Differences in the fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains.
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium, resulting in impaired lung function and respiratory failure. Investigation of the differences in individual susceptibility to the development of fibrosis may help to detect patients that are at risk to fibrosis when exposed to fibrogenic stimuli. In this study we used adenoviral gene transfer to transiently expose a fibrosis-prone (C57BL/6) and a fibrosis-resistant (Balb/c) mouse strain to high levels of active transforming growth factor (TGF)-beta1, a key profibrotic cytokine. Balb/c mice developed significantly less fibrosis compared with C57BL/6 mice in response to active TGF-beta1 despite higher levels of the transgene protein in the lung. This was not due to a general unresponsiveness of cells to TGF-beta1, because primary fibroblasts of both strains increased collagen synthesis upon stimulation with TGF-beta1 in vitro to the same degree. However, TGF-beta1 induced a strong upregulation of tissue inhibitor of metalloprotease-1 gene in pulmonary fibroblasts as well as in lungs of C57BL/6 mice, in contrast to a weak induction in Balb/c mice. These findings suggest that the differences in susceptibility to pulmonary fibrosis are downstream from TGF-beta1 and that fibrosis-prone individuals may have an altered collagen metabolism in the lungs that is balanced toward a "nondegrading" environment.
Kolb
Martin
M
Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
Bonniaud
Philippe
P
Galt
Tom
T
Sime
Patricia J
PJ
Kelly
Margaret M
MM
Margetts
Peter J
PJ
Gauldie
Jack
J
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D008168:Lung / Q000166:cytology / Q000473:pathology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D011480:Protease Inhibitors / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000503:physiopathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D011480:Protease Inhibitors; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D006909:Hydroxyproline