Neutrophil A2A receptors in sepsis

脓毒症中的中性粒细胞 A2A 受体

• 批准号: 10478933
• 负责人: George HASKO
• 金额: $ 53.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478933
• 关键词: ADORA2A gene; ADORA3 gene; Abnormal Neutrophil; Address; Adenosine; Adoptive Transfer; Agonist; Apoptosis; Bacteria; Binding; Brain Hypoxia-Ischemia; Cell surface; Cells; Cessation of life; Characteristics; Chemotaxis; Clinical; Clinical Trials; Coupled; Critical Care; Critical Illness; Data; FDA approved; Functional disorder; GTP-Binding Proteins; Gene Expression; Genetic; Goals; Growth; Helper-Inducer T-Lymphocyte; Hospitals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunosuppression; Individual; Infection; Inflammation; Inflammation Process; Ingestion; Innate Immune System; Life; Lipopolysaccharides; Mediating; Medicine; Metabolic stress; Metabolism; Modeling; Morbidity - disease rate; Multiple Organ Failure; Mus; Organ; Organ failure; Patients; Phagocytosis; Pharmacology; Phenotype; Plasma; Production; Purinergic P1 Receptors; Purines; Regulation; Regulatory T-Lymphocyte; Respiratory Burst; Role; Sepsis; Signal Transduction; Signaling Molecule; Site; Surface; Syndrome; TNF gene; Trauma; activated Protein C; antagonist; arm; base; cecal ligation puncture; cell type; chronic infection; clinically relevant; cytokine; exhaustion; extracellular; immune function; immunoregulation; macrophage; migration; monocyte; mortality; neutrophil; organ injury; pathogen; receptor; secondary infection; septic; septic patients; transcriptome sequencing

SUMMARY Sepsis is a clinical syndrome that complicates severe infection. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. There are no specific FDA-approved medicines for the treatment of sepsis. Current concepts of the pathophysiology of sepsis suggest that inappropriate regulation of neutrophil functions contribute to organ failure and mortality in sepsis. This manifests as an inability to control bacterial growth and dissemination, persistent and secondary infections, inflammation, and end organ injury. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine receptors (ARs) on the surface of neutrophils. A2AAR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased chemotaxis, diminished ability to ingest and kill bacteria and delayed apoptosis. Given this similarity between septic neutrophil alterations and the ones caused by A2AAR signaling, we hypothesized that endogenous adenosine would contribute to the sepsis-induced onset of neutrophil dysfunction via stimulation of A2AARs. Our preliminary data using both targeted genetic deletion and pharmacological antagonism in mice with cecal ligation and puncture-induced sepsis have confirmed that A2AARs contribute to bacterial dissemination, organ injury, and mortality. Our data with human patients demonstrate increased plasma adenosine and neutrophil A2AAR expression indicating increased A2AAR signaling leading to neutrophil dysfunction. Based on these data, we hypothesize that endogenous adenosine contributes to sepsis-induced immune dysregulation, bacterial dissemination, organ injury and mortality through A2AAR signaling in neutrophils. To address this hypothesis, we propose 2 Specific Aims. Specific Aim 1 will delineate the role of A2AAR signaling in neutrophils in contributing to bacterial dissemination, organ injury, and mortality in CLP-induced sepsis in mice. Specific Aim 2 will study the contribution of A2AAR signaling to neutrophil dysfunction in patients with sepsis. The long-term goal of this study is to pharmacologically target A2AAR signaling as a treatment option for the management of patients with sepsis.

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