Adenosine in trauma and sepsis

多器官功能衰竭（MOF）是外科重症监护病房中50%至80%的死亡原因。据记载，MOF发生在许多不同的临床条件下，包括机械和热创伤，胰腺炎和休克。 在一个大的患者亚组中，继发性感染可引发MOF的发展，这与过度代偿性抗炎反应（汽车）和全身免疫抑制状态的发展有关。 汽车的特征在于患者免疫表型的几种变化。 这些免疫表型变化中最重要的两个是辅助性T（Th）细胞群从Th 1应答转变为Th 2应答，以及巨噬细胞表型从促炎性转变为抗炎性。 巨噬细胞表型的这种转变的特征在于IL-12产生的减少和IL-10产生的增加。负责这种改变的免疫表型的发展的信号或机制尚未完全阐明。 最近，有人提出，这种免疫抑制状态可能是继发于各种介质，包括儿茶酚胺和糖皮质激素的激活应激系统的过度释放。 此外，似乎腺苷（ADO），另一种应激介质过度释放在汽车期间，也可能有助于在汽车中看到的免疫瘫痪，因为ADO似乎加强免疫受损状态的发展。 使用抗CD 3刺激的小鼠脾细胞系统，我们最近发现，细胞外ADO增加了Th 2细胞因子IL-4的产生，而它减少了Th 1细胞因子干扰素-γ的产生。 此外，我们已经获得证据表明，ADO增强免疫刺激的巨噬细胞产生IL-10和减少IL-12。 因此，我们将调查的假设，高细胞外浓度的ADO可能有助于有害的免疫低反应性观察汽车患者。 由于ADO通过与4种特异性细胞表面受体中的任何一种结合来发挥其生物学效应，我们还假设ADO通过激活T细胞和巨噬细胞上存在的某些ADO受体将免疫应答从促炎性转变为抗炎性。 我们将测试这些假设在体外使用T细胞和巨噬细胞系统，以及在体内使用小鼠盲肠结扎和穿孔模型的MOF。

Multiple organ failure (MOF) is the cause of 50 percent to 80 percent of all deaths in surgical intensive care units. MOF is documented to occur after a number of diverse clinical conditions, including mechanical and thermal trauma, pancreatitis and shock. In a large subgroup of patients, secondary infections serve to trigger the development of MOF, which is related to the development of an excessive compensatory anti-inflammatory reaction (CARS) and a generalized immunosuppressive state. CARS is characterized by several changes in the patients' immune phenotype. Two of the most important of these immune-phenotypic changes are a shift in T helper (Th) cell population from a Th1 to a Th2 response and shift in the macrophage phenotype from a proinflammatory to an anti-inflammatory one. This shift in the macrophage phenotype is characterized by a decrease in the production of IL-12 and an increase in the production of IL-10. Neither the signals nor mechanisms responsible for the development of this altered immune phenotype have been fully elucidated. Recently, it has been proposed that this immunosuppressed state may be secondary to the excessive release of a variety of mediators including catecholamines and glucocorticoids by activation of the stress system. In addition, it appears that adenosine (ADO), another stress mediator released excessively during CARS, could also contribute to the immune paralysis seen in CARS, since ADO appears to potentiate the development of an immune compromised state. Using an anti-CD3- stimulated mouse spleen cell system, we have recently discovered that extracellular ADO augments the production of the Th2 cytokine IL-4, whereas it reduces the production of the Th1 cytokine interferon-gamma. In addition, we have obtained evidence that ADO enhances IL-10 and decreases IL-12 production by immunostimulated macrophages. Thus, we will investigate the hypothesis that high extracellular concentrations of ADO may contribute to the deleterious immune hyporesponsiveness observed in patients with CARS. Because ADO exerts its biological effects by binding to any of 4 specific cell surface receptors, we also hypothesize that ADO shifts the immune response from a proinflammatory to an anti-inflammatory one through the activation of certain ADO receptors present on T cells and macrophages. We will test these hypotheses both in vitro using T cell and macrophage systems as well as in vivo using the mouse cecal ligation and puncture model of MOF.