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的 肺炎或败血症。几十年的深入研究集中在最初的炎症 然而，ARDS的死亡率仍然很高，因为新的 药物治疗还没有出现。在这个程序中项目补助竞争更新 应用程序，我们已经组建了一个世界级的领导者团队， 研究新的病理生理学模型，挑战现有的 认为ARDS只是一种高度炎症性疾病。在这个模型中，我们将 研究一个新概念，即在ARDS中，免疫抑制是一个标志， 在继发于独特的组合途径的患者亚组中的表现， 调节上皮细胞和骨髓细胞活力和先天免疫功能。我们 假设免疫抑制通过染色质重塑和泛素发生， 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，称为铁凋亡（项目2）， 通过表型的转变，从关键的宿主保护性淋巴细胞（CD 8+，MAIT）的丢失， 细胞）免疫抑制骨髓细胞（项目3），和氧化介导的 巨噬细胞细菌杀伤和吞噬功能受损（项目4）。评价 这一假设，研究人员将采用最先进的分子，细胞，人类为基础的 系统和脂质组学工具。这些方法将转化为补充2- 急性呼吸窘迫综合征受试者肺损伤和免疫抑制打击模型及分析。 该计划将得到两个高度互动的核心的支持， 生物储存服务和生物成像。这些研究的执行将提供 ARDS发病机制的范式改变概念模型，作为 治疗干预，并提供一个新的和持续的科学探究领域， 肺生物学