A2B receptor stimulation for sepsis

SUMMARYSepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection. Although the underlying infection can now be efficiently treated with antibiotics, there are no effective therapies to control the organ damage caused by the inflammatory response of the host. As a result, sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent anti-inflammatory effects by binding to and activating G protein-coupled A2B adenosine receptors (ARs) on the surface of immune and endothelial cells. Using A2BAR deficient mice and pharmacological antagonists, we have discovered that A2BARs protect mice against polymicrobial sepsis-induced inflammation, organ damage, and mortality. Based on these results, we hypothesize that pharmacological stimulation of A2BARs protects against septic mortality and organ injury by suppressing inflammation. To address this hypothesis, we will study the efficacy of two novel, potent and selective A2BAR agonists we developed, P453 and P517, in reversing septic mortality, inflammation, and organ dysfunction. The Specific Aims of the proposal are: Specific Aim 1. Assess the effect of P453 and P517 on mortality in murine sepsis. Specific Aim 2. Delineate the effect of P453 and P517 on inflammation and organ injury in murine sepsis. This proposal thus advances new therapeutic applications to control and/or alleviate sepsis-induced organ injury and mortality.NARRATIVESepsis remains the leading cause of mortality and morbidity in critically ill patients, because it triggers an overwhelming inflammatory response in the host. In the proposed studies, we will test two novel, potent and selective A2B adenosine receptor agonists we developed, P453 and P517, in reversing septic mortality, inflammation, and organ dysfunction. The ultimate goal of these studies is to develop A2B adenosine receptor agonists for the management of patients with sepsis.