Regulation of Pulmonary Inflammation by Leukotriene E4

白三烯 E4 对肺部炎症的调节

基本信息

批准号：
8826014
负责人：
Joshua A Boyce
金额：
$ 48.08万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8826014
关键词：
Adenosine Diphosphate Affinity Agonist Allergens Allergic Allergic Disease Amplifiers Antiplatelet Drugs Aspirin Asthma Binding Blood Platelets Breathing Bronchoalveolar Lavage Fluid Bronchoconstriction Bronchoconstrictor Agents Cells Characteristics Chemicals Complex Development Disease Drug Targeting Effector Cell Eosinophilia Excretory function Exhibits Functional disorder Funding G-Protein-Coupled Receptors Generations Goals Goblet Cells Histamine Human Immune system Individual Inflammation Interleukin-13 Leukocytes Leukotriene C4 Leukotriene D4 Leukotriene E4 Leukotriene Production Ligands Link Lung Mediating Metaplasia Molecular Mucous Membrane Mus Nose Nucleotides Ovalbumin Pathology Pathway interactions Patients Physiological Platelet Activation Process Property Pulmonary Eosinophilia Pulmonary Inflammation Purinoceptor Regulation Relative (related person)Role Therapeutic Thromboxane A2 Tissues Variant airway hyperresponsiveness airway inflammation airway remodeling aspirin-exacerbated respiratory disease asthmatic asthmatic airway autocrine base cellular targeting cysteinyl leukotriene receptor cysteinyl-leukotriene cytokine effective therapy eosinophil extracellular granulocyte human CCXCR1 receptor human GPR32 protein human disease in vivo lipid mediator migration mouse model paracrine prevent purinoceptor P2Y1 receptor response urinary

项目摘要

DESCRIPTION (provided by applicant): Leukotriene (LT)E4, the terminal product of cysteinyl leukotriene (cys-LT) generation, is a weak agonist of the classical cysteinyl leukotriene receptors (CysLTRs), but a potent inducer of bronchial eosinophilia and airway hyperresponsiveness in humans. LTE4 abounds in the airways of asthmatics, and is especially abundant in the lungs and nasal tissues of patients with aspirin-exacerbated respiratory disease (AERD). ADP, an abundant extracellular nucleotide, is the natural ligand for P2Y12 and P2Y1 receptors. In the current funding period, we determined that LTE4 markedly potentiates airway inflammation in sensitized mice through a pathway that is completely independent of classical CysLTRs, and requires both P2Y12 receptors and platelets. Surprisingly, however, LTE4 exhibits no direct binding at P2Y12 receptors. We have found that ADP is a molecular mimic of LTE4 in vivo, with potential function as an amplifier of pulmonary inflammation. The continuation of this proposal focuses on the mechanism(s) and cellular targets that are responsible for the effects of LTE4 in pulmonary inflammation, and the role of P2Y12 receptors in this process. The findings are expected to have immediate implications for asthma pathophysiology and treatment, especially in AERD, in which there is a substantial component of the disease that is driven by cys-LTs. This proposal is based on the central hypotheses that 1. P2Y12 receptors mediate a convergent pathway by which adenosine diphosphate (ADP) and leukotriene (LT)E4, respectively, facilitate the migration of effector cells to the allergen-challenged lung through platelet-dependent mechanisms, and 2. P2Y12 receptors interact with at least one additional GPCR to create a functional receptor for LTE4, and also interact with P2Y1 receptors to form a receptor complex for ADP. These complexes mediate the respective LTE4-dependent and LTE4-indepedent features of P2Y12 receptor contributions to pulmonary inflammation.

描述（申请人提供）：白三烯 (LT)E4 是半胱氨酰白三烯 (cys-LT) 生成的最终产物，是经典半胱氨酰白三烯受体 (CysLTR) 的弱激动剂，但却是支气管嗜酸性粒细胞增多和气道高反应性的有效诱导剂在人类中。 LTE4 在哮喘患者的气道中含量丰富，在阿司匹林急性呼吸道疾病 (AERD) 患者的肺和鼻组织中含量尤其丰富。 ADP 是一种丰富的细胞外核苷酸，是 P2Y12 和 P2Y1 受体的天然配体。在当前资助期间，我们确定 LTE4 通过完全独立于经典 CysLTR 的途径显着增强致敏小鼠的气道炎症，并且需要 P2Y12 受体和血小板。然而，令人惊讶的是，LTE4 并未表现出与 P2Y12 受体的直接结合。我们发现 ADP 是体内 LTE4 的分子模拟物，具有作为肺部炎症放大器的潜在功能。该提案的后续重点是 LTE4 在肺部炎症中产生作用的机制和细胞靶点，以及 P2Y12 受体在此过程中的作用。这些发现预计将对哮喘的病理生理学和治疗产生直接影响，特别是在 AERD 中，其中该疾病的很大一部分是由 cys-LT 驱动的。该提议基于以下中心假设：1. P2Y12 受体介导一条汇聚途径，二磷酸腺苷 (ADP) 和白三烯 (LT)E4 分别通过该途径通过血小板依赖性机制促进效应细胞迁移至过敏原挑战的肺部，和 2. P2Y12 受体与至少一个额外的 GPCR 相互作用，产生 LTE4 的功能性受体，并且还与 P2Y1 受体相互作用，形成 ADP 受体复合物。这些复合物分别介导 P2Y12 受体对肺部炎症的贡献的 LTE4 依赖性和 LTE4 独立特征。