Adenosine in trauma and sepsis

描述（由申请方提供）：由微生物侵入正常无菌的身体部位引发的全身性疾病称为败血症。脓毒症仍然是危重患者发病和死亡的主要原因。目前的概念表明，器官衰竭和 败血症的死亡率是由免疫系统的不适当调节引起的，其表现为在免疫抑制存在下的过度炎症。我们实验室收集的最新证据表明，脓毒症期间积累的细胞外腺苷通过激活免疫细胞表面的腺苷受体来调节免疫系统。细胞外腺苷的产生是其前体ATP和ADP的细胞释放的结果，以及它们的顺序细胞表面通过外核苷三磷酸二磷酸水解酶1（E-NTPDase 1，CD 39）磷酸水解为AMP，然后通过外-5 '-核苷酸酶（Ecto 5'Ntase，CD 73）磷酸水解为腺苷。我们发现，CD 39和CD 73在脓毒症期间上调，并通过启动腺苷受体信号传导在抑制炎症和器官损伤中起关键作用。Specific Aim 1将使用过继细胞转移技术、“cre-lox”技术和先天性免疫细胞的离体研究来测试CD 39和CD 73在脓毒症期间预防过度炎症和器官损伤的精确机制。具体目标2将定义巨噬细胞上CD 39和CD 73上调的分子基础，这可能有助于通过在脓毒症期间产生腺苷来抑制过度的巨噬细胞活化。本文的总体目标是描述由CD 39和CD 73组成的外核苷酸酶级联在预防脓毒症中的作用，并确定该级联是否可以在治疗上靶向管理脓毒症患者。

DESCRIPTION (provided by applicant): Systemic illness triggered by microbial invasion of normally sterile parts of the body is referred to as sepsis. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Current concepts suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune system, which manifests as excessive inflammation in the presence of immunosuppression. Recent evidence gathered in our laboratory suggests that extracellular adenosine that accumulates during sepsis modulates the immune system by activating adenosine receptors on the surface of immune cells. The production of extracellular adenosine is the consequence of the cellular release of its precursors ATP and ADP, and their sequential cell surface phosphohydrolysis to AMP by ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1, CD39) and then to adenosine by ecto-5'-nucleotidase (Ecto5'Ntase, CD73). We found that both CD39 and CD73 are upregulated during sepsis and have pivotal roles in restraining inflammation and organ damage by initiating adenosine receptor signaling. Specific Aim 1 will test the precise mechanisms by which CD39 and CD73 prevent excessive inflammation and organ injury during sepsis using adoptive cell transfer techniques, the "cre-lox" techology, and ex vivo studies on innate immune cells. Specific Aim 2 will define the molecular basis of the upregulation of CD39 and CD73 on macrophages, which may serve to curb excessive macrophage activation by producing adenosine during sepsis. The overarching goal here is to delineate the role of the ectonucleotidase cascade consisting of CD39 and CD73 in protecting against sepsis and to determine whether this cascade can be therapeutically targeted to manage patients with sepsis.