The A2a adenosine receptor modulates hyaluronan mediated lung inflammation

描述(申请人提供)：越来越清楚的是，组织微环境在调节炎症和组织破坏方面起着关键作用。慢性炎症和组织纤维化不仅导致炎症细胞/介质的涌入和细胞外基质的周转，而且还导致细胞外嘌呤核苷酸腺苷浓度的增加。最近，细胞外基质成分透明质酸(HA)的片段被证明在动物模型的肺部炎症和纤维化的发展中发挥核心作用。同样，腺苷已被证明是炎症的关键负面调节因子和免疫破坏的组织保护器。我们假设细胞外基质既是炎症的靶点，又是炎症细胞的中心激活物，而腺苷是HA诱导的炎症的关键调节剂。我们推测，在组织微环境中，腺苷发挥抗炎作用的一个关键机制是通过A2a腺苷受体(A2aR)调节HA片段引起的组织损伤。有趣的是，LMW HA片段还可能通过下调这种抗炎A2aR的表达和功能来增强炎症。因此，组织炎症的最终结果在一定程度上取决于低分子HA片段和组织衍生的腺苷之间的相互作用。为此，在特定的目标1中，我们假设A2aR连接调控HA片段诱导的炎症基因表达。我们将在巨噬细胞、呼吸道和肺泡上皮细胞中进行研究，以确定腺苷通过A2aR参与调节HA诱导的基因表达的分子途径。在特定的目标2中，我们假设LMW HA通过下调抗炎A2aR而增强炎症。我们将进行研究，以确定LMW HA调节A2aR表达的分子机制。具体目标3假设内源性腺苷调节博莱霉素诱导的肺部炎症和纤维化，并且给予A2aR激动剂的药物可以预防疾病。我们将进行体内实验，以证明在缺乏A2aR表达的情况下，博莱霉素的损伤更严重。此外，我们还将确定A2aR刺激在巨噬细胞、肺通道和肺泡上皮细胞中的作用。通过确定细胞外基质成分的促炎和抗炎特性，我们将能够更好地确定特定的药理靶点作为潜在的治疗方法。我们相信，这些研究将为A2aR特异性激动剂用于特发性肺纤维化、慢性支气管炎和肺气肿等炎症性肺部疾病的治疗提供临床前基础。

DESCRIPTION (provided by applicant): It is becoming increasingly clear that the tissue microenvironment plays a critical role in regulating inflammation and tissue destruction. Chronic inflammation and tissue fibrosis lead not only to an influx of inflammatory cells/mediators and turnover of the extracellular matrix, but also to increased extracellular concentrations of the purine nucleotide adenosine. Recently fragments of the extracellular matrix component hyaluronan (HA) have been shown to play a central role in the development of lung inflammation and fibrosis in animal models. Similarly, adenosine has been shown to be a crucial negative regulator of inflammation and tissue protector from immune destruction. We posit that the extracellular matrix is both the target of inflammation and a central activator of inflammatory cells and that adenosine is a key modulator of HA-induced inflammation. We hypothesize that within the tissue microenvironment, a critical mechanism by which adenosine exerts its anti-inflammatory effects is by modulating HA fragment induced tissue injury via engagement of the A2a adenosine receptor (A2aR). Interestingly, LMW HA fragments may also augment inflammation by down regulating expression and function of this anti-inflammatory A2aR. Thus the ultimate outcome of tissue inflammation is in part dictated by the interplay between LMW HA fragments and tissue derived adenosine. To this end, in Specific Aim 1, we hypothesize that A2aR ligation modulates HA fragment-induced inflammatory gene expression. We will perform studies in macrophages and airway and alveolar epithelial cells to define the molecular pathway by which adenosine, via A2aR engagement, modulates HA-induced gene expression. In Specific Aim 2, we hypothesize that LMW HA augments inflammation by downregulating the anti-inflammatory A2aR. We will perform studies to define the molecular mechanisms by which LMW HA modulates A2aR expression. Specific Aim 3 hypothesizes that endogenous adenosine modulates bleomycin-induced lung inflammation and fibrosis and that pharmacologic administration of A2aR agonists can protect against disease. We will perform in vivo experiments to demonstrate that bleomycin injury is worse in the absence of A2aR expression. Furthermore, we will define the role of A2aR stimulation on macrophages, and lung airway and alveolar epithelial cells in mediating this protective effect. By defining the pro- and anti-inflammatory properties of extra cellular matrix components, we will be better able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of A2aR specific agonists in the treatment of inflammatory lung diseases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema.