The A2a adenosine receptor modulates hyaluronan mediated lung inflammation

描述（由申请人提供）：越来越清楚的是，组织微环境在调节炎症和组织破坏中起着关键作用。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，而且还导致嘌呤核苷酸腺苷的细胞外浓度增加。最近，在动物模型中，细胞外基质成分透明质酸（HA）的片段已被证明在肺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和组织免受免疫破坏的关键负调节因子。我们假设细胞外基质既是炎症的目标，也是炎症细胞的中心激活剂，腺苷是ha诱导炎症的关键调节剂。我们假设，在组织微环境中，腺苷发挥其抗炎作用的一个关键机制是通过参与A2a腺苷受体（A2aR）来调节HA片段诱导的组织损伤。有趣的是，LMW HA片段也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部分取决于LMW HA片段和组织源性腺苷之间的相互作用。为此，在Specific Aim 1中，我们假设A2aR结扎调节HA片段诱导的炎症基因表达。我们将在巨噬细胞、气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Specific Aim 2中，我们假设LMW HA通过下调抗炎A2aR来增强炎症。我们将进行研究以确定LMW HA调节A2aR表达的分子机制。特异性Aim 3假设内源性腺苷调节博来霉素诱导的肺部炎症和纤维化，并且A2aR激动剂的药理学管理可以预防疾病。我们将通过体内实验证明，在A2aR表达缺失的情况下，博莱霉素损伤更严重。此外，我们将明确A2aR刺激对巨噬细胞、肺气道和肺泡上皮细胞在介导这种保护作用中的作用。通过定义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学靶点作为潜在的治疗方法。我们相信这些研究将为使用A2aR特异性激动剂治疗特发性肺纤维化、慢性支气管炎和肺气肿等炎性肺疾病提供临床前基础。

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.