| Co-Investigator(Kenkyū-buntansha) |
HORI Shingo Keio University, School of Medicine, Associate Professor (80129650)
FUJISHIMA Seitaro Keio University, School of Medicine, Assistant Professor (00173419)
SEKINE Kazuhiko Keio University, School of Medicine, Researcher (90296715)
YOH Kikuo Keio University, School of Medicine, Instructor (00327644)
MIYAKI Masaru Keio University, School of Medicine, Instructor (60365400)
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| Budget Amount *help |
¥16,740,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2007: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2006: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Research Abstract |
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
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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
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