PATHOPHYSIOLOGICAL BIOCHEMICAL CHANGES OF THERMAL INJURY

描述(申请人提供)：先前的研究表明，通过Toll/IL-1途径的信号在烧伤创伤的器官反应中发挥作用。这一应用将扩展这些研究，解决Toll/IL-1途径是一个损伤反应系统的假设，该系统感知感染以外的损伤；该途径的主要功能是检测/限制局部损伤。研究将检验这一假设，即烧伤会产生类似感染的初始侮辱，这反过来会增加脓毒症的易感性。具体目的1研究烧伤引起感染性损伤与肠道屏障功能丧失/内毒素/细菌移位有关的假说，提供一个触发烧伤后先天宿主反应的近端信号；将检测选择性消化道净化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。特异性目标2研究免疫细胞中Toll/IL-1信号对烧伤后心脏反应的作用。通过组织相容的小鼠品系间的过继转移，我们将产生TLR4嵌合体：具有TLR4+/+免疫系统的TLR4缺陷小鼠或造血细胞中缺乏TLR4的TLR4+/+动物。特定目标3检验了心肌细胞特异性Toll/IL-1信号在烧伤后心肌炎症/功能障碍中起作用的假说。转基因方法将允许在TLR4缺陷小鼠的心肌细胞中重建TLR4介导的信号。特定的目标4将确定在烧伤相关的心肌炎症/功能障碍中，TLR4的活性是否需要CD14信号。CD14活性是否是烧伤后Toll/IL-1信号传递的先决条件，将在烧伤(或假烧伤)后CD14基因敲除小鼠中进行检测，并在CD14基因敲除烧伤中给予可溶性CD14以重建CD14/TLR4信号。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。超声心动图、血清肌钙蛋白和心率变异性在大鼠和人(人类核心)中的测量将确定这些测量是否识别出败血症风险增加的受试者。这些研究应该确定激活导致烧伤/脓毒症相关炎症/功能障碍的信号转导通路的细胞外信号，允许开发治疗策略，不仅为烧伤创伤的受害者提供心脏保护，也为心脏功能障碍导致死亡率增加的患者群体提供保护。

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.