Purinergic signalling in the lung: involvement in the pathogenesis of asthma and COPD

肺部嘌呤能信号传导：参与哮喘和慢性阻塞性肺病的发病机制

• 批准号: 46096925
• 负责人: Professor Dr. Marco Idzko
• 金额: --
• 依托单位: Klinik für Innere Medizin II
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/46096925?language=en
• 关键词: Purinergic; signalling; lung; involvement; pathogenesis

The pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) is not fully understood yet. Endogenous released nucleotides (like ATP, ADP, UTP, UDP) have recently gained attention as a mediator of intercellular communication via the activation of purinergic receptors (P2XR and P2YR). While the role of adenosine (a metabolite of ATP/ADP) in the pathogenesis of asthma and COPD has been extensively studied, little is know about P2R-mediated immune-responses in airway inflammation. Recently we could show that ATP release into the airways during acute asthma, favours Th2 development by altering the function of lung DC. In addition neutralization of endogenous airway ATP or unselective blocking of P2R abrogates the cardinal features of asthma. Therefore, goal of the present project is: 1) to identify the precise P2R involved in mediating the typical features of acute; 2) to determine the role of P2R signalling in chronic asthma 3) to evaluate the clinical relevance by using hu-SCID mouse model of asthma (reconstituted with blood from asthmatic patients; 4) to measure nucleotides levels in bronchoalveolar lavage of asthmatic and COPD patients; 5) to ascertain the role of P2 signalling in COPD by neutralizing airway nucleotides levels and blocking of P2R in mouse model of COPD. These studies will provide important information on P2R signalling involved in the pathogenesis of asthma and COPD, and could lead to the discovery of a whole new therapeutic class of drugs to control chronic airway inflammation.

哮喘和慢性阻塞性肺疾病（COPD）的发病机制尚不完全清楚。内源性释放的核苷酸（如ATP， ADP， UTP， UDP）最近通过嘌呤能受体（P2XR和P2YR）的激活作为细胞间通讯的介质而受到关注。虽然腺苷（ATP/ADP的代谢物）在哮喘和COPD发病机制中的作用已被广泛研究，但对p2r介导的气道炎症免疫反应知之甚少。最近我们可以证明急性哮喘期间ATP释放到气道中，通过改变肺DC的功能促进Th2的发展。此外，内源性气道ATP的中和或P2R的非选择性阻断消除了哮喘的主要特征。因此，本项目的目标是：1)确定介导急性脑梗死典型特征的精确P2R；2)研究P2R信号在慢性哮喘中的作用；3)应用哮喘患者血液重建的hu-SCID小鼠哮喘模型评估其临床相关性；4)测定哮喘和COPD患者支气管肺泡灌洗液中核苷酸水平；5)在COPD小鼠模型中通过中和气道核苷酸水平和阻断P2R来确定P2信号在COPD中的作用。这些研究将提供P2R信号在哮喘和COPD发病机制中的重要信息，并可能导致发现一种全新的治疗类药物来控制慢性气道炎症。

项目成果

P2Y6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

• DOI: 10.1161/atvbaha.114.303585
• 发表时间: 2014-10
• 期刊: Arteriosclerosis, Thrombosis, and Vascular Biology
• 作者: P. Stachon;A. Peikert;N. Michel;S. Hergeth;T. Marchini;D. Wolf;B. Dufner;N. Hoppe;C. K. Ayata;M. Grimm;S. Cicko;Lisa Schulte;J. Reinöhl;C. von zur Muhlen;C. Bode;M. Idzko;A. Zirlik