Role of systemic hypothermia on inflammatory response and apoptosis in severe tissue injury

在严重组织损伤的炎症过程中，体温会发生变化，但体温对炎症反应的作用尚不清楚。体温调节反应从体温过低到发烧都有很大不同。尽管低温创伤患者的预后似乎更差，但有一个问题是，是低温本身还是产生低温的创伤的严重程度导致了死亡率的增加。拟议的项目重点研究亚低温如何调节局部和全身炎症反应以及组织损伤后的细胞凋亡。基于我们小组最近使用小鼠皮肤折叠室模型和高分辨率多荧光显微镜(FASE B J，2002)所做的工作，我们将评估低温(32°C-35°C)下严重损伤的p53+/+和p53-/-小鼠组织中的微血管、细胞和分子事件，强调低体温在P53介导的细胞凋亡组织死亡过程中的作用。此外，使用P53野生型和突变型细胞的体外方法进一步允许我们研究低于正常温度对细胞应激反应的影响。拟议的项目应该解决关于低温在严重创伤中的价值的争议，低温既是疾病的简单标志，也是疾病的主要贡献者。

Changes in body temperature occur during inflammation upon severe tissue injury, however the role of body temperature on inflammatory responses remains obscure. Thermoregulatory responses considerably vary from hypothermia to fever. Though hypothermic trauma patients seem to have a worse prognosis, there is the question whether it is the hypothermia per se or the severity of injury producing the hypothermia that is responsible for increased mortality. The proposed project focuses on how mild to moderate hypothermia modulates local and systemic inflammatory response and cell apoptosis upon tissue injury. Based on recent work of our group using the skinfold chamber model and high resolution multifluorescence microscopy in mice (FASEB J, 2002), we will assess microvascular, cellular and molecular events in severely injured tissue of p53+/+ and p53-/- mice with hypothermia (32°C-35°C), emphasising the role of low body temperature on the progress of p53-mediated apoptotic tissue death. Additionally, in vitro approaches using p53 wild-type and p53 mutant cells further allow us to study the effect of subnormal temperatures on cellular stress response. The proposed project should solve the controversy about the value of hypothermia in severe trauma, being either a simple marker of illness or a major contributor to disease.