Macrophage Death and Sepsis

巨噬细胞死亡和脓毒症

• 批准号: 6999778
• 负责人: Jiahuai Han
• 金额: $ 32.26万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999778
• 关键词: Macrophage; Death; Sepsis

DESCRIPTION (provided by applicant): Overproduction of proinflammatory cytokines by macrophages and other cells is critical in the development of septic shock. On the other hand, immunocompromise of macrophages and lymphocytes that developed during the onset of sepsis was also believed to contribute to the lethality of this disease. The lifespan of macrophages and lymphocytes was modulated in sepsis and is responsible, in part, for the uncontrolled inflammatory response and immunodepression. Recent studies have shown that inhibition of lymphocyte apoptosis increased the survival rate of sepsis in an animal model. However, the effect of macrophage apoptosis on the outcome of sepsis has not been addressed. We found that macrophage apoptosis was induced in the same animal model when caspase inhibitor was administered to prevent lymphocyte death. We also found that Nur77 was induced in apoptotic macrophages and Nur77 induction is required for macrophage death. As reported by others using other types of cells, Nur77 induction requires transactivation of MEF2, but a signaling triggered by bacterial components is also required for macrophage expression of Nur77. This proposal will use the knowledge we have of macrophage apoptosis to promote and inhibit macrophage death in septic mice and thereby determine whether macrophage apoptosis positively or negatively affects the outcome in septic mice. We will also further elucidate the molecular mechanisms underlying the macrophage apoptosis. The proposed study will provide information regarding whether macrophage death should be avoided or enhanced in the treatment of sepsis. Our study will also lead to a better understanding of how macrophage apoptosis is controlled, which is needed to develop therapeutically useful strategies to selectively promote or inhibit macrophage death.

描述（由申请人提供）：巨噬细胞和其他细胞对促炎细胞因子的生产过量对于败血性休克的发展至关重要。另一方面，在败血症发作期间发育的巨噬细胞和淋巴细胞的免疫功能也被认为有助于这种疾病的致命性。在败血症中调节了巨噬细胞和淋巴细胞的寿命，并部分负责不受控制的炎症反应和免疫抑制。最近的研究表明，抑制淋巴细胞凋亡会增加动物模型中败血症的存活率。但是，巨噬细胞凋亡对败血症结果的影响尚未得到解决。我们发现，当caspase抑制剂被施用以防止淋巴细胞死亡时，在同一动物模型中诱导了巨噬细胞凋亡。我们还发现，NUR77是在凋亡巨噬细胞中诱导的，巨噬细胞死亡需要NUR77诱导。正如其他人使用其他类型细胞的报道的那样，NUR77诱导需要MEF2进行反式激活，但是通过细菌成分触发的信号传导也需要NUR77的巨噬细胞表达。该提案将利用我们对巨噬细胞凋亡的知识来促进和抑制败血症小鼠的巨噬细胞死亡，从而确定巨噬细胞凋亡是积极或负面影响败血症小鼠的结果。我们还将进一步阐明巨噬细胞凋亡的分子机制。拟议的研究将提供有关在治疗败血症时应避免或增强巨噬细胞死亡的信息。我们的研究还将更好地理解如何控制巨噬细胞凋亡，这是开发有用的有用策略以选择性促进或抑制巨噬细胞死亡所需的。