| Project/Area Number |
13670467
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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 |
内科学一般
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| Research Institution | Nara Medical University |
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Principal Investigator |
KITA Eiji Nara Medical University, Bacteriology, Professor, 医学部, 教授 (90133199)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | EHEC / Shiga toxin / PDE inhibitors / cytokines / Encephalopathy / intervention therapy / postinfection window / フォスフォジエステラーゼ阻害剤 / HUS |
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| Research Abstract |
Shiga toxin-producing Escherichia coli (STEC) O157:H7 infection often leads to severe combined diseases such as HUS and acute encephalopathy. Pathogenesis of the combined diseases may be ascribed to the synergy of Shiga toxin and proinflammatory cytokines. These combined diseases usually occur several days after the onset of intestinal symptoms, the period of which is defined as postinfection window.
Combinations of phosphodiesterase (PDE) inhibitors (types 3 and 4) were tested for the possibility as an intervention therapy for a postinfection window of STEC Ol57:H7 using mice with protein calorie malnutrition (PCM). Evaluation of the efficacy of this treatment was determined by the ability to prevent the development of acute encephalopathy in the PCM mice infected with STEC.
Types 3 and 4 PDE inhibitors at doses higher than 1.5 mg/ml were all capable of inhibiting the production TNF-alpha from freshly-isolated mouse brain microglias, and mesangial ceils during 24-h stimulation with endo
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toxin (10 ng/ml) and Stx2 (10 pg/ml). In contrast, IL-10 production by stimulated these cells was significantly enhanced by these inhibitors. An oral dose of individual drugs at 7.5 mg/kg of body weight maintained plasma concentration of individual inhibitors above 2 mg/ml when mice received this dose twice a day at 1 2-h intervals. This treatment was done from day 2 throughout day 4.
This intervention therapy reduced neurological symptoms and generated higher than 95% of survival rates, while control animals died within 10 days. With this treatment, Stx 2 was not detected in serum, and TNF-alpha levels in the brain and serum were significantly reduced, contrasting to the enhanced production of IL-10. The brain of treated mice was histologically normal and immunoreactions of Stx2 were not detected. These findings suggest that the combination therapy with PDE inhibitors (types 3 and 4) is clinically available for the prevention of HUS and acute encephalopathy resulting from STEC infection. Less
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