THERMAL INJURY INDUCED ALTERATIONS IN IMMUNE FUNCTION

描述（由申请人提供）：烧伤后促炎级联反应的激活似乎在随后免疫功能障碍、脓毒症易感性和多器官衰竭的发展中很重要。巨噬细胞（Mphi）是促炎介质的主要生产者，在烧伤后观察到生产能力增加。因此，Mphi活动过度（定义为促炎介质的生产能力增加）可能在这些并发症的发展中至关重要。尽管如此，负责M？活动不清楚。我们已经利用了鼠烧伤模型（3度，25%总体表面积），并且我们的初步结果表明，在烧伤后4-7天，Mphi是“过度活跃的”（增加的一氧化氮、TNF-α、IL-6和PGE 2的生产能力），T细胞功能被抑制，并且存在对脓毒症的增加的易感性。我们已经观察到显着的死亡率（约75%）在最初的48小时。烧伤后期间，在小鼠缺乏γ/δ T细胞（γ/δ T细胞敲除小鼠）和M？从烧伤后7天存活的小鼠中分离出的细胞似乎不是“过度活跃的”。这些研究结果表明，双重作用？/？烧伤发病机制中的T细胞; 1）早期存活; 2）M？之后的过度活跃。表达M？烧伤后多动似乎与对cAMP敏感性的改变有关，然而，负责烧伤后Mphi多动和免疫功能障碍的介质和机制尚不清楚。此外，目前还不清楚烧伤后固定组织免疫细胞功能的变化是否与临床评估的外周血单核细胞（PBMC）功能的变化相关。我们的假设是烧伤后Mphi活动过度是由γ/δ T细胞介导的，cAMP反应的改变导致免疫功能障碍的发展。我们建议确定以下内容：1）γ/δ T细胞，Mphi带存活早期（最初48小时）之间的关系。烧伤后; 2）的作用？/？T细胞在M？过度活跃后期（7天）烧伤后; 3）负责M？烧伤后高活动度; 4）烧伤对PBMC功能的影响。更全面地了解M？烧伤后T细胞活性、T细胞功能和免疫功能的变化有望为烧伤患者的治疗方案的改进提供依据。申请人研究的长期目标是确定热损伤后免疫功能障碍的介质和机制。该奖项沿着外科研究中心开展这些研究的优良环境，将大大促进申请人作为独立研究者的进一步发展。

DESCRIPTION (provided by applicant): The activation of a pro-inflammatory cascade after bum injury appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. Macrophages (Mphi) are major producers of pro-inflammatory mediators with increased productive capacity being observed post-burn. Thus, Mphi hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) may be of critical importance in the development of these complications. Nonetheless, the mechanisms responsible for the alterations in M? activity are unclear. We have utilized a murine scald burn model (3rd degree, 25% total body surface area) and our preliminary results indicated that at 4-7 days post-burn Mphi were "hyperactive" (increased productive capacity for nitric oxide, TNF-alpha, IL-6 and PGE2), T cell function is suppressed and increased susceptibility to sepsis exists. We have observed significant mortality (approximately 75%) during the initial 48 hr. post-burn period in mice lacking gamma/delta T cells (gamma/delta T cell knock-out mice) and M? isolated from surviving mice at 7 days post-burn appear not to be "hyperactive". These findings suggest a dual role for ?/? T cells in burn injury pathogenesis; 1) survival early and; 2) induction of M? hyperactivity later. The expression of M? hyperactivity post-burn appears to be related to altered sensitivity to cAMP, however, the mediators and mechanisms responsible for Mphi hyperactivity and immune dysfunction post-burn are unknown. Moreover, it is unclear whether changes in fixed tissue immune cell function post-burn correlate with changes in peripheral blood mononuclear cell (PBMC) function, which is assessed clinically. It is our hypothesis that Mphi hyperactivity post-burn is mediated by gamma/delta T cells and altered cAMP responses leading to the development of immune dysfunction. We propose to determine the following: 1) The relationship between gamma/delta T cells, Mphi band survival early (initial 48 hr.) post-burn; 2) The role of ?/? T cells in the induction of M? hyperactivity late (7 days) post-burn; 3) The mechanisms responsible for M? hyperactivity post-burn; and 4) The effect of burn injury on PBMC function. A more comprehensive understanding of the relationship between M? activity, T cell function, and immune dysfunction after thermal injury should hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients. The long term goals of the applicant's research are to determine the mediators and mechanisms responsible for immune dysfunction after thermal injury. This award along with the excellent environment in the Center for Surgical Research for conducting these studies will significantly facilitate the applicant's further development as an Independent Investigator.