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

哮喘和慢性阻塞性肺疾病（COPD）的发病机制尚未完全清楚。内源性释放的核苷酸（如ATP、ADP、UTP、UDP）最近作为通过激活嘌呤能受体（P2 XR和P2 YR）的细胞间通讯的介质而受到关注。虽然腺苷（ATP/ADP的代谢产物）在哮喘和COPD发病机制中的作用已被广泛研究，但对气道炎症中P2 R介导的免疫反应知之甚少。 最近，我们可以表明，在急性哮喘期间，ATP释放到气道中，通过改变肺DC的功能来促进Th 2的发展。此外，内源性气道ATP的中和或P2 R的非选择性阻断消除了哮喘的主要特征。因此，本研究的目的是：1）鉴定参与急性哮喘典型特征的P2 R; 2）确定P2 R信号转导在慢性哮喘中的作用; 3）利用hu-SCID小鼠哮喘模型评估其临床意义。（用来自哮喘患者的血液重构; 4）测量哮喘和COPD患者的支气管肺泡灌洗液中的核苷酸水平; 5）通过在COPD小鼠模型中中和气道核苷酸水平和阻断P2 R来确定P2信号传导在COPD中的作用。这些研究将提供有关哮喘和COPD发病机制中P2 R信号传导的重要信息，并可能导致发现一种全新的治疗药物来控制慢性气道炎症。

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.