TGF-beta1 induces progressive pleural scarring and subpleural fibrosis.
Pleural fibrosis is a misunderstood disorder which can cause severe restrictive lung disease with high morbidity and even mortality. The condition can develop in response to a large variety of diseases and tissue injury, among them infectious disease, asbestos, drugs, and radiation therapy. There is no efficient treatment to reverse established pleural fibrosis. TGF-beta1 is suspected, even if not proven, as a key cytokine in this process. In this study, we used adenoviral gene transfer of TGF-beta1 to the pleural mesothelium in rats. We show that local and transient TGF-beta1 overexpression induces homogenous, prolonged, and progressive pleural fibrosis without pleurodesis, associated with severe impairment of pulmonary function. We further demonstrate that pleural fibrosis can expand into the lung parenchyma from the visceral layer, but not into the muscle from the parietal layer. We provide evidence that matrix accumulation and fibrosis within the parenchyma evolved through a process involving "mesothelial-fibroblastoid transformation" and suggest that the pleural mesothelial cell may be an important player involved in the development of the subpleural distribution pattern known to be a hallmark of pulmonary fibrosis. This new model of pleural fibrosis will allow us to better understand the mechanisms of progressive fibrogenesis, and to explore novel antifibrotic therapies in the pleural cavity.
Decologne
Nathalie
N
Faculty of Medicine and Pharmacy, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 866, Dijon, France.
Kolb
Martin
M
Margetts
Peter J
PJ
Menetrier
Franck
F
Artur
Yves
Y
Garrido
Carmen
C
Gauldie
Jack
J
Camus
Philippe
P
Bonniaud
Philippe
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018450:Disease Progression; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D053773:Transforming Growth Factor beta1