The Pharmacology of Dermal Fibrosis

基质替换和修复是伤口愈合所必需的，但是当该过程过度时， 增生的，如在疤痕或瘢痕疙瘩形成中，或当它不适当地发生时，如硬皮病 和其它纤维化疾病，它可导致发病，并且在硬皮病的情况下，可导致死亡。 虽然很明显生长因子在纤维化中起着核心作用，但小分子的作用 在病理性纤维化中的作用还没有很好的研究。我们最近证明， 嘌呤核苷腺苷通过腺苷A2 A受体起作用，在 肝硬化和硬皮病实验模型中出现的纤维化。我们 在此建议进一步确定腺苷和腺苷受体是否在 病理性纤维化，并剖析腺苷A2 A受体的分子机制， 刺激胶原蛋白和其他基质成分的过度产生。为此 我们建议研究：一。腺苷受体在病理性纤维化中的作用 在皮肤瘢痕形成和弥漫性瘢痕形成模型中研究肥厚性瘢痕形成的发展， 野生型、腺苷A1、A2 A、A2 B和A3中博来霉素处理诱导的真皮纤维化 受体敲除小鼠，产生较少细胞外腺苷（外5 '核苷酸酶）的小鼠 和核苷三磷酸焦磷酸酶敲除小鼠）和用腺苷处理的小鼠 受体拮抗剂; II.腺苷A2 A受体信号传导与纤维化的初步研究 实验中我们观察到腺苷A2 A受体的刺激减少了核fl 水平，CTGF表达的组成性阻遏物，可能介导促纤维化的变化， 腺苷和A2 A受体的作用。我们将剖析信号通路， 腺苷A2 A受体对fli 1表达的抑制和核定位的影响 药理学和siRNA介导的敲低技术的组合; III.串话 腺苷A2 A受体和“抗纤维化”细胞因子受体之间的关系 先前证明干扰素-γ，一种抗纤维化细胞因子， 受体的表达，更戏剧性的是，功能。我们将研究 干扰素-γ下调腺苷A2 A受体功能， 药理学和分子（siRNA介导的敲低）方法。在未来的实验中 我们将研究腺苷受体在瘢痕疙瘩形成中的作用以及其他临床相关的 病理性纤维化（如放射性纤维化）。因为腺苷受体 拮抗剂正在开发用于治疗多种医学病症， 可以快速将这些研究中获得的信息带到临床。

Matrix replacement and repair is required for wound healing but when the process is overly exuberant, as in scar or keloid formation, or when it occurs inappropriately, as in Scleroderma and other fibrosing diseases, it can lead to morbidity and, in the case of Scleroderma, mortality. Although it is clear that growth factors play a central role in fibrosis the role of small molecules in pathologic fibrosis has not been well explored. We have recently demonstrated that the purine nucleoside adenosine, acting through the adenosine A2A receptor, plays a central role in the fibrosis that develops in experimental models of hepatic cirrhosis and scleroderma. We propose here to further determine whether adenosine and adenosine receptors play a role in pathologic fibrosis and to dissect the molecular mechanism by which adenosine A2A receptors on fibroblasts stimulate overproduction of collagen and other matrix constituents. To this end we have proposed to study: I. The role of adenosine receptors in pathologic fibrosis We will study the development of hypertrophic scarring in a model of dermal scarring and diffuse dermal fibrosis induced by bleomycin treatment in wild type, adenosine A1, A2A, A2B and A3 receptor knockout mice, mice that generate less extracellular adenosine (ecto‐5’Nucleotidase and nucleoside triphosphate pyrophosphatase knockout mice) and mice treated with adenosine receptor antagonists; II. Signaling at adenosine A2A receptors for fibrosis In preliminary experiments we have observed that adenosine A2A receptor stimulation diminishes nuclear fli1 levels, a constitutive repressor of CTGF expression, a change which may mediate the profibrotic effects of adenosine and the A2A receptor. We will dissect the signaling pathways from adenosine A2A receptors to suppression of fli1 expression and nuclear localization using a combination of pharmacologic and siRNA‐mediated knockdown techniques; III. Cross‐talk between adenosine A2A receptors and receptors for “anti‐fibrotic” cytokines We have previously demonstrated that interferon‐γ, an anti‐fibrotic cytokine, diminishes adenosine A2A receptor expression and, more dramatically, function. We will study the mechanism by which interferon‐γ downregulates adenosine A2A receptor function with a combination of pharmacologic and molecular (siRNA‐mediated knockdown) methods. In future experiments we will examine the role of adenosine receptors in keloid formation and other clinicallyrelevant forms of pathologic fibrosis (e.g. radiation fibrosis). Because adenosine receptor antagonists are under development for the treatment of a variety of medical conditions it may be possible to quickly bring the information garnered in these studies to the clinic.