TGFβ信号转导通路及以其为靶点的肝纤维化治疗

肝纤维化是指由多种慢性疾病引起的肝脏持续的创伤修复反应而导致的细胞外基质(ECM)过度沉积和肝脏功能的受损。激活的肝星状细胞(HSC)是促进ECM过度沉积的主要细胞。转化生长因子β(TGFβ)可激活HSC和调节ECM的合成和沉积,被认为是肝纤维化中最关键的因素。介导TGFβ信号进入细胞核内的最主要途径是Smad转导通路,而越来越多的证据表明,非Smad途径也参与了TGFβ的信号转导。TGFβ信号通路对维持内环境的稳态非常重要并涉及多种病理状态。这种具有多重生物活性的细胞因子对正常健康的维持同样非常重要,所以在TGFβ信号转导中通过阻断对纤维化的形成具有特异性作用的下游通路且不影响其他的生物活性而治疗肝纤维化具有重要的挑战性。

TGFβ signal pathway and anti TGFβ strategies for treatment of liver fibrosis

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins that occurs in most types of chronic liver diseases. Hepatic stellate cells (HSCs) are major sources of the excess ECM deposited in fibrotic liver. Transforming growth factor β (TGF-β) is considered to play a generic role in the development of tissue fibrosis, as it stimulates the synthesis and deposition of ECM components. Smad pathways are central mediators of signals from the receptors for transfor- ming TGF-β to the nucleus. However, growing biochemical and developmental evidence supports the notion that non-Smad pathways also participate in TGF-β signalling. TGF-β signalling pathways play an important role in regulating tissue homeostasis and have been implicated implicated in diverse pathological conditions. It is oow our challenge to design ways of blocking the fibrosis-specific actions of TGF-β through downstream signalling pathways and mediators without compromising the other activities of this multifunctional cytokine, which is essential for health.