PKC Signaling in Thrombin-Activated Lung Fibroblasts

描述(申请人提供)：硬皮病(系统性硬化症，SSC)是一种 自身免疫性结缔组织病，以微血管损伤和 纤维化症，在美国影响25万人(主要是女性)。一项主要事业 硬皮病患者死亡的主要原因是肺功能障碍 进行性间质性肺纤维化。据推测，激活的 成纤维细胞(肌成纤维细胞)参与肺纤维化的发病机制。 肺成纤维细胞活化的一种媒介是凝血酶，一种多功能的 丝氨酸蛋白酶和G蛋白偶联受体配体 立即到达血管损伤的地方。最近我们观察到暴露在 正常培养的人肺成纤维细胞对凝血酶诱导的肌成纤维细胞 表型。这种向SSC表型的改变是通过蛋白激酶C epsilon实现的 (PKC-e)信号转导。这些观察结果开辟了一条有趣的道路 系统性红斑狼疮发病机制的探讨。我们最重要的假设是 凝血酶在正常肺和SSc肺中触发不同的PKC信号机制 成纤维细胞。在这两种细胞类型中介导的反应的特异性可以 可通过PKC与特定锚定蛋白的相互作用来解释。更好 了解这些相互作用的机制可能会提供一个有用的 硬皮病肺部疾病新治疗干预措施的目标 目前还没有得到证实的有效治疗方法。

DESCRIPTION (provided by applicant):Scleroderma (systemic sclerosis, SSc) is an autoimmune, connective tissue disease characterized by microvascular injury and fibrosis, affecting 250,000 people (mostly women) in the USA. A leading cause of death in scleroderma patients is pulmonary dysfunction as a result of progressive interstitial lung fibrosis. It is postulated that activated fibroblasts (myofibroblasts) are involved in the pathogenesis of lung fibrosis. One mediator of lung fibroblast activation is thrombin, a multifunctional serine protease and G-protein coupled receptor ligand, which is generated immediately at sites of vascular injury. Recently we observed that exposure of normal cultured human lung fibroblasts to thrombin induces the myofibroblast phenotype. This change to an SSc phenotype occurs via protein kinase C epsilon (PKC-e) signal transduction. These observations open an interesting avenue in the investigation of the pathogenesis of SSc. Our overlying hypothesis is that thrombin triggers distinct PKC signaling mechanisms in normal and SSc lung fibroblasts. Specificity of the responses mediated in these two cell types can be explained by interaction of PKC with specific anchoring proteins. Better understanding of the mechanisms of these interactions may provide a useful target for novel therapeutic interventions in scleroderma lung disease, for which no proven, effective therapy exists.