A2A receptor blockade for sepsis

SUMMARY Sepsis is a clinical syndrome that complicates severe infectionSepsis remains the leading cause of morbidity and mortality in critically ill patientsThere are no specific FDA approved medicines for the treatment of sepsisCurrent concepts of the pathophysiology of sepsis suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune systemThis manifests as an inability to control bacterial growth and disseminationand excessive inflammationprocesses that are interrelated and are duein a large partto dysfunction of both the adaptive and innate immune systemsExtracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsisExtracellular adenosine has potent immunosuppressive effects by binding to and activating G protein coupled A A adenosine receptorsARson the surface of immune cellsA AAR signaling reproduces many of the phenotypic changes in immune cells that are characteristic of sepsisincluding T helper lymphocyte deactivation and exhaustion and diminished ability of monocytes and macrophages to ingest and kill bacteria and other sepsis causing pathogensGiven this similarity between septic immune alterations and the ones caused by A AAR signalingwe hypothesized that endogenous adenosine would contribute to the sepsis induced onset of immune dysfunction via stimulation of A AARsOur preliminary data using both targeted genetic deletion and pharmacological antagonism have confirmed that A AARs contribute to both septic immune dysfunction and mortality in miceWe thus propose to develop A AAR antagonists for the management of patients with sepsisWe have synthesized two novelhighly potent and selective A AAR antagonistsTPand TPwhich we will test for efficacy in preventing septic mortalityThe Specific Aim of the proposal is to assess the effect of TPand TPon mortality in murine sepsisWe expect that TPand TPwill reduce mortality in septic miceThe long term goal of this study is to develop TPand TPas safe and effective treatment options for the management of patients with sepsis NARRATIVE Sepsis remains the leading cause of mortality in critically ill patientsbecause it impairs the immune response of the host leading to bacterial spread and organ damageIn the proposed studieswe will test two novel moleculesTPand TPthat have immune stimulatory effectsfor efficacy in protecting against mortality in sepsisThe long term goal is to develop TPand TPas safe and effective therapeutic interventions for sepsis patients