IMPROVED BURN THERAPY THROUGH THE REGULATION OF INFLAMMATION

通过调节炎症改善烧伤治疗

• 批准号: 6240397
• 负责人: JEFFREY A GELFAND
• 金额: $ 44.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240397
• 关键词: activation product; antibody; burn therapy; burns; complement pathway; cytokine; cytokine receptors; human subject; human therapy evaluation; immunoglobulin structure; immunoregulation; immunotherapy; inflammation; interleukin 1; interleukin 10; monocyte; platelet activation; protein structure function; selectins; tumor necrosis factor alpha

Our central hypothesis is that burn injury may result in the activation of inflammatory mechanisms and the generation of dysfunctional levels of potent mediators. In effect, an "escape from control". These mediators in turn lead to a prolonged, intensive inflammatory/hypermetabolic response, providing a self-destructive process which adds to the physical injury of the burn. We have approached burn injury as the ultimate form of "inflammatory disease". Our initial studies focused on the role of complement activation as a major pathophysiologic component of burn injury. We found that, in patients, animals and in vitro, thermal injury activated complement, generating the anaphylatoxins C5a and C3a. More recently, our efforts turned to the role of cytokines in burn injury, sepsis, and shock. We now believe there is a major link between complement activation and cytokine generation and regulation. Thus, to design therapies to ensure a optimal host response to burn injury, we propose to study various factors involved in the stimulation, regulation, and inhibition of mediators involved in burn injury, drawing on our own expertise to focus on the proinflammatory cytokines and complement. Our specific aims are to: 1) characterize the precise structure-functional relationships whereby C5a stimulates cytokinemia. We have evidence to suggest that, by understanding precisely how C5a stimulates cytokine transcription and translation, we may intervene, therapeutically in this process; 2) study cytokine stimulation by activated platelets, again with an eye towards therapy; 3) better understand the recently documented differences in initial cytokine production in pure burn injury and in endotoxemia and Gram-positive infection. We specifically believe injury "primes" cells early in injury to produce proinflammatory cytokines and that they later become "hyposensitized", adding to immune dysregulation; 4) characterize specific organ cytokine production and related dysfunction; 5) further localize this to the cellular level; 6) characterize the regulation of cytokine responses of PBMCs in burn patients and correlate these with clinical parameters; 7) study expression of IL-1 receptors by cells of burn patients, as compared to normals; 8) develop a model in rats to study specific cytokine inhibitors in burns; 9) study endogenous IL-l receptor antagonist and TNF-binding protein in burn patients and normals, to define the response and establish levels necessary for therapy; 10) determine anaphylatoxin (C3a, C5a) control of IL-1 receptor antagonist, TNF-binding protein, or the inhibitory cytokine IL-10. The intent of all of these is ultimately to better regulate the inflammatory response to the benefit of the burn patient.

我们的中心假设是，烧伤可能导致激活 炎症机制和产生功能失调的水平， 有效的调解人。 实际上，这是一种“逃离控制”。 这些介质 继而导致长期、强烈炎症/代谢亢进 反应，提供了一个自我毁灭的过程，增加了物理 烧伤的伤害。 我们已经接近烧伤作为最终形式 “炎症性疾病”。 我们最初的研究集中在 补体激活是烧伤的主要病理生理组成部分 损伤 我们发现，在患者、动物和体外实验中， 激活补体，产生过敏毒素C5 a和C3 a。 更 最近，我们的努力转向烧伤损伤中细胞因子的作用， 败血症和休克 我们现在相信 补体激活和细胞因子的产生和调节。 从而 设计治疗方法，以确保最佳的主机响应烧伤，我们 建议研究参与刺激，调节， 和抑制介质参与烧伤，借鉴我们自己的 专业知识，专注于促炎细胞因子和补体。 我们 具体目标是：1）表征精确的结构-功能 C5 a刺激细胞因子血症的关系。 我们有证据 这表明，通过精确理解C5 a如何刺激细胞因子， 转录和翻译，我们可以干预，治疗，在这方面， 过程; 2）研究活化血小板的细胞因子刺激，再次用 对治疗的看法; 3）更好地理解最近记录的 单纯烧伤和烧伤后早期细胞因子产生的差异 内毒素血症和革兰氏阳性菌感染。 我们特别认为 在损伤早期“启动”细胞以产生促炎细胞因子， 他们后来变得“低敏”，增加了免疫失调; 4)表征特定器官细胞因子产生和相关 功能障碍; 5）进一步将其定位于细胞水平; 6） 表征烧伤中PBMC的细胞因子应答的调节 患者并将其与临床参数相关联; 7）研究 烧伤患者细胞的IL-1受体表达，与 8）在大鼠中建立模型以研究特异性细胞因子抑制剂 9）研究内源性IL-1受体拮抗剂和TNF-α结合 烧伤患者和正常人的蛋白质，以确定反应， 确定治疗所需的水平; 10）测定过敏毒素（C3 a， C5 a）IL-1受体拮抗剂、TNF-结合蛋白的控制，或 抑制性细胞因子IL-10。 所有这些的目的最终都是为了 更好地调节炎症反应， 病人