BIOCHEMISTRY OF NEUTROPHIL DYSFUNCTION IN THERMAL INJURY

热损伤导致大鼠脑内主要效应器功能的严重抑制 中性粒细胞的作用机制目前知之甚少。最近来自 我们的实验室使用了一种豚鼠烫伤模型 证明细胞内环-3‘，5’-腺苷一磷酸(CAMP) 对热损伤的反应是升高的，这反过来又抑制了 这些细胞的杀菌活性。超氧阴离子(O2-)生产 用甲酰甲硫基-亮氨酰-苯丙氨酸(fMet-Leu- Phe)在该模型中随之减少，这表明这 改变也可能与细胞内cAMP升高有关。这个 在这项申请中提出的研究将确定生化事件 导致产生O2-，而这些O2-会因几内亚的热损伤而改变 猪模型(即生产肌醇磷酸，1，2-二酰基甘油 胞浆钙和蛋白激酶C的产生、升高 激活)。此外，细胞内cAMP参与了 介导这些改变和对fMet-1的适应性趋化反应 我们在这个模型中观察到的Leu-Phe将被确定。 FMet-Leu-Phe受体亲和力的修饰 FMet-Leu-Phe适应性趋化反应的机制也将 被探索。腺苷环化酶系统参与血管内皮细胞 烫伤后中性粒细胞内cAMP的升高 循环因子在调节这一过程和其他生化反应中的作用 与中性粒细胞功能障碍相关的改变将在 豚鼠模型。此外，当前的概念源自我们的 动物研究将在#年接受验证性临床研究。 人类。了解中性粒细胞功能障碍的生化基础 热损伤后是确定是否 这种改变可以通过药物干预来逆转。 受伤患者和此类干预的目标地点。基本信息 这项研究得出的概念也可能适用于中性粒细胞。 与其他形式的创伤相关的功能障碍。

Thermal injury induces a profound depression in major effector functions of neutrophils by mechanisms that are poorly understood. Recent studies from our laboratory utilizing a guinea pig model of thermal injury have demonstrated that intracellular cyclic-3',5'-adenosine monophosphate (cAMP) is elevated in response to thermal injury, and this in turn depresses the bactericidal activity of these cells. Superoxide anion (O2-) production following stimulation with formylmethionyl-leucyl-phenylalanine (fMet-Leu- Phe) is reduced concomitantly in this model, suggesting that this alteration also may be related to elevation of intracellular cAMP. The studies proposed in this application will identify the biochemical events leading to O2- production that are altered by thermal injury in the guinea pig model (i.e., inositol phosphate production, 1,2-diacylglycerol production, elevation of cytosolic calcium and protein kinase C activation). In addition, the involvement of intracellular cAMP in mediating these alterations and the adaptive chemotactic response to fMet- Leu-Phe that we have observed in this model will be determined. Modification of the affinity of fMet-Leu-Phe receptors as a possible mechanism for the adaptive chemotactic response to fMet-Leu-Phe also will be explored. The involvement of the adenylate cyclase system in the elevation of intracellular cAMP in neutrophils following thermal injury and the role of circulating factors in mediating this and other biochemical alterations associated with neutrophil dysfunction will be determined in the guinea pig model. In addition, current concepts derived from our animal studies will be subjected to confirmatory clinical investigation in humans. Understanding the biochemical basis for neutrophil dysfunction following thermal injury is an essential first step in determining whether this alteration can be reversed by pharmacologic intervention in thermally injured patients and the target sites for such intervention. Basic concepts resulting from this research also may be applicable to neutrophil dysfunction associated with other forms of trauma.