Transforming growth factors-beta 1, -beta 2, and -beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis.
Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating fibroblast collagen deposition. TGF-beta 1 is implicated in the pathogenesis of pulmonary fibrosis, but the role of TGF-beta 2 and TGF-beta 3 remains unclear. We examined their effects on lung fibroblast procollagen metabolism in vitro and localized their gene expression during bleomycin-induced lung fibrosis using in situ hybridization with digoxigenin-labeled riboprobes. All three isoforms stimulated fibroblast procollagen production. TGF-beta 3 was the most potent and also reduced procollagen degradation. In normal mouse lung, TGF-beta 1 and TGF-beta 3 mRNA transcripts were abundant in bronchiolar epithelium. After bleomycin, TGF-beta 1 gene expression was maximally enhanced at 10 days, with the signal being predominant in macrophages. Signal was also enhanced in mesenchymal, pulmonary endothelial, and mesothelial cells. After 35 days, the pattern of TGF-beta 1 gene expression returned to that of control lung. TGF-beta 3 gene expression remained unchanged throughout compared with controls. TGF-beta 2 mRNA was not detected with the antisense probe, but signal obtained with the sense probe suggests the presence of a naturally occurring antisense. This study demonstrates that TGF-beta 1, -beta 2, and -beta 3 all exert profibrotic effects in vitro. However, TGF-beta isoform gene expression is differentially controlled during experimental pulmonary fibrosis with TGF-beta 1 the predominant isoform expressed during pathogenesis.
Coker
R K
RK
Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, University College London Medical School, United Kingdom.
Laurent
G J
GJ
Shahzeidi
S
S
Lympany
P A
PA
du Bois
R M
RM
Jeffery
P K
PK
McAnulty
R J
RJ
D000818:Animals; D001761:Bleomycin; D002352:Carrier Proteins / Q000235:genetics* / Q000494:pharmacology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000139:chemically induced; D015870:Gene Expression; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D007536:Isomerism; D053779:Latent TGF-beta Binding Proteins; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011347:Procollagen / Q000096:biosynthesis*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000494:pharmacology
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D011347:Procollagen; D016212:Transforming Growth Factor beta; D001761:Bleomycin