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Intervention therapy for the prevention of hemolytic uremic syndrome (HUS) following STEC infection

预防 STEC 感染后溶血性尿毒症综合征 (HUS) 的干预治疗

基本信息

批准号：
13670467
负责人：
KITA Eiji
金额：
$ 2.05万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

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 … More 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

产滋贺毒素大肠杆菌（STEC）O 157：H7感染常导致严重的混合性疾病如溶血尿毒综合征和急性脑病。滋贺毒素与促炎细胞因子的协同作用可能是其发病机制之一。这些合并疾病通常发生在肠道症状发作后数天，这段时间被定义为感染后窗口，磷酸二酯酶（PDE）抑制剂（3型和4型）的组合被测试作为STEC 0157：H7感染后窗口的干预治疗的可能性，使用蛋白质热量营养不良（PCM）小鼠。通过预防感染STEC的PCM小鼠发生急性脑病的能力来评估这种治疗的疗效。剂量高于1.5 mg/ml的3型和4型PDE抑制剂都能够在24小时内抑制来自新鲜分离的小鼠脑小胶质细胞和系膜细胞的TNF-α的产生。 ...更多信息毒素（10 ng/ml）和Stx 2（10 pg/ml）。相反，这些抑制剂显著增强了刺激这些细胞产生的IL-10。当小鼠以12小时间隔每天两次接受7.5 mg/kg体重的口服剂量的个体药物时，个体抑制剂的血浆浓度维持在2 mg/ml以上。从第2天到第4天进行这种治疗。这种干预治疗减少了神经系统症状，并产生了高于95%的存活率，而对照组动物在10天内死亡。通过这种治疗，血清中未检测到Stx 2，脑和血清中的TNF-α水平显著降低，与IL-10的产生增强形成对比。治疗组小鼠脑组织学正常，未检测到Stx 2的免疫反应。这些结果表明，PDE抑制剂（3型和4型）的联合治疗在临床上可用于预防由STEC感染引起的HUS和急性脑病。少