PATHOGENESIS OF FEVER IN HUMANS

人类发烧的发病机制

• 批准号: 3126288
• 负责人: Charles anthony Dinarello
• 金额: $ 21.07万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1987-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3126288
• 关键词: Staphylococcus aureus; T lymphocyte; acute phase protein; arachidonate; autoradiography; body fluids; body temperature regulation; calcium metabolism; cell type; chemical structure function; density gradient ultracentrifugation; endotoxins; enzyme linked immunosorbent assay; gel electrophoresis; gel filtration chromatography; histiocytic lymphoma; human tissue; hybridomas; hyperthermia; hypothalamus; immunofluorescence technique; ion exchange chromatography; ionophores; membrane activity; monoclonal antibody; monocyte; pyrogens; radioimmunoassay; radiotracer; tissue /cell culture

The hypothesis that fever is initiated by the action of the polypeptide leukocytic pyrogen (LP) on the thermoregulatory system is well established; however, considerable evidence now supports the concept that LP also mediates several aspects of the acute phase response and plays an essential role in lymphocyte function. Purification and characterization of LP using fever as well as lymphocyte proliferation and other biological assays have been unable to separate these activities, and the term interleukin-1 (IL-1) has been adopted to denote the activity and hormonal nature of this molecule. Continued investigation is indicated on the biological activities and structure-function relationship of LP. Experiments will focus on large scale production of LP from human monocytes and the histocytic lymphoma line U937 stimulated with the potent LP-inducer, toxic shock toxin. Purification and amino acid sequence studies of LP are included since large scale production and purification schemes have been established. Data from sequence studies are vital to understanding the nature of LP and its effects on the host. Using intrinsic labeling of LP with radioactive amino acids, purification can be monitered and important studies on cell receptors initiated. Specific receptors for LP have not been identified and experiments are designed to use intrinsically labeled, purified human LP to locate areas in the hypothalamus which bind LP. Also, receptor identification on T-cells and human neutrophil membrane vesicles will be undertaken. Demonstrating LP binding to these cells and membranes provides the basis for receptor identification. Despite increasing evidence for the role of LP in mediating several components of the acute phase response, the mechanism by which this molecule affects so many different cell types remains unclear. Therefore, fundamental studies on the ability of LP to act as a calcium ionophore and inducer of arachidonic acid release are included. The role of LP in human disease requires studies on in vitro production and improved biological and immunoassays; recent progress has shed new light on how best to approach detection systems in human body fluids during health and disease. Also included in this proposal are the recovery and characterization of LP in the drainage fluid from patients on peritoneal dialysis and experiments to determine how this procedure stimulates LP production in vivo. The overall purpose of these studies is to link the production of LP to its actions on various host tissues.

发烧是由多肽的作用引起的假说 白细胞致热原（LP）对体温调节系统的影响已得到充分证实; 然而，现在有相当多的证据支持这样一个概念，即LP还 介导急性期反应的几个方面， 淋巴细胞功能的作用。 LP的纯化和表征，使用 发烧以及淋巴细胞增殖和其他生物学测定， 一直无法区分这些活动，术语白细胞介素-1（IL-1） 已经被采用来表示这种活性和激素性质， 分子。 生物学上指示继续调查 活性和结构功能关系。 实验将 专注于从人单核细胞大规模生产LP， 组织细胞性淋巴瘤细胞系U937用强效的脂蛋白诱导剂刺激，毒性 休克毒素 LP的纯化和氨基酸序列的研究 包括，因为大规模生产和纯化方案已经 确立了习 来自序列研究的数据对于理解 LP的性质及其对宿主的影响。 使用LP的内在标记 对于放射性氨基酸，纯化可以被监控， 细胞受体研究开始。 LP的特异性受体没有 已经确定并设计了实验来使用固有标记， 纯化的人LP以定位下丘脑中结合LP的区域。 还有， T细胞和人中性粒细胞膜囊泡上的受体鉴定 将进行。 证明LP与这些细胞和膜结合 为受体鉴定提供了基础。 尽管越来越多 LP在介导急性炎症的几个组分中的作用的证据 相位响应，这种分子影响如此多的机制， 不同的细胞类型仍不清楚。 因此，基础研究 LP作为钙离子载体和花生四烯酸诱导剂能力 酸释放也包括在内。 LP在人类疾病中的作用需要 研究体外生产和改进的生物和免疫测定法; 最近的进展为如何最好地进行检测提供了新的线索 健康和疾病期间人体体液中的系统。 中还包括 这一建议是回收和表征LP在排水 腹膜透析患者的液体和实验，以确定如何 该方法刺激体内LP产生。 的总体目的 这些研究是为了将LP的生产与其在各种方面的作用联系起来， 宿主组织