title: Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta3.
abstract: Tissue repair is a well-orchestrated biological process involving numerous soluble mediators, and an imbalance between these factors may result in impaired repair and fibrosis. Transforming growth factor (TGF)-beta is a key profibrotic element in this process and it is thought that its three isoforms act in a similar way. Here, we report that TGF-beta3 administered to rat lungs using transient overexpression initiates profibrotic effects similar to those elicited by TGF-beta1, but causes less severe and progressive changes. The data suggest that TGF-beta3 does not lead to inhibition of matrix degradation in the same way as TGF-beta1, resulting in non-fibrotic tissue repair. Further, TGF-beta3 is able to downregulate TGF-beta1-induced gene expression, suggesting a regulatory role of TGF-beta3. TGF-beta3 overexpression results in an upregulation of Smad proteins similar to TGF-beta1, but is less efficient in inducing the ALK 5 and TGF-beta type II receptor (TbetaRII). We provide evidence that this difference may contribute to the progressive nature of TGF-beta1-induced fibrotic response, in contrast to the limited fibrosis observed following TGF-beta3 overexpression. TGF-beta3 is important in "normal wound healing", but is outbalanced by TGF-beta1 in "fibrotic wound healing" in the lung.
authors.affiliation: Department of Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Ask
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonniaud
authors.forename: Katja
authors.initials: K
authors.lastname: Maass
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Margetts
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: John
authors.initials: J
authors.lastname: Groffen
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3