2000 Fiscal Year Final Research Report Summary
Mechanisms of sepsis-induced cholestatic liver injury
| Project/Area Number |
11671162
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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 |
General surgery
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| Research Institution | Osaka University |
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Principal Investigator |
NISHIDA Toshirou Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40263264)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIYAMA Yasuo Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (10049091)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Endotoxin / Apotosis / Hepatocyte / Kupffer cell / Bilirubin / Bile Acids / Caspase-3 / MAP Kinases |
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| Research Abstract |
We have examined the effect and mechanism of sepsis-induced cholestatic liver injury. We showed bilirubin and bile acid clearance from the blood and their output into the bile were reduced in the presence of infection. One of main causes of this phenomenon has been considered to be lipopolysaccharide (LPS) and peptidglycan from bacteria. Next, we examined cytological mechanisms using LPS-injection model of rats. Injection of LPS induced time- and dose-dependent hepatocyte apoptosis with concomitant activation of caspase-3 in hepatocytes. When Kupffer cells were inactivated, there was no apoptosis. Addition of anti-TNFα antibody decreased activation of caspase-3 as well as apoptosis of hepatocytes. Even in survived hepatocytes, expression of transport proteins for bile acids and bilirubin, such as NTCP, OATP and CMOAT, was time- and dosedependently decreased after injection of LPS.Decrease in these transport proteins was also suppressed by Kupffer cell inactivation. The decrease in NTCP, OATP and CMOAT expression was inhibited by addition of anti-IL-1α antibody, but not anti-TNFα antibody. By LPS addition, activation of MAP kinases (ERK, JNK and p38 MAP kinases) has been confirmed and we showed that inhibitors of these kinases inhibited decrease in expression of these transporters. These results suggested that LPS induced hepatocyte apoptosis (decrease in the number of hepatocytes) and decreased in expression of bile acid and bilirubin transporters via cytokines secreted from activated Kupffer cells. Consequently, it may be considered that bile secretion of the liver is decreased.
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