THERMAL INJURY INDUCED ALTERATIONS IN IMMUNE FUNCTION

免疫功能障碍、脓毒症易感性和多器官功能衰竭是与热损伤相关的并发症。有证据表明，烧伤后促炎级联反应的激活在其发展中起着重要作用。关于这一点，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具有根本的重要性。 然而，Mphi活性改变的确切机制尚不清楚。 我们已经利用了鼠烧伤模型（三度，25%的总体表面积），我们的初步结果表明，在烧伤后4-7天，Mphi是“过度活跃的”，因为观察到一氧化氮、TNF-α、IL-6和PGE 2的生产能力增加。 此外，在烧伤后4-7天，但不是更早，Mphi活动过度是T细胞功能抑制的原因，在烧伤后7天，小鼠对脓毒症的致死作用明显更敏感。关于T细胞，我们已经观察到在缺乏γ/δ T细胞的小鼠（γ/δ T细胞敲除小鼠）中在烧伤后最初48小时期间显著的死亡率（约75%），并且从烧伤后7天的存活小鼠中分离的Mphi似乎不是“过度活跃的”。 这些发现表明γ/δ T细胞在烧伤发病机制中的双重作用; 1）早期存活和; 2）以后诱导Mphi过度活跃。我们的初步研究结果表明，烧伤后Mphi高活性与CAMP敏感性的改变有关，但负责烧伤后Mphi高活性的介质和机制及其在免疫功能障碍中的作用仍有待阐明。 此外，烧伤切除，一种常见的临床实践，对Mphi活动过度和烧伤后脓毒症易感性的影响尚不清楚。 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。 因此，我们建议确定以下内容：1）γ/δ T细胞，Mphi和早期生存（最初48小时）之间的关系。烧伤后; 2）烧伤后晚期（7天）γ/δ T细胞在诱导Mphi过度活跃中的作用; 3）烧伤后Mphi过度活跃的机制;以及4）烧伤伤口切除对Mphi过度活跃和对脓毒症的易感性增加的影响。 更全面地了解Mphi活性、T细胞功能和热损伤后免疫功能障碍的发展之间的关系，有望为改善烧伤患者的治疗方案提供基础。

Immune dysfunction, susceptibility to sepsis and multiple organ failure are complications associated with thermal injury. Evidence suggests that activation of a pro-inflammatory cascade after burn injury plays an important role in their development. With regards to this, 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 fundamental importance in the development of these complications. Nonetheless, the precise mechanisms responsible for the alterations in Mphi activity are unclear. We have utilized a murine scald burn model (3rd degree, 25 percent total body surface area) and our preliminary results indicated that at 4-7 days post-burn Mphi were "hyperactive" as increased productive capacity for nitric oxide, TNF-alpha, IL-6 and PGE2 was observed. Furthermore, at 4-7 days post-burn, but not earlier, Mphi hyperactivity was responsible for the suppression of T cell function and at 7 days post-burn mice were significantly more susceptible to the lethal effects of sepsis. With regards to T cells, we have observed significant mortality (approximately 75 percent) during the initial 48 hr. post-burn period in mice lacking gamma/delta T cells (gamma/delta T cell knock-out mice) and Mphi isolated from surviving mice at 7 days post-burn appear not to be "hyperactive". These findings suggest a dual role for gamma/delta T cells in burn injury pathogenesis; 1) survival early and; 2) induction of Mphi hyperactivity later. Our preliminary results suggest that Mphi hyperactivity post-burn is related to alterations in sensitivity to CAMP, however, the mediators and mechanisms responsible for Mphi hyperactivity post-burn and its role in immune dysfunction remain to elucidated. Moreover, the impact of burn excision, a common clinical practice, on Mphi hyperactivity and susceptibility to sepsis post-burn is unknown. 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. Therefore, we propose to determine the following: 1) The relationship between gamma/delta T cells, Mphi and survival early (initial 48 hr.) post-burn; 2) The role of gamma/delta T cells in the induction of Mphi hyperactivity late (7 days) post-burn; 3) The mechanisms responsible for Mphi hyperactivity post-burn; and 4) The effect of burn wound excision on Mphi hyperactivity and increased susceptibility to sepsis. A more comprehensive understanding of the relationship between Mphi activity, T cell function, and the development of immune dysfunction following thermal injury should hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients.