Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung.
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.
Sime
P J
PJ
Molecular Virology and Immunology Program, Health Sciences Center, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Xing
Z
Z
Graham
F L
FL
Csaky
K G
KG
Gauldie
J
J
D000199:Actins / Q000032:analysis; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003094:Collagen / Q000032:analysis; D004549:Elastin / Q000032:analysis; D005353:Fibronectins / Q000032:analysis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D000199:Actins; D005353:Fibronectins; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D004549:Elastin; D006909:Hydroxyproline