Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease

调节炎症性和纤维增生性肺病的宿主因素

• 批准号: 8337988
• 负责人: Monica Kraft
• 金额: $ 200.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337988
• 关键词: Acute; Acute Lung Injury; Allergens; Allergic inflammation; Animals; Asthma; Bacteria; Biochemical; Biological Response Modifiers; Biology; Biopsy; Breathing; Bronchoalveolar Lavage; Bronchoscopy; CD44 Antigens; Cell Surface Receptors; Cell surface; Cells; Chronic; Chronic lung disease; Data; Development; Disease; Endogenous Factors; Environment; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibrosis; Flow Cytometry; Foundations; Generations; Genetic Models; Glycosaminoglycans; Growth Factor; Hamman-Rich syndrome; Host Defense; Human; Human Biology; Hyaluronan; Immune; Immune response; Immunohistochemistry; Individual; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-13; Invaded; Investigation; Lead; Lung; Lung Inflammation; Lung diseases; Maintenance; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Nature; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Play; Polymers; Population; Process; Production; Program Research Project Grants; Property; Proteins; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Recruitment Activity; Refractory; Regulation; Research; Respiratory physiology; Role; Sampling; Second Messenger Systems; Signal Transduction; Source; Structure of parenchyma of lung; System; Talents; Testing; Therapeutic; Tissue Sample; Tissues; Toll-like receptors; Toxic Environmental Substances; Transforming Growth Factor beta; Translational Research; Virus; airway inflammation; airway remodeling; asthmatic airway; asthmatic patient; chemokine; cytokine; hyaluronan synthase 1; injured; insight; interstitial; lung injury; man; mortality; novel; pollutant; programs; receptor; response; restoration; second messenger; surfactant

DESCRIPTION (provided by applicant): This Program Project Grant application will test the hypothesis that endogenous host factors generated in the context of either acute non-infectious lung injury or allergic inflammation play a fundamental role in the initiation and maintenance of inflammation and fibrosis associated with diseases such as pulmonary fibrosis and asthma. The collaborative studies that form the foundation of this proposal have shown that the extracellular matrix glycosaminoglycan hyaluronan (HA) is generated in the context of non-infectious acute lung injury and chronic inhaled allergen exposure. The overall hypothesis to be tested is that when unchecked, matrix fragments accumulating in the injured lung will propogate inflammation and facilitate an environment leading to the emergence of an invasive fibroblast phenotype that causes irreversible loss of lung function. Each project will probe different, yet complementary and sequencial processes of this proposed inflammatory cascade. Among the first wave of defense against excess inflammation are surfactant proteins. In the absence of SP-A and SP-D, HA fragment accumulation is augmented and both inflammation and fibrosis are more severe leading to irreversible loss of lung function. Project 2 (Wright) focuses on the mechanisms by which SP-A and SP-D interfere with matrix-driven inflammation and antagonize the functions of critical pro-fibrotic mediators such as TGF-beta. An important source of HA production are mesenchymal cells. When myofibroblasts are targeted to over-express hyaluronan synthase 2 (HAS2) in the mouse, a severe phenotype is generated leading to HA accumulation, unremitting inflammation and fibrodestructive lung disease with increased mortality. Project 1 (Noble) will determine the mechanisms by which HAS2 promotes airway remodeling and interstitial fibrosis using novel genetic models. Fibroblasts from asthmatic patients constitutively produce HA fragments and acquire an invasive phenotype in response to IL-13. Project 3 (Kraft) investigates the mechanisms by which HA and IL-13 regulate the development of the asthma phenotype in both man and mouse. Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases.

描述（由申请人提供）： 该计划项目拨款申请将检验以下假设：急性非感染性肺损伤或过敏性炎症中产生的内源性宿主因子在与肺纤维化和哮喘等疾病相关的炎症和纤维化的引发和维持中发挥着重要作用。构成该提案基础的合作研究表明，细胞外基质糖胺聚糖透明质酸（HA）是在非感染性急性肺损伤和慢性吸入过敏原暴露的背景下产生的。待测试的总体假设是，如果不加以控制，受损肺部中积累的基质碎片将传播炎症，并促进导致出现侵袭性成纤维细胞表型的环境，从而导致肺功能不可逆转的丧失。每个项目都将探讨这种拟议的炎症级联的不同但互补和连续的过程。针对过度炎症的第一波防御是表面活性蛋白。在缺乏 SP-A 和 SP-D 的情况下，HA 片段积累增加，炎症和纤维化更加严重，导致肺功能不可逆转的丧失。项目 2 (Wright) 重点研究 SP-A 和 SP-D 干扰基质驱动的炎症并拮抗关键促纤维化介质（如 TGF-β）功能的机制。 HA 生产的一个重要来源是间充质细胞。当小鼠的肌成纤维细胞过度表达乙酰透明质酸合酶 2 (HAS2) 时，会产生严重的表型，导致 HA 积累、持续炎症和纤维破坏性肺部疾病，从而增加死亡率。项目 1（Noble）将利用新型遗传模型确定 HAS2 促进气道重塑和间质纤维化的机制。哮喘患者的成纤维细胞持续产生 HA 片段并获得对 IL-13 的侵袭性表型。项目 3 (Kraft) 研究 HA 和 IL-13 调节人和小鼠哮喘表型发展的机制。这些项目都有一个共同的主题，即宿主因素的相互作用调节炎症和纤维化肺部疾病。