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)最常见的原因是严重 肺炎或败血症。几十年的紧张研究集中在最初的炎性反应上 ARDS阶段，但ARDS的死亡率仍然非常高，因为较新的 药疗还没有出现。在本计划中，项目授予竞争性续订 应用，我们已经组建了一支世界级的领导者团队，与 专门研究一种新的病理生理模型，挑战现有的 ARDS仅仅是一种炎症性疾病的概念。在此模型中，我们将 研究一个新的概念，即免疫抑制是ARDS的标志 继发于独特的组合路径的患者子集的表现 调节上皮细胞和髓样细胞的活性以及天然免疫功能。我们 假设免疫抑制是通过染色质重塑和泛素- 降解途径(项目1)，通过一组不同的细胞死亡途径，包括 一种新形式的氧化驱动的非凋亡性细胞死亡称为铁下垂(项目2)， 通过失去关键的宿主保护性淋巴细胞(CD8+，MAIT)的表型转变 细胞)至免疫抑制髓系细胞(项目3)，以及氧化介导 巨噬细胞杀菌和吞噬功能受损(项目4)。评估 在这一假设下，研究人员将采用最先进的分子、细胞、人类为基础 系统和脂质组学工具。这些方法将转化为互补的2- 急性呼吸窘迫综合征患者肺损伤和免疫抑制的HIT模型及分析 该计划将由两个在人力资源方面具有专业知识的高度互动的核心提供支持 生物库服务和生物成像。这些研究的执行将提供一个 作为ARDS发病机制基础的改变范式的概念模型 治疗干预和提供一个新的和持续的科学研究领域 肺部生物学。