1 Department of Respiratory Medicine and Rheumatology and.
Am J Respir Cell Mol Biol. 2013 Oct;49(4):536-43. doi: 10.1165/rcmb.2012-0277OC.
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor β to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor β, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.
黏着斑激酶（FAK）是一种非受体酪氨酸激酶，参与多种生物学功能，包括细胞存活、增殖、迁移和黏附。FAK 是转化生长因子 β诱导肌成纤维细胞分化的重要因素。在本研究中，我们研究了使用特异性抑制剂 TAE226 靶向抑制 FAK 是否具有调节肺纤维化的潜力。TAE226 显示出对肺成纤维细胞中 FAK 酪氨酸 397 自身磷酸化的抑制活性。在体外，TAE226 抑制了包括血小板衍生生长因子和胰岛素样生长因子 I 在内的各种生长因子对肺成纤维细胞增殖的作用。TAE226 强烈抑制肺成纤维细胞产生 I 型胶原。此外，用 TAE226 处理成纤维细胞可降低转化生长因子 β诱导的α-平滑肌肌动蛋白的表达，表明抑制成纤维细胞向肌成纤维细胞的分化。即使在治疗后期使用 TAE226 也可改善博来霉素诱导的小鼠肺纤维化。TAE226 处理小鼠肺部增殖的间充质细胞数量减少。这些数据表明 FAK 信号在肺纤维化的进展中起重要作用，它可能成为治疗肺纤维化的有前途的靶点。
