Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung.

TLDR

Transforming growth factor‑β1 is known to drive fibrosis through matrix induction and is elevated in fibrotic tissues, yet the distinct in vivo roles of its latent and active forms remain unclear. The authors developed a new rat model of pulmonary fibrosis to evaluate therapies that target active TGF‑β1. They used replication‑deficient adenovirus vectors to deliver porcine TGF‑β1 cDNA directly to rat lung tissue, enabling assessment of the cytokine’s effects. Transient overexpression of active, but not latent, TGF‑β1 produced prolonged, severe interstitial and pleural fibrosis with extensive collagen, fibronectin, elastin deposition and myofibroblast emergence, underscoring the importance of TGF‑β1 activation for antifibrotic strategies.

Abstract

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.