Adenovector-mediated gene transfer of active transforming growth factor-beta 1 induces prolonged severe fibrosis in rat lung

Transforming growth factor (TGF)-beta 1 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-beta 1 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-beta 1 to rat lung, we have been able to study the effect of TGF-beta 1 protein in the respiratory tract directly, We have demonstrated that transient overexpression of active, but not latent, TGF-beta 1 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-beta 1 and the importance of its activation in the pulmonary fibrotic process, and suggest that targeting active TGF-beta 1 and steps involved In TGF-beta 1 activation are likely to be valuable antifibrogenic therapeutic strategies. This new and versatile model of pulmonary fibrosis can be used to study such therapies.