| Project/Area Number |
09470256
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
HIRATA Koichi Sapporo Medical University, Professor, 医学部, 教授 (50136959)
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| Co-Investigator(Kenkyū-buntansha) |
MITAKA Toshihiro Sapporo Medical University, Associate Professor, 医学部, 助教授 (50231618)
MOCHIZUKI Yohichi Sapporo Medical University, Professor, 医学部, 教授 (40045381)
KATSURAMAKI Tadashi Sapporo Medical University, Assistant Professor, 医学部, 講師 (50253993)
KOHGO Yutaka Asahikawa Medical College, Professor, 医学部, 教授 (10133183)
HIRATA Koichi Sapporo Medical University, Professor (50136959)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Keywords | cholestasis / bile canaliculus / hepatocyte membrane / cytokine / hepatocyte / dynamic imaging / 周術期 / 感染症 / ヒトAGB / AGPR / ヒトAGP |
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| Research Abstract |
A.Sepsis and Cholestasis
---Basic findings in the sinusoid and in bile canaliculus---
Hepatic dysfunction, as one of unfavorable the pathophysiologic condition in sepsis, is induced by the alterations in both macro- and microcirculatory disturbance and by functional failure in intrahepatic cellular system. The stereotypical response of the liver in the process of hepatic failure has been well reported. However, little is known in its mechanisms ; for example the developmental mechanism of cholestasis, which is characteristics as a result in hepatic failure^1. Cholestatic liver disease is one form of liver injury that promotes cirrhosis, follows extrahepatic bile duct obstruction or intrahepatic metabolic abnormalities^2. The essential pathogenesis of cholestasis developing during sepsis is due to the latter reason and is based on the disturbance of intra- and extra- cellular transportation system of bilirubin in hepatocytes, influenced by responses of the hepatic parenchymal cells and th
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e sinusoidal lining cells. There are well known that the structure of sinusoid in liver is characteristic in information-exchange between blood stream and the organ functional cells, in relative to those of general capillary vessels or the sinusoid of the adrenal gland. To investigate the pathogenesis of cholestasis under severe infection might contribute to the essential understanding of this condition and to future therapy. Bile canaliculi, the smallest components of the biliary tree lie between the apical surfaces of adjacent hepatocytes. They are surrounded by actin and myosin and possess contractile activity, which has a major role in facilitating the transport of bile through the canalicular route. Treatment of rats with drugs that impair polymerization and depolymerization of actin results in bile secretary failure and detective bile canalicular contraction.
B.Tumor Necrosis Factor- α Induces Bile Juice Leakage from Rat Bile Canaliculi
Surgeons sometimes encounter hyperbilirubinemia without any physical obstruction of the bile duct after operations on the gastrointestinal tract and/or liver. In most cases the patients have accompanying bacterial infections and endotoxemia. It is known that Kupffer cells are stimulated by endotoxins to secrete inflammatory cytokines such as tumor necrosis factor- α(TNF- α) and interleukin-6(IL-6). We hypothesized that TNF- α and IL-6 might be involved in the hyperbilirubinemia. Methods : Bile canalicular contractions of hepatocytes couplets isolated from rat livers were monitored and time-lapse images were taken every 10 sec for 2 hr. The common bile ducts of rats were cannulated and bile juice was collected. The livers, perfused with lanthanum and fixation solution after the injection of TNF- α and/or IL-6, were ultrastructurally examined. Results : Rapid streams at the intercellular spaces of couplets were observed when TNF- α was added to the medium. The number of bile canalicular contractions decreased in the couplets treated with TNF- α and IL-6, and the contractive velocity of bile canaliculi was faster than that of bile canaliculi in controls. Bile secretion of rats injected with TNF- α and/or IL-6 was significantly reduced compared with that of the control. In TNF-α-treated rats the total bile acid concentration of the serum increased and lanthanum temporarily accumulated in bile canaliculi. Conclusions : These results suggest that TNF- α may loosen the tight junctional structure and that bile juice may leak from bile canaliculi. Less
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