AUGMENTED INJURY DUE TO AUTOLOGOUS INFLAMMATORY ATTACK

自体炎症发作导致损伤加重

• 批准号: 6600689
• 负责人: FRANCIS D MOORE
• 金额: $ 157.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6600689
• 关键词: clinical research; human subject; injury; ischemia; reperfusion

This proposal represents a continuing highly integrated examination of the mechanisms by which injured tissue elicits a response from the host and of the harmful effects of this response. Data derived from our past studies of the complement pro-inflammatory serum protein system suggests that, in model reperfusion injury of several organs, the complement response causes more of an injury than the original ischemic insult itself. Accordingly, inhibition of complement activation by a variety of means or in a variety of genetically modified mice has produced a diminution in the degree of final injury. Therefore, we hypothesize that major injury is critically exacerbated by the autologous inflammatory response. We wish (1) to understand the mechanism by which injured tissue activates the inflammatory response, (2) to understand the specific sequence of events leading from an ischemic insult to inflammatory activation, (3) to modify the antibody-binding component of the immune system activation caused by reperfusion injury, (4) to fully characterize human reperfusion injury and attempt to ameliorate it with the knowledge gained from this grant to date, and (5) to synthesize these data to produce an effective therapeutic strategy to reduce the degree of tissue damage which results from a specific injury occurrence. The Trauma Center Core (Project I) will provide the financial support for the knock-out mice used by 3 of the projects, the data support for the clinical project, and the administrative support for the overall grant and its outreach programs. Project II will use techniques of molecular biology to identify potential neoantigens on injured tissue. Project III will investigate and modify a range of murine B1 cell natural antibody clones to fully define the role of natural antibody in reperfusion injury. Project IV will investigate the role of mast cell degranulation in the genesis of reperfusion injury and resulting complement activation. Project V will characterize human mesenteric reperfusion injury utilizing newly available techniques. By this funding mechanism, we wish to efficiently, and by multiple techniques, arrive at specific therapy for mesenteric reperfusion injury, the related injury of other organ systems, and an avenue of prevention for organ failure following massive traumatic injury and its accompanying shock.

这一建议代表了对受损组织激发宿主反应的机制以及这种反应的有害影响的持续高度综合的研究。来自我们过去补体促炎血清蛋白系统研究的数据表明，在几个器官的再灌注损伤模型中，补体反应比原始缺血性损伤本身引起更多的损伤。因此，通过各种手段或在各种遗传修饰的小鼠中抑制补体活化已经产生了最终损伤程度的降低。因此，我们假设严重的损伤是严重加剧了自体炎症反应。我们希望（1）了解 损伤组织激活炎症反应的机制，（2）了解从缺血损伤到炎症激活的特定事件顺序，（3）修饰由再灌注损伤引起的免疫系统激活的抗体结合组分，（4）充分表征人类再灌注损伤并试图用迄今为止从该授权获得的知识改善它，以及（5）综合这些数据以产生有效的治疗策略，从而降低由特定损伤发生引起的组织损伤程度。创伤中心核心（项目I）将为其中3个项目使用的基因敲除小鼠提供财政支持，为临床项目提供数据支持，并为整体赠款及其推广计划提供行政支持。项目II将使用分子生物学技术来鉴定受损组织上潜在的新抗原。项目III将研究和修改一系列鼠B1细胞天然抗体克隆， 明确天然抗体在再灌注损伤中的作用。项目四将研究肥大细胞脱颗粒在再灌注损伤和由此产生的补体激活的发生中的作用。项目V将利用新的可用技术表征人类肠系膜再灌注损伤。通过这种资助机制，我们希望通过多种技术有效地达到肠系膜再灌注损伤的特异性治疗，其他器官系统的相关损伤，以及预防大规模创伤性损伤及其伴随的休克后器官衰竭的途径。