Immunosuppression in Acute Lung Injury

急性肺损伤中的免疫抑制

• 批准号: 10399554
• 负责人: Rama K Mallampalli
• 金额: $ 233.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-03 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399554
• 关键词: Acetyltransferase; Acute Lung Injury; Acute Respiratory Distress Syndrome; Alveolar; Amino Acids; Animal Model; Bacterial Infections; Bacterial Pneumonia; Biological Markers; Biology; CD8B1 gene; Cardiolipins; Cell Death; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cessation of life; Chemotaxis; Clinical; Complement; Cytokine Gene; Defect; Degradation Pathway; Development; Disease; Effector Cell; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Equilibrium; Evolution; FRAP1 gene; Functional disorder; Gene Expression; Genes; Gram-Negative Bacterial Infections; Host Defense; Human; Hydroxyeicosatetraenoic Acids; IL10 gene; IRF1 gene; Immune; Immunity; Immunosuppression; Impairment; In Vitro; Inflammation; Inflammatory; Innate Immune Response; Interleukin-10; Lead; Ligands; Link; Lipids; Liver; Lung; Lung infections; Lymphocyte; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Molecular Target; Multiple Organ Failure; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; NF-kappa B; Natural Immunity; Oxidation-Reduction; PPAR gamma; Paraoxonase-2; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phagocytosis; Pharmacotherapy; Phase; Phenotype; Phosphatidylethanolamine; Phospholipids; Pneumonia; Population; Program Research Project Grants; Proteins; Reactive Oxygen Species; Research Personnel; Respiratory Failure; Risk Factors; Scientific Inquiry; Secondary to; Sepsis; Services; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Ubiquitin; Virulent; base; biobank; bioimaging; body system; chemokine; chromatin remodeling; clinically relevant; combinatorial; cytokine; design; histone modification; human subject; in vivo; inhibitor; innate immune function; insight; lipidomics; lung injury; macrophage; mortality; novel; oxidation; pathogenic bacteria; pathogenic microbe; patient subsets; physiologic stressor; preservation; programs; response; small molecule inhibitor; tool; ubiquitin-protein ligase

Acute respiratory distress syndrome (ARDS) is most commonly due to severe pneumonia or sepsis. Decades of intense study have focused on the initial inflammatory phase of ARDS, and yet mortality rates for ARDS are still very high because newer pharmocotherapies have not emerged. In this Program Project Grant competing renewal application, we have assembled a team of world-class leaders with complementary expertise to investigate a new pathophysiologic model that challenges the existing concept that ARDS is solely a hyper-inflammatory disorder. In this model, we will investigate a novel concept that in ARDS, immunosuppression is a signature manifestation in a subset of patients secondary to unique, combinatorial pathways that modulate epithelial and myeloid cell viability and innate immune function. We hypothesize that immune suppression occurs via chromatin remodeling and ubiquitin- degradative pathways (Project 1), through a set of distinct cell death pathways including a new form of oxidation driven, non-apoptotic cell death termed ferroptosis (Project 2), through a phenotypic shift from loss of crucial host-protective lymphocytes (CD8+, MAIT cells) to immunosuppressive myeloid cells (Project 3), and oxidation-mediated impairment of macrophage bacterial killing and phagocytosis (Project 4). To evaluate this hypothesis, investigators will employ state-of-art molecular, cell, human-based systems, and lipidomic tools. These approaches will be translated to complementary 2- hit models of lung injury and immunosuppression and analysis in ARDS human subjects. The Program will be supported by two highly interactive Cores with expertise in human biorepository services and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.

急性呼吸窘迫综合征（ARDS）最常见的原因是病情严重