THERMAL INJURY INDUCED ALTERATIONS IN IMMUNE FUNCTION

描述(由申请人提供)：烧伤后促炎性级联反应的激活在随后的免疫功能障碍、败血症和多器官衰竭的发展中似乎是重要的。巨噬细胞(Mphi)是促炎介质的主要生产者，烧伤后可观察到生产能力的增加。因此，MPHI过度活动(定义为促炎介质生产能力的增加)在这些并发症的发生中可能是至关重要的。尽管如此，导致M？活动情况尚不清楚。我们采用了一种小鼠烫伤模型(三度烫伤，总体表面积的25%)，我们的初步结果表明，在烧伤后4-7天，MPHI处于“过度活跃”状态(一氧化氮、肿瘤坏死因子-α、IL-6和PGE2的生产能力增加)，T细胞功能受到抑制，脓毒症的易感性增加。在最初的48小时内，我们观察到显著的死亡率(约75%)。烧伤后缺乏γ/Delta T细胞的小鼠(Gamma/Delta T细胞敲除小鼠)和M？从烧伤后7天存活的小鼠身上分离出来的病毒似乎并不“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)早期存活；2)M？以后会有多动症。M？烧伤后多动似乎与cAMP敏感性改变有关，然而，导致烧伤后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临床评估的外周血单个核细胞(PBMC)功能的变化相关。我们的假设是烧伤后Mphi过度活动是由γ/Delta T细胞和改变的cAMP反应介导的，从而导致免疫功能障碍的发生。我们建议确定以下内容：1)γ/Delta T细胞与早期(最初48小时)Mphi带存活期之间的关系。烧伤后；2)？/？T细胞在诱导M？烧伤后晚期(7天)多动；3)M？烧伤后多动；4)烧伤对PBMC功能的影响。更全面地认识M？烧伤后的活性、T细胞功能和免疫功能障碍有望为改进烧伤患者的治疗方案提供依据。申请者研究的长期目标是确定导致热损伤后免疫功能障碍的介质和机制。这一奖项加上外科研究中心进行这些研究的良好环境，将极大地促进申请者作为独立调查者的进一步发展。

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.