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: 8514685
• 负责人: Yutong Zhao
• 金额: $ 33.95万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514685
• 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.

描述（由申请人提供）： 急性肺损伤（ALI）是由急性肺部炎症引起的急性呼吸衰竭。气道上皮为吸入颗粒、过敏原和环境毒素提供了复杂的物理和生化屏障，因此在宿主防御中发挥着至关重要的作用。上皮完整性的破坏是导致通透性增加和肺泡充满富含蛋白质的水肿液的主要原因，这是 ALI 的一个标志。然而，对肺上皮对损伤反应的了解仍然不完整。 E-钙粘蛋白调节的粘附连接起着至关重要的作用，因为粘附连接的形成随后导致其他细胞连接的形成。脂多糖 (LPS) 诱导的肺损伤是研究和表征 ALI 免疫病理变化和机制的非常有用的实验模型。我们和其他人发现，在 LPS 诱导的 ALI 小鼠模型和原代培养的肺上皮细胞中，肺上皮中 E-钙粘蛋白的细胞质错误定位会诱导上皮脱落并增加肺上皮通透性。此外，我们和其他人的几项研究表明 E-钙粘蛋白和酪氨酸激酶受体（例如 c-Met 酪氨酸激酶）之间存在关联，表明上皮细胞中 E-钙粘蛋白定位的调节存在复杂的分子机制。我们最近报道，溶血磷脂酸 (LPA) 是一种从活化血小板中释放的生物活性磷脂生长因子，通过增加人支气管上皮细胞 (HBEpC) 中 IL-8、PGE2 和 IL-13R α2 的分泌来增强先天免疫并减弱适应性免疫。然而，肺上皮屏障功能的分子机制尚不清楚，在该提案中，假设“LPA后处理通过LPA-R和c-Met之间的串扰导致细胞-细胞连接处E-钙粘蛋白积累增强，可防止LPS引起的肺上皮屏障功能障碍”。以下具体目标将使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 小鼠模型来探讨 LPA 介导的呼吸道上皮屏障功能的作用和调节。具体目标#1将通过恢复细胞-细胞连接处的E-钙粘蛋白积累来定义LPA在LPS诱导的上皮屏障功能障碍中的保护作用。具体目标#2 将描述 G 蛋白偶联 LPA 受体和 c-Met 受体酪氨酸激酶之间的串扰在 LPA 介导的 c-Met 和 E-钙粘蛋白重新分布到细胞-细胞连接以及 LPA 减弱 LPS 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 后处理在预防 LPS 诱导的小鼠肺损伤中的作用。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，这对于开发旨在改善肺部炎症性疾病的新疗法至关重要。

项目成果

Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling.

• DOI: 10.4049/jimmunol.1401414
• 发表时间: 2015-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zhao J;Wei J;Bowser RK;Traister RS;Fan MH;Zhao Y
• 通讯作者: Zhao Y

De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II.

去泛素化酶USP11，通过稳定转化生长因子β受体II来促进生长因子β-1信号传导。

• DOI: 10.1038/cddis.2016.371
• 发表时间: 2016-11-17
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Jacko AM;Nan L;Li S;Tan J;Zhao J;Kass DJ;Zhao Y
• 通讯作者: Zhao Y

Non-small cell lung cancer is susceptible to induction of DNA damage responses and inhibition of angiogenesis by telomere overhang oligonucleotides.

• DOI: 10.1016/j.canlet.2013.09.010
• 发表时间: 2014-02-01
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Puri N;Pitman RT;Mulnix RE;Erickson T;Iness AN;Vitali C;Zhao Y;Salgia R
• 通讯作者: Salgia R

Molecular regulation of lysophosphatidic acid receptor 1 trafficking to the cell surface.

分子调节溶血磷脂酸受体1运输到细胞表面。

• DOI: 10.1016/j.cellsig.2014.07.005
• 发表时间: 2014-11
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Zhao J;Wei J;Bowser RK;Dong S;Xiao S;Zhao Y
• 通讯作者: Zhao Y

F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation.

• DOI: 10.1186/1476-4598-13-76
• 发表时间: 2014-04-01
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Dong S;Zhao J;Wei J;Bowser RK;Khoo A;Liu Z;Luketich JD;Pennathur A;Ma H;Zhao Y
• 通讯作者: Zhao Y