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而被越来越多地认为是哮喘发病机制的一个促成因素。 腺苷通过四种不同的细胞表面受体发挥作用，然而，腺苷通过哪些特定受体来促进哮喘发病机制尚不清楚。 该提案将测试的假设是，腺苷通过可识别的细胞表面受体对哮喘中的气道张力和气道炎症产生影响，并且这些受体的失活将影响支气管收缩和气道炎症的程度。 我们选择测试利用假设的小鼠，其中每个腺苷受体都已通过基因靶向失活。 我们建议实现三个具体目标来检验我们的假设。 首先，我们将确定介导腺苷在小鼠气道中的支气管收缩作用的腺苷受体和细胞类型。 其次，我们将使用卵清蛋白哮喘模型确定腺苷受体在过敏性肺部炎症中负责促炎和抗炎作用。 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。 由于这种复杂的生理学涉及多种腺苷受体，具有多种且有时相反的生理作用，因此腺苷受体阻断的全部治疗潜力尚未得到充分利用。 该提案旨在更好地定义哮喘动物模型中腺苷通过每种受体发挥作用的病理生理学，以便可以在哮喘患者中研究通过选择性药理学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.