Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta3.
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.
Ask
Kjetil
K
Department of Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
Bonniaud
Philippe
P
Maass
Katja
K
Eickelberg
Oliver
O
Margetts
Peter J
PJ
Warburton
David
D
Groffen
John
J
Gauldie
Jack
J
Kolb
Martin
M
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*
D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3