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TGF-1 Induces Progressive Pleural Scarring and Subpleural Fibrosis¹

Nathalie Decologne^*, Martin Kolb, Peter J. Margetts, Franck Menetrier^*, Yves Artur, Carmen Garrido^*, Jack Gauldie, Philippe Camus^*, and Philippe Bonniaud^2,*,

^* Faculty of Medicine and Pharmacy, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 866, Dijon, France; UMR 1129, Flaveur, Vision et Comportement du Consommateur, Institut National de la Recherche Agronomique, Etablissement National d’Enseignement Supérieur Agronomique de Dijon, University of Burgundy, Dijon, France; Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada; and Service de Pneumologie et Réanimation Respiratoire, Centre Hospitalier Universitaire du Bocage, Dijon, France

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-1 is suspected, even if not proven, as a key cytokine in this process. In this study, we used adenoviral gene transfer of TGF-1 to the pleural mesothelium in rats. We show that local and transient TGF-1 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ N.D. was supported by the Comité de Côte d’Or de la Ligue Contre le Cancer and by the Société de Pneumologie de Langue Française. P.B. was supported by Pneumologie Développement. M.K. is a Parker B. Francis Fellow and was supported by a Career Development Award of Department of Medicine, McMaster University. P.J.M. is a Canadian Institutes for Health Research Clinician Scientist.

² Address correspondence and reprint requests to Dr. Philippe Bonniaud, Service de Pneumologie et Réanimation Respiratoire, Centre Hospitalier Universitaire du Bocage, 21079 Dijon, France. E-mail address: philippe.bonniaud{at}chu-dijon.fr

³ Abbreviations used in this paper: EMT, epithelial-to-mesenchymal transition; MFT, mesothelial-fibroblastoid transformation; PLF, pleural lavage fluid; BAL, bronchoalveolar lavage; BALF, BAL fluid; HSP, heat shock protein; SMA, smooth muscle actin; MMP, matrix metalloproteinase.

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