Role of Adenosine in Allergic Lung Disease

描述(申请人提供)：哮喘患者肺部和呼气中腺苷水平升高，并在抗原攻击后进一步增加，表明这种无处不在的介质可能在哮喘的病理生理学中起作用。腺苷在哮喘肺中的许多作用依赖于肥大细胞。腺苷对肥大细胞既有促炎作用，又有抗炎作用，这是因为细胞表面表达了多种腺苷受体，每个受体都能够激活非常不同的细胞内信号通路。在这个提案中，我们将检验这样一个假设，即促炎和抗炎信号都是通过腺苷通过激活不同的细胞表面受体传递到肥大细胞的，并且腺苷与这些受体的结合影响AHR、炎症细胞内流和呼吸道重塑。在目标1中，我们将研究肥大细胞上的A3受体在AHR、呼吸道炎症和重塑中的促炎作用。在目标2中，我们将研究激动剂诱导激活Gs偶联的腺苷受体以限制AHR、呼吸道炎症和重塑的能力。在目标3中，我们将研究A2B受体的构成活性。为了达到所有目的，我们将用人类肥大细胞进行体外实验，以及利用肥大细胞上缺乏腺苷受体的一系列模型进行体内机械性实验。完成这些目标将确定肥大细胞上的促炎和抗炎信号通路，并确定腺苷诱导的肥大细胞激活对哮喘基本特征的作用机制。与公共卫生相关。哮喘是一种常见的慢性疾病，在美国大约有10%的人受到影响。更好地了解与这种疾病有关的炎症介质，如腺苷，将有助于确定新的治疗途径，从而导致更好地治疗哮喘。

DESCRIPTION (provided by applicant): Elevated adenosine levels in the lungs and exhaled breath of asthmatics, with further increases following antigen challenge, suggests that this ubiquitous mediator may contribute to the pathophysiology of asthma. Many of the effects of adenosine in the asthmatic lung are mast cell-dependent. Adenosine has both pro- and anti-inflammatory effects on mast cells, due to the expression of multiple adenosine receptors on the cell surface, each capable of activating very different intracellular signaling pathways. In this proposal we will test the hypothesis that both pro- and anti-inflammatory signals are transmitted to the mast cell by adenosine via the activation of distinct cell-surface receptors, and that engagement of these receptors by adenosine influences AHR, inflammatory cell influx, and airway remodeling. In aim 1 we will investigate the pro- inflammatory role of A3 receptors on mast cells in AHR, airway inflammation, and remodeling. In aim 2 we will investigate the capacity of agonist-induced activation of Gs-coupled adenosine receptors to limit AHR, airway inflammation, and remodeling. In aim 3 we will investigate constitutive activity of the A2B receptor. For all aims we will conduct in vitro experiments with human mast cells as well as mechanistic in vivo experiments using a series of models lacking adenosine receptors on mast cells. Completion of these aims will define pro- vs. anti-inflammatory signaling pathways on the mast cell, and identify the mechanisms by which adenosine- induced mast cell activation contributes to the cardinal features of asthma. PUBLIC HEALTH RELEVANCE. Asthma is a common chronic disease affecting approximately 10% of people in the United States. A better understanding of the inflammatory mediators involved in this disease, such as adenosine, will help identify new avenues of therapy, leading to better treatments for asthma.