Sime P J, Xing Z, Graham F L, Csaky K G, Gauldie J
Molecular Virology and Immunology Program, Health Sciences Center, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
J Clin Invest. 1997 Aug 15;100(4):768-76. doi: 10.1172/JCI119590.
Transforming growth factor (TGF)-beta1 has been implicated in the pathogenesis of fibrosis based upon its matrix-inducing effects on stromal cells in vitro, and studies demonstrating increased expression of total TGF-beta1 in fibrotic tissues from a variety of organs. The precise role in vivo of this cytokine in both its latent and active forms, however, remains unclear. Using replication-deficient adenovirus vectors to transfer the cDNA of porcine TGF-beta1 to rat lung, we have been able to study the effect of TGF-beta1 protein in the respiratory tract directly. We have demonstrated that transient overexpression of active, but not latent, TGF-beta1 resulted in prolonged and severe interstitial and pleural fibrosis characterized by extensive deposition of the extracellular matrix (ECM) proteins collagen, fibronectin, and elastin, and by emergence of cells with the myofibroblast phenotype. These results illustrate the role of TGF-beta1 and the importance of its activation in the pulmonary fibrotic process, and suggest that targeting active TGF-beta1 and steps involved in TGF-beta1 activation are likely to be valuable antifibrogenic therapeutic strategies. This new and versatile model of pulmonary fibrosis can be used to study such therapies.
基于其在体外对基质细胞的基质诱导作用，转化生长因子（TGF）-β1已被认为与纤维化的发病机制有关，并且研究表明多种器官的纤维化组织中总TGF-β1的表达增加。然而，这种细胞因子的潜伏形式和活性形式在体内的确切作用仍不清楚。利用复制缺陷型腺病毒载体将猪TGF-β1的cDNA转移至大鼠肺，我们得以直接研究TGF-β1蛋白在呼吸道中的作用。我们已经证明，活性TGF-β1（而非潜伏性TGF-β1）的瞬时过表达会导致长期且严重的间质和胸膜纤维化，其特征为细胞外基质（ECM）蛋白胶原蛋白、纤连蛋白和弹性蛋白的大量沉积，以及出现具有肌成纤维细胞表型的细胞。这些结果阐明了TGF-β1的作用及其激活在肺纤维化过程中的重要性，并表明靶向活性TGF-β1及其激活过程中涉及的步骤可能是有价值的抗纤维化治疗策略。这种新型且通用的肺纤维化模型可用于研究此类治疗方法。
