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：
8648975
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/8648975
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 Lung diseases Mediating Metaplasia Molecular Mucous Membrane Mus Nose Nucleotides Ovalbumin Pathology Pathway interactions Patients Physiological Platelet Activation Pneumonia Process Property Pulmonary Eosinophilia Purinoceptor Regulation Relative (related person)Role Therapeutic Thromboxane A2 Tissues Variant airway hyperresponsiveness airway inflammation airway remodeling 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.

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在哮喘患者气道中含量为，并且在患有阿司匹林过度呼吸系统疾病（AERD）患者的肺和鼻组织中尤其丰富。 ADP是一种丰富的细胞外核苷酸，是P2Y12和P2Y1受体的天然配体。在当前的资金期间，我们确定LTE4通过完全独立于经典Cysltr的途径显着增强了敏化小鼠的气道炎症，并且需要P2Y12受体和血小板。然而，令人惊讶的是，LTE4在P2Y12受体上没有直接结合。我们发现ADP是体内LTE4的分子模拟物，潜在的功能是肺部炎症的放大器。该提案的延续着重于导致LTE4在肺部炎症中影响的机制和细胞靶标，以及P2Y12受体在此过程中的作用。预计这些发现对哮喘病理生理学和治疗有直接的影响，尤其是在AERD中，其中该疾病的大部分是由CYS-LT驱动的。 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 LTE4的受体，并与P2Y1受体相互作用，形成ADP的受体复合物。这些复合物介导了P2Y12受体对肺部炎症的各自依赖性LTE4依赖性和LTE4的特征。