Role of Adenosine in Allergic Lung Disease

描述（由申请人提供）：腺苷通过其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一个贡献者。腺苷通过四种不同的细胞表面受体起作用，然而，腺苷参与哮喘发病机制的具体受体在很大程度上是未知的。本提案将验证的假设是，腺苷通过可识别的细胞表面受体参与哮喘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气道炎症的程度。我们选择测试假设利用小鼠，其中每个腺苷受体已被基因靶向灭活。我们建议实施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小鼠气道中腺苷的支气管收缩作用。其次，我们将使用卵清蛋白哮喘模型确定在变应性肺部炎症中负责腺苷的促炎和抗炎作用的腺苷受体。最后，我们将确定参与腺苷诱导的过敏性炎症调节的特定细胞类型。腺苷受体阻断的全部治疗潜力尚未被开发，因为这种复杂的生理涉及多个腺苷受体具有不同的，有时相反的生理作用。本研究旨在更好地定义哮喘动物模型中腺苷通过每种受体作用的病理生理学，以便在哮喘患者中使用选择性药理工具更合理地利用这些受体。

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.