THERMAL INJURY INDUCED ALTERATIONS IN IMMUNE FUNCTION

描述（由申请人提供）：烧伤损伤后促炎级联的激活似乎在随后的免疫功能障碍、败血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，在烧伤后观察到其生产能力增加。因此，Mphi过度活跃（通过增加促炎介质的生产能力来定义）可能对这些并发症的发生至关重要。尽管如此，导致M？活动尚不清楚。我们利用小鼠烫伤模型（三度，体表面积25%），我们的初步结果表明，烧伤后4-7天Mphi“过度活跃”（一氧化氮、tnf - α、IL-6和PGE2的生产能力增加），T细胞功能受到抑制，对败血症的易感性增加。在最初的48小时内，我们观察到显著的死亡率（约75%）。缺乏γ / δ T细胞的小鼠（γ / δ T细胞敲除小鼠）和M？从烧伤后7天存活小鼠中分离出来的小鼠似乎没有“过度活跃”。这些发现表明？/？T细胞在烧伤发病机制中的作用1)早期生存；2) M？以后多动。M的表达式？烧伤后多动似乎与cAMP敏感性改变有关，然而，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，目前尚不清楚烧伤后固定组织免疫细胞功能的变化是否与外周血单核细胞（PBMC）功能的变化相关，这是临床评估的。我们的假设是，烧伤后Mphi过度活跃是由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)烧伤后早期（最初48小时）γ / δ T细胞与Mphi带存活之间的关系；？/?的作用T细胞诱导M？烧伤后期（7天）多动；3) M？多动症烧伤后;4)烧伤对PBMC功能的影响。更全面地了解M？热损伤后T细胞活性、T细胞功能和免疫功能的变化有望为改进烧伤患者的治疗方案提供依据。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。该奖项以及外科研究中心开展这些研究的良好环境将极大地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.