NEUTROPHILS, CYTOKINES AND CYTOKINE RECEPTORS IN SEPTIC SHOCK

感染性休克中的中性粒细胞、细胞因子和细胞因子受体

• 批准号: 3852898
• 负责人: CHARLES E MCCALL
• 金额: --
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3852898
• 关键词: cytokine receptors; enzyme linked immunosorbent assay; gene expression; human subject; inflammation; interferons; leukocytosis; neutrophil; phenotype; receptor expression; shock; tumor necrosis factor alpha; virus infection mechanism

Human polymorphonuclear leukocytes (PMNL) synthesize, secrete, contain specific membrane receptors for, and respond to the cytokines IL-1 alpha and beta and TNF beta. Both of these cytokines and PMNL play an essential role in the pathogenesis of acute disseminated inflammation with organ failure which may follow microbial infection (septic shock). Our objective is to show that septic shock in humans is consistently associated with amplified expression of receptors for IL-1 on blood PMNL, and tolerance of these PMNL to LPS- and IL-1 alpha-induced expression of the IL-1 beta gene, and that such phenotypic changes play an important role in acquisition, severity, or outcome of highly lethal septic shock. This research will: 1. Determine if the phenotypic changes typical of sepsis-PMNL are also found in other inflammatory pathologies: A. acute disseminated microbial-induced inflammation without organ failure; B. acute disseminated inflammation not caused by infection and with or without organ failure; C. localized infection without fever or leukocytosis; D. viral infection. 2. Prospectively study patients at high risk for developing septic shock (trauma-patients) to test the hypothesis that the phenotypic alterations found in sepsis-PMNL correlate with risk, severity, or outcome of septic shock. 3. Test the hypothesis that increased synthesis of receptor protein is responsible for increased expression of IL-1 R on sepsis-PMNL by evaluating transcriptional and translational processes. 4. Determine the site responsible for the adaptation of sepsis-PMNL to IL-1 beta gene expression. Our findings should provide insight into cellular events which regulate the human response to severe inflammation, and have implications for risk, prognosis, and therapy of septic shock.

人多形核白细胞（PMNL）合成、分泌、含有 细胞因子IL-1 α的特异性膜受体，并对细胞因子IL-1 α作出反应 以及β和TNF β。 这两种细胞因子和PMNL都在细胞内起着重要的作用。 在急性播散性炎症发病机制中的作用 可能伴随微生物感染的衰竭（败血性休克）。 我们的目标 是为了证明人类感染性休克 血PMNL上IL-1受体的表达增强， 这些PMNL对LPS和IL-1 α诱导的IL-1 β基因的表达， 并且这种表型变化在获得中起重要作用， 严重程度或高致死性脓毒性休克的结果。 本研究将：1. 确定是否也发现败血症-PMNL的典型表型变化 在其他炎症病理学中：A.急性播散性微生物感染 无器官衰竭的炎症; B.急性播散性炎症 由感染引起，伴有或不伴有器官衰竭; C.局部 感染无发热或白细胞增多; D.病毒感染2. 脓毒性休克高危患者的预防性研究 （创伤患者）来检验表型改变 发现脓毒症-PMNL与脓毒症的风险，严重程度或结果相关 冲击. 3.检验受体蛋白合成增加的假设 负责脓毒症-PMNL上IL-1 R的表达增加， 评估转录和翻译过程。 4.确定 脓毒症-PMNL适应IL-1 β基因的位点 表情 我们的研究结果应该提供深入了解细胞事件， 调节人类对严重炎症的反应， 感染性休克的风险、预后和治疗。