THERMAL INJURY INDUCED ALTERATIONS IN IMMUNE FUNCTION

免疫功能障碍、对脓毒症的易感性和多器官衰竭是与热损伤相关的并发症。有证据表明，烧伤后促炎症级联反应的激活在其发展过程中起着重要作用。在这方面，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。然而，导致Mphi活性改变的确切机制尚不清楚。我们采用了小鼠烫伤模型(三度烫伤，总体表面积的25%)，初步结果表明，烧伤后4-7天，随着一氧化氮、肿瘤坏死因子-α、IL-6和前列腺素E_2生产能力的增加，MPHI“过度活跃”。此外，在烧伤后4-7天，但不是更早的时候，Mphi过度活跃导致T细胞功能受到抑制，而在烧伤后7天，小鼠更容易受到脓毒症的致命影响。至于T细胞，我们观察到在最初的48小时内有显著的死亡率(约75%)。缺乏伽马/德尔塔T细胞(伽马/德尔塔T细胞敲除小鼠)的小鼠在烧伤后7天从存活的小鼠中分离到的MPHI似乎并不“过度活跃”。这些发现表明，γ/Delta T细胞在烧伤发病机制中具有双重作用：1)早期存活；2)后期诱导Mphi过度活动。我们的初步结果表明，烧伤后Mphi高活性与cAMP敏感性的改变有关，然而，导致烧伤后Mphi高活性的介质和机制及其在免疫功能障碍中的作用仍未阐明。此外，烧伤切除这一常见的临床做法对烧伤后Mphi过度活动和脓毒症易感性的影响尚不清楚。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。因此，我们建议确定以下内容：1)伽马/德尔塔T细胞、MPHI和早期存活(最初48小时)之间的关系。烧伤后；2)γ/Delta T细胞在烧伤后晚期(7天)Mphi过度活动中的作用；3)烧伤后Mphi过度活动的机制；4)烧伤创面切除对Mphi过度活动和增加脓毒症易感性的影响。更全面地了解烧伤后Mphi活性、T细胞功能与免疫功能障碍之间的关系，有望为改进烧伤患者的治疗方案提供依据。

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.