2004 Fiscal Year Final Research Report Summary
THE ROLE OF HMGB-1 AS CYTOKINE IN INFECTION
| Project/Area Number |
15590397
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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 | Kitasato University |
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Principal Investigator |
HASUNUMA Ryoichi KITASATO UNIVERSITY, SCHOOL OF SCIENCE, RESEARCH ASSOCIATE, 理学部, 助手 (30104566)
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| Co-Investigator(Kenkyū-buntansha) |
TAKIMOTO Hiroaki KITASATO UNIVERSITY, SCHOOL OF SCIENCE, LECTURE, 理学部, 講師 (00253534)
KUMAZAWA Yoshio KITASATO UNIVERSITY, SCHOOL OF SCIENCE, PROFESSOR, 理学部, 教授 (30072375)
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| Project Period (FY) |
2003 – 2004
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| Keywords | HMGB-1 / ENDOTOXIN SHOCK / S. typhimurium INFECTION / GALACTOSAMINE CHALLENGED MICE / FLAVONOIDS / NARINGIN / HESPERIDIN |
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| Research Abstract |
Lipopolysaccharide (LPS)-elicited chromogenic Limulus reaction was suppressed by pretreating LPS with a citrus flavonoid hesperidin (HES). Administration of HES to mice before LPS challenge significantly reduced tumor necrosis factor (TNF)-α production in a dose-dependent manner. Treatment of HES 3 h before intraperitoneal (i.p.) infection with 108 CFU Salmonella typhimurium aroA resulted in rescue from lethal shock as similar to LPS-nonresponder mice. Not only bacterial numbers in livers and spleens but also plasma LPS levels significantly decreased by pretreating with HES. In addition, HES markedly suppressed plasma TNF-a levels, decreased the number of apoptotic cells in livers and normalized the activated states of blood coagulation factors such as prothrombin time and platelet numbers caused by infection.
The protective effect of Citrus flavanone naringin was demonstrated in an endotoxin shock model based on Salmonella infection. Intraperitoneal (i.p.) infection with 10^8 CFU Salmo
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nella typhimurium aroA caused lethal shock in lipopolysaccharide (LPS)-responder but not -nonresponder mice. Administration of 1 mg naringin 3 h before infection resulted in protection from lethal shock, similar to LPS-nonresponder mice. The protective effect of naringin was time- and dose-dependent. Treatment with naringin resulted not only in a significant decrease in bacterial numbers in spleens and livers, but also a decrease in plasma LPS levels. In addition, naringin markedly suppressed TNF-a and normalized the activated states of blood coagulation factors such as prothrombin time, fibrinogen concentration and platelet numbers caused by infection. Interestingly, treatment with naringin suppressed high levels of soluble CD14 and high mobility group-1 molecule caused by infection.
The protective effects of an antibiotic polymyxin B (PLB), having lipopolysaccharide (LPS)-binding activity, on infection-induced endotoxin shock in mice were investigated. Infection with 10^8 colony forming units of an attenuated Salmonella typhimurium aroA strain caused lethal endotoxin shock to ddY mice. Treatment with PLB 1 h post infection (p.i.) resulted in significant reduction of mortality and bacterial numbers in livers. In addition, treatment with PLB 1 h p.i. resulted in a transient increase at the early stage and gradual decline in plasma LPS levels. Although plasma levels of sCD14 and high mobility group box chromosomal protein-1 (HMGB-1) increased according with progression of infection, increases in plasma levels of sCD14 and HMGB-1 were downregulated by treatment with PLB 1 h p.i. However, the lethal shock was not blocked by treatment with anti-CD14 monoclonal antibody at 3 h and 6 h p.i. Interestingly, administration of PLB 6 h p.i. did not show any protective activities, indicating that a time window for effective PLB action is present. Less
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Research Products
(6 results)
