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

1.烧伤致敏内毒素血症的小鼠模型我们打算阐明IL-18衍生的烧伤致敏内毒素血症的存活益处的机制。在IL-18处理的小鼠中，急性肺损伤（ALI）在组织学上减弱。肺组织TNF-α、MIP-2、IFN-γ、IL-12、IL-4的含量较低，而IL-10的含量高于IL-1.8未处理的阳性对照组。在另一组实验中，我们发现烧伤后肺CCL 22/MDC含量增加，并表明用CCR 4拮抗剂治疗导致存活率增加。CCR 4拮抗剂治疗组肺组织TNF-α、IL-6、MDC和TARC含量增加，提示其作用并非通过抑制细胞因子的产生而介导.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，我们检测了脾细胞在体外产生细胞因子的变化。在IL-18处理小鼠的脾细胞中， ...更多信息 LPS诱导的TNF-α、MIP-2离子减少，而IL-10离子增加。此外，我们在不同浓度的IL-18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。为了检测高氧对内皮细胞的直接影响，我们用改进的显微镜监测系统观察了人脐静脉内皮细胞的形态学变化，发现TNT-α和高氧协同诱导内皮细胞凋亡.高温对危重病人的影响：我们已经经历了几例DIC或器官功能障碍似乎是由高温引起的病例。通过精确地检查他们的临床病程，我们推测了高温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二聚体水平显著升高，AT III和蛋白C水平显著降低。此外，在第7天临床状况恶化的组中，蛋白C水平显著较低。在第三组研究中，我们发现在ALI/ARDS患者中，肺氧合恶化组的NE-AT和e-XDP水平显著较高。

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