Adenosine in trauma and sepsis

描述(申请人提供)：由微生物侵入身体正常无菌部位引发的全身性疾病称为败血症。脓毒症仍然是危重病人发病率和死亡率的主要原因。目前的概念表明，器官衰竭和 脓毒症的死亡是由免疫系统的不适当调节引起的，表现为免疫抑制时的过度炎症。我们实验室最近收集的证据表明，在脓毒症过程中积聚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。胞外腺苷的产生是其前体ATP和ADP被胞外核苷三磷酸二磷酸水解酶1(E-NTPDase1，CD39)释放到AMP，然后被胞外-5‘-核糖核酸酶(Ecto5’-Ntase，CD73)水解为腺苷的结果。我们发现，CD39和CD73在脓毒症过程中均上调，并通过启动腺苷受体信号通路在抑制炎症和器官损伤中发挥关键作用。具体目标1将通过过继细胞转移技术、cre-lox技术和对先天性免疫细胞的体外研究，测试CD39和CD73在脓毒症期间防止过度炎症和器官损伤的确切机制。特异性目标2将确定巨噬细胞上CD39和CD73上调的分子基础，这可能有助于在脓毒症期间通过产生腺苷来抑制巨噬细胞的过度激活。这里的首要目标是描述由CD39和CD73组成的ECA级联在预防脓毒症中的作用，并确定该级联是否可以作为治疗靶点来管理脓毒症患者。

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.