Adenosine in trauma and sepsis

多器官衰竭(MOF)是外科重症监护病房50%至80%死亡的原因。多器官功能衰竭是在多种不同的临床条件下发生的，包括机械和热创伤、胰腺炎和休克。在一大群患者中，继发性感染有助于触发MOF的发展，这与过度的代偿性抗炎反应(CARS)和全身性免疫抑制状态的发展有关。CARS的特点是患者的免疫表型发生了几个变化。其中两个最重要的免疫表型改变是辅助性T细胞(Th)从Th1反应转变为Th2反应，以及巨噬细胞表型从促炎转变为抗炎。巨噬细胞表型的这种转变的特征是IL-12的产生减少，而IL-10的产生增加。导致这种改变的免疫表型的信号和机制尚未完全阐明。最近，有人提出，这种免疫抑制状态可能是由于应激系统的激活而导致包括儿茶酚胺和糖皮质激素在内的多种介质过度释放所致。此外，另一种在CARS过程中过度释放的应激介质腺苷(ADO)似乎也可能导致CARS中出现的免疫瘫痪，因为ADO似乎会促进免疫受损状态的发展。利用抗CD3刺激的小鼠脾细胞系统，我们最近发现细胞外ADO增加了Th2细胞因子IL-4的产生，而它减少了Th1细胞因子干扰素-γ的产生。此外，我们还获得了ADO通过免疫刺激的巨噬细胞增加IL-10和减少IL-12产生的证据。因此，我们将调查这一假设，即细胞外高浓度的ADO可能导致CARS患者观察到的有害免疫低反应。由于ADO通过与4种特定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受体而将免疫应答从促炎反应转变为抗炎反应。我们将在体外使用T细胞和巨噬细胞系统以及在体内使用MOF的小鼠盲肠结扎和穿孔模型来验证这些假说。

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.