Distler J H W, Distler O
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Germany.
Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v10-1. doi: 10.1093/rheumatology/ken276.
Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparation.
组织纤维化是硬皮病患者死亡的主要原因，但目前尚无针对纤维化的选择性疗法可用于常规临床治疗。最近的临床前研究表明，靶向c-Abl、血小板衍生生长因子（PDGF）受体或Src激酶的选择性酪氨酸激酶抑制剂可能是抗纤维化治疗的有前景的靶点。伊马替尼和尼洛替尼对c-Abl和PDGF受体的双重抑制，以及SU6656对Src激酶的选择性抑制或达沙替尼与c-Abl和PDGF的联合抑制均发挥了强大的抗纤维化作用。伊马替尼、尼洛替尼、达沙替尼和SU6656在体外可剂量依赖性地减少人皮肤成纤维细胞中细胞外基质蛋白的合成，并在博来霉素诱导的皮肤纤维化小鼠模型中预防纤维化。慢性髓性白血病患者的临床数据表明，伊马替尼、尼洛替尼和达沙替尼耐受性良好。基于有前景的临床前数据，目前正在对伊马替尼进行治疗硬皮病纤维化的临床试验评估，并且正在准备开展其他酪氨酸激酶抑制剂的试验。
