TGF-beta, Smad3 and the process of progressive fibrosis.
Transient adenovirus-mediated gene transfer of active TGF-beta1 (transforming growth factor-beta1) induces severe and progressive fibrosis in rodent lung without apparent inflammation. Alternatively, transfer of IL-1beta (interleukin 1beta) induces marked tissue injury and inflammation, which develops into progressive fibrosis, associated with an increase in TGF-beta1 concentrations in lung fluid and tissue. Both vector treatments induce a fibrotic response involving myofibroblasts and progressive matrix deposition starting at the peri-bronchial site of expression and extending over days to involve the entire lung and pleural surface. Administration of the TGF-beta1 vector to the pleural space induces progressive pleural fibrosis, which minimally extends into the lung parenchyma. The mechanisms involved in progressive fibrosis need to account for the limitation of fibrosis to specific organs (lung fibrosis and not liver fibrosis or vice versa) and the lack of effect of anti-inflammatory treatments in regulating progressive fibrosis. TGF-beta1 is a key cytokine in the process of fibrogenesis, using intracellular signalling pathways involving the ALK5 receptor and signalling molecules Smad2 and Smad3. Transient gene transfer of either TGF-beta1 or IL-1beta to Smad3-null mouse lung provides little evidence of progressive fibrosis and no fibrogenesis-associated genes are induced. These results suggest that mechanisms of progressive fibrosis involve factors presented within the context of the matrix that define the microenvironment for progressive matrix deposition.
Gauldie
J
J
Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St West, Hamilton, ON, Canada L8N 3Z5. gauldie@mcmaster.ca
Bonniaud
P
P
Sime
P
P
Ask
K
K
Kolb
M
M
D000818:Animals; D006801:Humans; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D051900:Smad3 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D051900:Smad3 Protein; D016212:Transforming Growth Factor beta