Gharaee-Kermani M, Hu B, Phan S H, Gyetko M R
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical School, 2215 Fuller Road, 11 R, Ann Arbor, MI 48105, USA.
Curr Med Chem. 2009;16(11):1400-17. doi: 10.2174/092986709787846497.
Idiopathic Pulmonary Fibrosis (IPF) is characterized by injury and loss of lung epithelial cells, accumulation of fibroblasts/myofibroblasts and abnormal remodeling of the lung parenchyma. The prognosis for IPF patients is poor and current therapies are largely ineffective in preventing respiratory failure. Current therapeutic approaches target epithelial cell replacement, manipulation of fibroblasts/myofibroblasts, modulation of procoagulant/fibrinolytic activities, cytokine and growth factor production, angiogenesis, and reduction of oxidative stress. Myofibroblasts are the primary effector cells in fibrosis. These cells may be derived by the activation and proliferation of resident lung fibroblasts, from epithelial-mesenchymal transition (EMT), or through recruitment of circulating fibrocytes. Transforming growth factor beta (TGFbeta) is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown. TGFbeta acts through the promoter of the type 1 collagen gene causing increased collagen synthesis. In addition, TGFbeta induces EMT in alveolar epithelial cells (AECs) in vitro and in vivo. AECs exhibit substantial plasticity and may serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. Therapeutic interventions interfering with the pathways that lead to myofibroblast expansion and AEC apoptosis should be of considerable benefit in the treatment of IPF. This review will focus on the critical role of TGFbeta on AECs EMT and myofibroblasts in the development of fibrosis.
特发性肺纤维化（IPF）的特征是肺上皮细胞损伤和丧失、成纤维细胞/肌成纤维细胞积聚以及肺实质异常重塑。IPF患者的预后很差，目前的治疗方法在预防呼吸衰竭方面大多无效。当前的治疗方法旨在进行上皮细胞置换、调控成纤维细胞/肌成纤维细胞、调节促凝血/纤溶活性、细胞因子和生长因子生成、血管生成以及减轻氧化应激。肌成纤维细胞是纤维化过程中的主要效应细胞。这些细胞可能源自肺内常驻成纤维细胞的激活和增殖、上皮-间质转化（EMT），或通过循环纤维细胞的募集产生。转化生长因子β（TGFβ）是一种促纤维化因子，可增加成纤维细胞增殖、刺激结缔组织的合成与沉积，并抑制结缔组织分解。TGFβ通过1型胶原基因的启动子发挥作用，导致胶原合成增加。此外，TGFβ在体外和体内均可诱导肺泡上皮细胞（AEC）发生EMT。AEC具有显著的可塑性，可能是肺纤维化中成纤维细胞和/或肌成纤维细胞的来源。干扰导致肌成纤维细胞扩张和AEC凋亡途径的治疗干预措施在IPF治疗中可能具有显著益处。本综述将聚焦于TGFβ在AEC的EMT以及纤维化发展过程中肌成纤维细胞方面的关键作用。
