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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 141-150, 2002
© 2002 American Thoracic Society

Differences in the Fibrogenic Response after Transfer of Active Transforming Growth Factor-ß1 Gene to Lungs of "Fibrosis-prone" and "Fibrosis-resistant" Mouse Strains

Martin Kolb, Philippe Bonniaud, Tom Galt, Patricia J. Sime, Margaret M. Kelly, Peter J. Margetts and Jack Gauldie

Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada; Medizinische Klinik, Julius-Maximilians-Universität, Würzburg, Germany; Service de Pneumologie et Réanimation Respiratoire, CHU Dijon et Université de Bourgogne, France; and Department of Medicine, University of Rochester Medical School, Rochester, New York

Address correspondence to: Jack Gauldie, Ph.D., Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada. E-mail: gauldie{at}mcmaster.ca

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium, resulting in impaired lung function and respiratory failure. Investigation of the differences in individual susceptibility to the development of fibrosis may help to detect patients that are at risk to fibrosis when exposed to fibrogenic stimuli. In this study we used adenoviral gene transfer to transiently expose a fibrosis-prone (C57BL/6) and a fibrosis-resistant (Balb/c) mouse strain to high levels of active transforming growth factor (TGF)-ß1, a key profibrotic cytokine. Balb/c mice developed significantly less fibrosis compared with C57BL/6 mice in response to active TGF-ß1 despite higher levels of the transgene protein in the lung. This was not due to a general unresponsiveness of cells to TGF-ß1, because primary fibroblasts of both strains increased collagen synthesis upon stimulation with TGF-ß1 in vitro to the same degree. However, TGF-ß1 induced a strong upregulation of tissue inhibitor of metalloprotease-1 gene in pulmonary fibroblasts as well as in lungs of C57BL/6 mice, in contrast to a weak induction in Balb/c mice. These findings suggest that the differences in susceptibility to pulmonary fibrosis are downstream from TGF-ß1 and that fibrosis-prone individuals may have an altered collagen metabolism in the lungs that is balanced toward a "nondegrading" environment.

Abbreviations: acute respiratory distress syndrome, ARDS • bronchoalveolar lavage, BAL • bronchiolitis obliterans organizing pneumonia, BOOP • extracellular matrix, ECM • interleukin-1 receptor antagonist, IL-1RA • matrix metalloprotease, MMP • nonspecific interstitial pneumonia, NSIP • phosphate-buffered saline, PBS • transforming growth factor ß1, TGF-ß1 • tissue inhibitor of metalloprotease, TIMP




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