Role of Adenosine in Allergic Lung Disease

描述(由申请人提供)：腺苷通过对气道张力和气道炎症的影响，越来越被认为是哮喘发病机制的贡献者。腺苷通过四种不同的细胞表面受体发挥作用，然而，腺苷通过哪一种特异性受体(S)参与哮喘的发病机制尚不清楚。这项提议将检验的假设是，腺苷通过可识别的细胞表面受体促进哮喘的气道张力和气道炎症，这些受体的失活将影响支气管收缩和呼吸道炎症的程度。我们选择测试利用假设的小鼠，在其中每个腺苷受体已经被基因靶向失活。我们提出了三个具体目标来检验我们的假设。首先，我们将确定腺苷受体和细胞类型介导腺苷在小鼠呼吸道的收缩作用。其次，我们将利用卵蛋白哮喘模型确定腺苷在变应性肺部炎症中的促炎和抗炎作用的腺苷受体。最后，我们将确定有助于腺苷诱导的过敏性炎症调节的特定细胞类型。腺苷受体阻滞剂的全部治疗潜力尚未得到充分发挥，因为这种复杂的生理机制涉及多种腺苷受体，这些受体具有不同的、有时是相反的生理效应。这项建议旨在更好地定义腺苷在哮喘动物模型中通过每个受体发挥作用的病理生理学，以便可以在哮喘患者中研究更合理地利用这些受体的选择性药理工具。

DESCRIPTION (provided by applicant): Adenosine has become increasingly recognized as a contributor to the pathogenesis of asthma through its effects on airway tone and airway inflammation. Adenosine acts through four distinct cell surface receptors, however, the specific receptor(s) through which adenosine acts to contribute to asthma pathogenesis is largely unknown. The hypothesis that will be tested in this proposal is that adenosine contributes to both the airway tone and airway inflammation in asthma through identifiable cell surface receptors, and that inactivation of these receptors will influence the degree of bronchoconstriction and airway inflammation. We have chosen to test the hypothesis-utilizing mouse in which each adenosine receptor has been inactivated by gene targeting. We propose to carry out three specific aims to test our hypothesis. First, we will determine the adenosine receptors and cell types mediating the bronchoconstrictor effects of adenosine in the murine airway. Second, we will determine the adenosine receptors responsible for the pro- and anti-inflammatory effects of adenosine in allergic lung inflammation using the ovalbumin asthma model. Finally, we will determine the specific cell types contributing to adenosine-induced modulation of allergic inflammation. The full therapeutic potential of adenosine receptor blockade has not been exploited due to this complex physiology involving multiple adenosine receptors with diverse and sometimes opposing physiological effects. This proposal seeks to better define the pathophysiology of adenosine, acting through each receptor, in an animal model of asthma, so that a more rational exploitation of these receptors with selective pharmacological tools can be investigated in patients with asthma.