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 以微血管损伤为特征的自身免疫性结缔组织病， 纤维化，影响美国25万人（主要是女性）。一个主要原因 硬皮病患者死亡的原因是肺功能障碍， 进行性肺间质纤维化据推测， 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介质是凝血酶，其是一种多功能调节因子。 丝氨酸蛋白酶和G-蛋白偶联受体配体， 立即在血管损伤部位。最近我们观察到， 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SSc表型的改变是通过蛋白激酶C β （PKC-e）信号转导。这些观察打开了一个有趣的途径， SSc发病机制的研究。我们的假设是 凝血酶在正常和SSc肺中触发不同的PKC信号传导机制 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 这可以通过PKC与特定锚定蛋白的相互作用解释。更好 了解这些相互作用的机制可能会提供一个有用的 作为硬皮病肺病新治疗干预的靶点， 目前还没有有效的治疗方法

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.