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Immunological and metabolic changes induced by severe insults : insights into its pathophysiology and a development of new therapies

严重损伤引起的免疫和代谢变化：对其病理生理学的见解和新疗法的开发

基本信息

批准号：
17390482
负责人：
AIKAWA Naoki
金额：
$ 10.71万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390482/
关键词：
SIRS sepsis priming LPS Sepsis CCL22 MDC 高濃度酸素高温環境高体温 protein C TNF

项目摘要

1. Mouse model of burn-primed endotoxemia We have intended to elucidate the mechanisms of IL-18-derived survival benefit for burn-primed endotoxemia. In IL-18-treated mice, acute lung injury (ALI) was histologically attenuated. Lung contents of TNF-alpha, MIP-2, IFN-gamma, IL-12, IL-4 were lower, whereas those of IL-10 were higher than those of IL-1.8-untreated positive controls. In another set of experiments, we found the increase of lung CCL22/MDC contents after burn injury and showed that treatment with a CCR4 antagonist resulted in the increase in survival. In CCR4 antagonist-treated group, lung contents of TNF-alpha IL-6, MDC, and TARC were increased, suggesting that its effects were not mediated by the inhibition of cytokines production.2. In vitro culture of endothelial cells and spleen cells: To elucidate the immunomodulatory roles of IL-18, we have examined the change in cytokines production by spleen cell in vitro. In spleen cells obtained from IL-18-treated mice, the product … More ion of TNF-alpha, MIP-2 in response to LPS was attenuated, whereas that of IL-10 was increased. Furthermore, we cultured spleen cells at various IL-18 concentrations and found that the production of MIP-2 was attenuated at IL-18 100 pg/ml as compared with that at 30 pg/ml. The induction of IL-10 production was not observed with the increase in IL-18 concentration.To examine the direct effect of hyperoxia, we examined morphological changes of human umbilical endothelial cells using an improved microscopic monitoring system and found that TNT-alpha and hyperoxia synergistically induce endothelial cell apoptosis.3. Effects of hyperthermia in critical patients: We have experienced several cases in which DIC or organ dysfunctions seemed to be induced by hyperthermia. By precisely examining their clinical courses, we speculated the direct immunomodulatory effects of hyperthermia in these patients. In the second set of study, we found that D dimer levels were significantly higher and those of AT III and protein C were significantly lower in patients with sepsis. Furthermore, protein C levels were significantly lower in the group with deteriorating clinical conditions on day 7. In the third set of study, we found that NE-AT and e-XDP levels were significantly higher in the group with deteriorating lung oxygenation, among ALI/ARDS patients Less

1.烧伤引发的内毒素血症的小鼠模型我们旨在阐明IL-18衍生的烧伤引发的内毒素血症的生存获益的机制。在IL-18治疗的小鼠中，急性肺损伤（ALI）在组织学上得到减轻。与未经IL-1.8处理的阳性对照相比，肺中TNF-α、MIP-2、IFN-γ、IL-12、IL-4的含量较低，而IL-10的含量较高。在另一组实验中，我们发现烧伤后肺 CCL22/MDC 含量增加，并表明 CCR4 拮抗剂治疗可导致生存率增加。 CCR4拮抗剂治疗组肺脏中TNF-α、IL-6、MDC、TARC含量升高，提示其作用并非通过抑制细胞因子产生来介导。2．内皮细胞和脾细胞的体外培养：为了阐明IL-18的免疫调节作用，我们在体外检测了脾细胞产生细胞因子的变化。在从 IL-18 处理的小鼠获得的脾细胞中，响应 LPS 的 TNF-α、MIP-2 产物离子减弱，而 IL-10 产物离子增加。此外，我们在不同IL-18浓度下培养脾细胞，发现与30 pg/ml相比，IL-18 100 pg/ml时MIP-2的产生减弱。随着IL-18浓度的增加，并没有观察到IL-10产生的诱导。为了检验高氧的直接影响，我们使用改进的显微监测系统检查了人脐带内皮细胞的形态变化，发现TNT-α和高氧协同诱导内皮细胞凋亡。 3．热疗对危重患者的影响：我们经历过几起因热疗而引发 DIC 或器官功能障碍的病例。通过精确检查他们的临床过程，我们推测了热疗对这些患者的直接免疫调节作用。在第二组研究中，我们发现脓毒症患者D二聚体水平显着升高，AT III和蛋白C水平显着降低。此外，第 7 天临床状况恶化的组中蛋白 C 水平显着较低。在第三组研究中，我们发现 ALI/ARDS 患者中肺氧合恶化的组中 NE-AT 和 e-XDP 水平显着较高