Role of Adenosine in Allergic Lung Disease

描述（由申请方提供）：哮喘患者肺和呼出气中腺苷水平升高，抗原激发后进一步升高，表明这种普遍存在的介质可能有助于哮喘的病理生理学。腺苷在哮喘肺中的许多作用是肥大细胞依赖性的。腺苷对肥大细胞具有促炎和抗炎作用，这是由于在细胞表面上表达多种腺苷受体，每种腺苷受体能够激活非常不同的细胞内信号传导途径。在这个建议中，我们将测试的假设，即促炎和抗炎信号通过腺苷通过激活不同的细胞表面受体传递到肥大细胞，这些受体的参与腺苷影响AHR，炎症细胞流入，气道重塑。在目的1中，我们将研究肥大细胞上A3受体在AHR、气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的Gs偶联腺苷受体活化限制AHR、气道炎症和重塑的能力。在目标3中，我们将研究A2B受体的组成活性。对于所有的目标，我们将进行体外实验与人类肥大细胞以及机械体内实验，使用一系列的模型缺乏腺苷受体的肥大细胞。这些目标的完成将定义肥大细胞上的促炎与抗炎信号传导途径，并确定腺苷诱导的肥大细胞活化促成哮喘主要特征的机制。公共卫生相关性。哮喘是一种常见的慢性疾病，影响美国约10%的人。更好地了解这种疾病中涉及的炎症介质，如腺苷，将有助于确定新的治疗途径，从而更好地治疗哮喘。

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.