2005 Fiscal Year Final Research Report Summary
The mechanism of liver dysfunction in endogenous septic shock model mice
| Project/Area Number |
15590402
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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 |
Bacteriology (including Mycology)
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| Research Institution | Tokyo University of Pharmacy and Life Sciences |
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Principal Investigator |
OHNO Naohito Tokyo University of Pharmacy and Life Sciences, Pharmacy, Professor, 薬学部, 教授 (80152213)
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| Co-Investigator(Kenkyū-buntansha) |
ADACHI Yoshiyuki Tokyo University of Pharmacy and Life Sciences, Pharmacy, Associate Professor, 薬学部, 助教授 (60222634)
MIURA Noriko Tokyo University of Pharmacy and Life Sciences, Pharmacy, Assistant Professor, 薬学部, 講師 (30218036)
NAMEDA Sachiko Tokyo University of Pharmacy and Life Sciences, Pharmacy, Assistant, 薬学部, 助手 (80339100)
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| Project Period (FY) |
2003 – 2005
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| Keywords | sepsis / NSAIDs / beta-glucan / liver injury / nitric oxide / intestinal bacteria / antibiotics |
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| Research Abstract |
Sepsis is a systemic inflammatory syndrome commonly caused by bacterial infection and is associated with multiple organ failure and dysfunction. Despite effective antibiotics, septic shock remains the high mortality. We have developed an animal model of sepsis in mice by repeatedly administering two drugs, indomethacin (IND) and β-glucan (BG). The combination of BG and IND induced severe lethality and increased the number of leukocytes in various organs and these cells were activated.
1. The livers of BG/IND treated mice were fixed in buffered formalin and stained with hematoxylin-eosin. The rate of nonparenchymal cell was increased in the livers of septic mice. BG/IND mice contained significantly higher numbers of bacteria than control mice in various organs. Moreover, TNF-α,MCP-1, and IL-6 concentrations of BG/IND administered mice in sera were enhanced. It suggested that severe damage and increased permeability of the gastrointestinal tract led to ulcers, inflammation of multiple organs and sepsis on administration of BG/IND.
2. The mice administered BG/IND produced a significant concentration of nitric oxide (NO) from peritoneal exuded cells (PEC) culture. To examine the effect of NO on the lethality, a NOS inhibitor, L-NAME was administered. L-NAME increased the mortality. Treatment with L-NAME and BG/IND enhanced production of IL-1β,IL-6 and TNF-α in PEC was significantly increased. The release of GOT and GPT was also increased in mice treated with the combination of L-NAME and BG/IND. It suggested that the production of NO has a protective effect in this model.
3. BG/IND administered mice treated with antibiotics prolonged the survival. Moreover, LPS elicited productions of inflammatory cytokines were decreased in sera of mice treated with antibiotics. These facts strongly suggested that the antibiotics treatment protected mice from the sensitization to LPS and thus reduced risk of sepsis, such as microbial translocation and leukocyte accumulation in the gut.
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