IMPROVED BURN THERAPY THROUGH THE REGULATION OF INFLAMMATION

通过调节炎症改善烧伤治疗

• 批准号: 5212043
• 负责人: JEFFREY A GELFAND
• 金额: --
• 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/5212043
• 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; 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 炎症机制和功能障碍水平的产生 强有力的调解人。实际上，这是一种“逃离控制”。这些调解人 进而导致长期、强烈的炎症/高代谢 响应，提供了一个自我毁灭的过程，这增加了物理 烧伤造成的伤害。我们已经将烧伤作为终极形式 “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成分 受伤。我们发现，在患者、动物和体外，热损伤 激活补体，产生过敏毒素C5a和C3a。更多 最近，我们的努力转向细胞因子在烧伤中的作用， 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。因此，要 设计治疗方法以确保对烧伤的最佳宿主反应，我们 建议研究涉及刺激、调节、 以及抑制参与烧伤损伤的介体，依靠我们自己 专注于促炎细胞因子和补体的专业知识。我们的 具体目标是：1)表征精确的结构-功能 C5a刺激细胞分裂素血症的关系。我们有证据证明 建议，通过准确了解C5a是如何刺激细胞因子的 转录和翻译，我们可能会介入，在治疗方面 过程；2)研究激活的血小板对细胞因子的刺激，再次使用 着眼于治疗；3)更好地理解最近记录的 单纯烧伤与烧伤患者初始细胞因子产生的差异 内毒素血症与革兰氏阳性感染。我们特别认为受伤 “启动”细胞在损伤早期产生促炎细胞因子和 它们后来变得“低敏”，加剧了免疫失调； 4)表征特定器官细胞因子的产生和相关 功能障碍；5)进一步定位于细胞水平；6) 烧伤时外周血单核细胞细胞因子反应的调控特征 患者及其与临床参数的相关性；7)研究 烧伤患者细胞IL-1受体表达的比较 正常；8)建立大鼠模型以研究特定的细胞因子抑制物 内源性IL-L受体拮抗剂与肿瘤坏死因子结合的研究 蛋白质在烧伤患者和正常人中的表达，以确定反应和 建立治疗所需的水平；10)测定过敏毒素(C3a， C5a)控制IL-1受体拮抗剂、肿瘤坏死因子结合蛋白或 抑制性细胞因子IL-10。所有这些措施的最终目的是 更好地调节炎症反应，有利于烧伤 有耐心的。