF MEDICAL SCIENCES, PROFESSOR, 大学院・医学研究院, 教授 (90198664)
KAWANAKA Hirofumi KYUSHU UNIVERSITY, GRADUATE SCHOOL OF MEDICAL SCIENCES, RESEARCH ASSOCIAT, 大学病院, 助手 (10363334)
富川 盛雅 九州大学, 大学院・医学研究院, 助手 (60325454)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2003: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | portal hypertension / hyperdynamic circulation / intrahepatic vascular resistance / endothelial nitric oxide synthase (eNOS) / hepatic stellate cell (HSC) / nitric oxide (NO) / Rho kinase / Akt / シグナルトランスダクション / ROCK / RHOkinase阻害剤 / 肝線維化 / 肝硬変治療 |
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| Research Abstract |
Portal hypertension is characterized by the hyperdynamic circulation in the splanchnic organs as well as by the increased intrahepatic vascular resistance. Excessive nitric oxide production by endothelial nitric oxide synthase (eNOS) and elevated tumor necrosis factor-α (TNF-α) are implicated in the development of the systemic hyperdynamic circulation and portal hypertensive (PHT) gastropathy. The increased intrahepatic vascular resistance is associated with a contraction of hepatic stellate cells (HSCs) and a reduction of nitric oxide (NO) production in sinusoidal endothelial cells. HSCs also plays a major role in hepatic fibrogenesis, leading to portal hypertension. However, the molecular mechanisms for these phenomena remain to be elucidated. The aims of our studies are to determine the molecular basis for the hyperdynamic circulation of splanchnic organs and the intrahepatic microcirculatory disturbance.
Our present study demonstrates for the first time that : (1)eNOS activation in
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PHT gastric mucosa is due to : (a)increased phosphorylation of eNOS at serine 1177 ; (b)activation of the PI 3-kinase/Akt signaling pathway ; (c)enhanced binding of Akt to eNOS ; and, (2)TNF-α neutralizing antibody reduces phosphorylation of eNOS and activation of the PI 3-kinase/Akt signaling pathway in PHT gastric mucosa to the normal levels. In PHT gastric mucosa elevated TNF-α induces phosphorylation of eNOS at serine 1177 (required for its activation) via activation of the PI 3-kinase/Akt signaling pathway.
PHT gastric mucosa is highly susceptible to injury caused by alcohol, aspirin and other noxious factors, but the mechanism is not fully understood. Since such mucosal injury is initially mediated by oxygen free radicals, and since MAP kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we demonstrated that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from an underlying oxidative state, and is ameliorated by inhibiting MKP-1. Supplementing vitamin E, a free radical scavenger, normalizes MKP-1 expression in PHT gastric mucosa and completely reverses the increased susceptibility to alcohol injury. Our findings provide the molecular mechanism for the pathophysiology of PHT gastropathy and should expedite developing effective non-invasive therapy.
In the rat model of liver fibrosis induced by dimethlnitrosamine(DMN), fasudil (a novel specific inhibitor of Rho kinase) conceptation orally reduced fibrosis of the liver in 3 weeks. HSCs activation induced by liver injuary, as shown by the decreased the number of activated HSCs (_-SMA positive cells) and the protein expression_-SMA was also reduced in 3weeks. Moreover, oral administration of fasudil significantly reduced portal pressure of DMN rats at both 1 and 3 weeks, compared to DMN alone. This study indicates that oral administration of fasudil reduce extracellular matrix deposition and portal hypertension in vivo. In vitro experiments showed 1_M fasudil induced HSC apoptosis. The reduction of liver fibrosis and portal hypertension is likely to be induced by inhibition of HSC activation and apoptosis. These points will impact on the new therapiutic drug for cirrhotic patients.
The present study demonstrates in cirrhotic rats by the bile duct ligation that (1)Rho kinase signaling and its dawnstream _-SMA protein is upregulated; and (2)the long-term inhibition of Rho kinase with fasudil leads to the reduced contraction of HSCs and the upregulation of eNOS phosphorylation and prevents the microcirculatory disturbance, finally improving the portal hypertension in liver cirrhosis. Less
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