Lysophosphatidic Acid in Airway Barrier Function and Remodeling

溶血磷脂酸在气道屏障功能和重塑中的作用

• 批准号: 8119667
• 负责人: Yutong Zhao
• 金额: $ 48.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119667
• 关键词: Acids; Acute; Acute Lung Injury; Acute respiratory failure; Address; Adhesions; Aftercare; Allergens; Alveolar; Attenuated; Biochemical; Blood Platelets; Blood capillaries; Breathing; Cell Line; Cell membrane; Cells; Complex; Coupled; Cytoplasm; Data; Development; Dinoprostone; Disease; E-Cadherin; Edema; Electrical Resistance; Endotoxins; Epithelial; Epithelial Cells; Epithelium; Experimental Models; Extravasation; Floods; Functional disorder; GTP-Binding Proteins; Growth Factor; Health; Heterotrimeric G Protein Subunit; Host Defense; Human; IL8 gene; Inflammation; Inflammatory; Injury; Intercellular Junctions; Investigation; Link; Lipopolysaccharides; Liquid substance; Lung; Lysophosphatidic Acid Receptors; Lysophospholipids; Maintenance; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Natural Immunity; Permeability; Phospholipids; Phosphorylation; Play; Pneumonia; Protein Isoforms; Protein Kinase C; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Role; Signal Pathway; Structure of parenchyma of lung; Structure of respiratory epithelium; Therapeutic Agents; Toxic Environmental Substances; Tyrosine; Virus Diseases; adaptive immunity; airway epithelium; alveolar type II cell; attenuation; capillary; clinical application; cytokine; interleukin-13 receptor; lung injury; lysophosphatidic acid; meetings; migration; neutrophil; novel; novel therapeutics; particle; response; treatment strategy

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a condition of acute respiratory failure resulting from acute pulmonary inflammation. The airway epithelium provides a complex physical and biochemical barrier to inhaled particles, allergens, and environmental toxins and thus plays a vital role in host defense. Disruption of epithelial integrity is a major contributor to increased permeability and alveolar flooding with protein-rich edema fluid, a hallmark of ALI. However, understanding of the responses of the pulmonary epithelium to injury remains incomplete. E-cadherin-modulated adhesion junction plays a critical role since the formation of adhesion junction subsequently leads to the formation of other cell junctions. Lipopolysaccharide (LPS)-induced lung injury is a very useful experimental model for the investigation and characterization of immunopathogenic changes and mechanisms in ALI. We and others have found that cytoplasmic mislocalization of E-cadherin in pulmonary epithelium induces epithelial shedding and increases pulmonary epithelial permeability in a LPS-induced murine model of ALI and in primary cultured pulmonary epithelial cells. Also, several studies from ours and others have indicated an association between E-cadherin and tyrosine kinase receptor, such as c-Met tyrosine kinase, suggesting a complex molecular mechanisms of regulation of E-cadherin localization in epithelial cells. We recently reported that lysophosphatidic acid (LPA), a bioactive phospholipid growth factor released from activated platelets, enhances innate immunity and attenuates adaptive immunity via increasing IL-8, PGE2, and IL-13R alpha2 secretion in human bronchial epithelial cells (HBEpCs). However, molecular mechanisms of pulmonary epithelial barrier function are poorly defined and in this proposal it is hypothesized that "LPA post-treatment protects against pulmonary epithelial barrier dysfunction caused by LPS through cross-talk between LPA-Rs and c-Met resulting in enhanced E-cadherin accumulation at cell-cell junctions". The following Specific Aims will address the role and regulation of LPA-mediated barrier function in respiratory epithelium using primary human bronchial epithelial cells, alveolar type II epithelial cells, alveolar type II cell line and a murine model of ALI. Specific aim #1 will define the protective role of LPA in LPS-induced epithelial barrier dysfunction via restoring E-cadherin accumulation at cell-cell junctions. Specific aim #2 will characterize role of the cross-talk between G-protein-coupled LPA receptors and c-Met receptor tyrosine kinase in LPA-mediated c-Met and E-cadherin redistribution to cell-cell junctions and LPA attenuation of LPS mediated pulmonary epithelial barrier dysfunction. Specific aim #3 will characterize the role of LPA posttreatment in protecting against LPS-induced lung injury in mice. These studies will identify the molecular mechanisms linking the LPA signaling pathways involving LPA receptors to the pulmonary epithelium barrier function, which is critical to the development of new therapies directed at ameliorating lung inflammatory diseases. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) is a cause of acute respiratory failure resulting from acute pulmonary inflammation. The pulmonary epithelium provides a complex physical and biochemical barrier to inhaled particles, allergens, and environmental toxins and thus plays a vital role in host defense. These studies will identify the molecular mechanisms linking the lysophophatidic acid (LPA) and LPA receptors to maintenance of normal pulmonary epithelium barrier function, which is critical in developing novel therapies directed at ameliorating lung inflammatory diseases.

描述(申请人提供)：急性肺损伤(ALI)是一种由急性肺部炎症引起的急性呼吸衰竭。呼吸道上皮对吸入颗粒物、过敏原和环境毒素提供了一种复杂的物理和生化屏障，因此在宿主防御中发挥着重要作用。上皮完整性的破坏是导致肺泡通透性增加和富含蛋白质的水肿液泛滥的主要原因，这是ALI的一个特征。然而，对肺上皮细胞对损伤的反应的了解仍然不完全。E-钙粘附素调控的黏附连接起着至关重要的作用，因为黏附连接的形成会导致其他细胞连接的形成。脂多糖(LPS)诱导的肺损伤是研究ALI免疫病理变化及其机制的重要实验模型。我们和其他人发现，在脂多糖诱导的小鼠ALI模型和原代培养的肺上皮细胞中，E-钙粘附素在细胞质中的错误定位导致肺上皮细胞脱落并增加肺上皮细胞的通透性。此外，我们和其他人的几项研究表明，E-钙粘蛋白与酪氨酸激酶受体(如c-Met酪氨酸激酶)之间存在关联，这表明E-钙粘蛋白在上皮细胞中的定位调控存在复杂的分子机制。我们最近报道，溶血磷脂酸(LPA)是一种从活化的血小板中释放出来的生物活性磷脂生长因子，通过增加人支气管上皮细胞(HBCs)分泌IL-8、PGE2和IL-13Rα2来增强天然免疫和减弱获得性免疫。然而，肺上皮屏障功能的分子机制尚不清楚，在这一建议中，假设LPA后处理通过LPA-R和c-Met之间的相互作用，导致E-钙粘素在细胞-细胞连接处聚集，从而保护内毒素引起的肺上皮屏障功能障碍。以下具体目标将利用原代人支气管上皮细胞、肺泡II型上皮细胞、肺泡II型细胞系和ALI小鼠模型来研究LPA介导的呼吸道上皮屏障功能的作用和调节。具体目标#1将确定LPA通过恢复E-钙粘素在细胞-细胞连接处的积聚来保护脂多糖诱导的上皮屏障功能障碍的作用。具体目的#2将表征G蛋白偶联的LPA受体和c-Met受体酪氨酸激酶之间的相互作用在LPA介导的c-Met和E-cadherin重新分布到细胞-细胞连接和LPA在脂多糖介导的肺上皮屏障功能障碍中的作用。具体目标#3将描述LPA后处理在保护小鼠免受脂多糖诱导的肺损伤中的作用。这些研究将确定涉及LPA受体的LPA信号通路与肺上皮屏障功能之间的分子机制，这对于开发针对改善肺部炎症性疾病的新疗法至关重要。公共卫生相关性：急性肺损伤(ALI)是由急性肺部炎症引起的急性呼吸衰竭的原因之一。肺上皮对吸入颗粒物、过敏原和环境毒素提供了一种复杂的物理和生化屏障，因此在宿主防御中起着至关重要的作用。这些研究将确定溶血磷脂酸(LPA)和LPA受体与维持正常肺上皮屏障功能之间的分子机制，这对于开发针对改善肺部炎症性疾病的新疗法至关重要。