PATHOPHYSIOLOGICAL BIOCHEMICAL CHANGES OF THERMAL INJURY

描述（由申请人提供）：先前的研究表明，通过Toll/IL-1途径的信号传导在烧伤创伤的器官反应中起作用。本申请将扩展这些研究，解决Toll/IL-1途径是一种损伤反应系统的假设，该系统感知除感染外的损伤;该途径的主要功能是检测/限制局部损伤。研究将检验烧伤产生类似感染的初始损伤的假设，这反过来又增加了败血症的易感性。具体目标1检验了以下假设：烧伤产生与肠道屏障功能丧失/内毒素/细菌移位相关的感染样损伤，提供触发烧伤后先天性宿主反应的近端信号;将检查消化道选择性去污对烧伤后继发脓毒症（IT链球菌或肺炎克雷伯菌）反应的影响。特异性目的2检查了免疫细胞中Toll/IL-1信号传导对烧伤后心脏反应的贡献。使用组织相容性小鼠品系之间的过继转移，我们将产生TLR 4嵌合体：具有TLR 4 +/+免疫系统的TLR 4缺陷小鼠或在造血细胞中缺乏TLR 4的TLR 4 +/+动物。具体目标3检验了心肌细胞特异性Toll/IL-1信号传导在烧伤创伤后心肌炎症/功能障碍中起作用的假设。转基因方法将允许在TLR 4缺陷小鼠的心肌细胞中重建TLR 4介导的信号传导。特异性目标4将确定烧伤相关心肌炎症/功能障碍中TLR 4活性是否需要CD 14信号传导。将在给予烧伤（或假烧伤）损伤的CD 14敲除小鼠中和给予可溶性CD 14的CD 14敲除烧伤中检查CD 14活性是否是烧伤创伤后Toll/IL-1信号传导的先决条件，以重建CD 14/TLR 4信号传导。具体目标5将检验烧伤后心肌炎症/损伤/功能障碍程度预测感染/脓毒症易感性的假设。在大鼠和人（人体核心）中测量的超声心动图、血清肌钙蛋白和心率变异性将确定这些指标是否识别出脓毒症风险增加的受试者。这些研究应该识别激活信号传导途径导致烧伤/脓毒症相关炎症/功能障碍的细胞外信号，允许开发提供心脏保护的治疗策略，不仅为烧伤创伤的受害者，而且为心脏功能障碍导致死亡率增加的患者群体。

DESCRIPTION (provided by applicant): Previous studies suggested that signaling through Toll/IL-1 pathway plays a role in organ responses to burn trauma. This application will extend these studies, addressing the hypothesis that Toll/IL-1 pathway is an injury response system which senses injury other than infection; a primary function of this pathway is to detect/limit local injury. Studies will examine the hypothesis that burn injury produces an initial insult resembling infection, which in turn, increases susceptibility to sepsis. Specific Aim 1 examines the hypothesis that burn injury produces an infectious-like injury related to loss of gut barrier function/translocation of endotoxin/bacteria, providing one proximal signal that triggers postburn innate host response; effects of selective decontamination of the digestive tract on postburn responses to subsequent sepsis (IT Streptococcus or Klebsiella pneumoniae) will be examined. Specific Aim 2 examines contribution of Toll/IL-1 signaling in immune cells to postburn cardiac responses. Using adoptive transfer between histocompatible mouse strains, we will generate TLR4 chimeras: TLR4 deficient mice with TLR4 +/+ immune systems or TLR4 +/+ animals lacking TLR4 in hematopoietic cells. Specific Aim 3 examines the hypothesis that cardiomyocyte-specific Toll/IL-1 signaling plays a role in myocardial inflammation/dysfunction after burn trauma. A transgenic approach will allow reconstitution of TLR4-mediated signaling in cardiomyocytes of TLR4 deficient mice. Specific Aim 4 will determine if CD14 signaling is required forTLR4 activity in burn-related myocardial inflammation/dysfunction. Whether CD14 activity is a pre-requisite for Toll/IL-1 signaling after burn trauma will be examined in CD14 knockout mice given burn (or sham burn) injury and in CD14 knockout burns given soluble CD14 to reestablish CD14/TLR4 signaling. Specific Aim 5 will examine the hypothesis that the degree of myocardial inflammation/injury/dysfunction after burn injury predict susceptibility to infection/sepsis. Echocardiography, serum troponin, and heart rate variability measured in rats and man (Human Core) will determine if these measures identify subjects at increased risk for sepsis. These studies should identify extracellular signals which activate signal transduction pathways leading to burn/sepsis related inflammation/dysfunction, allow development of therapeutic strategies providing cardioprotection, not only for victims of burn trauma but also for patient populations in whom cardiac dysfunction contributes to increased mortality.