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Published ahead of print on November 24, 2004, doi:10.1164/rccm.200405-612OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 889-898, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200405-612OC

Original Article

Progressive Transforming Growth Factor ß1–induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor

Philippe Bonniaud, Peter J. Margetts, Martin Kolb, Jane Ann Schroeder, Ann M. Kapoun, Debby Damm, Alison Murphy, Sarvajit Chakravarty, Sundeep Dugar, Linda Higgins, Andrew A. Protter and Jack Gauldie

Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada; Service de Pneumologie et Réanimation Respiratoire, CHU du Bocage and Université de Bourgogne, Dijon, France; Medizinische Klinik, Julius-Maximilians-Universität, Wurzburg, Germany; Scios, Inc., Fremont, California

Correspondence and requests for reprints should be addressed to Jack Gauldie, Ph.D., F.R.S.C., Professor and Chair, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Room 2N16, Hamilton, ON, Canada L8N 3Z5. E-mail: gauldie{at}mcmaster.ca

Pulmonary fibrosis is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. Idiopathic pulmonary fibrosis (IPF) is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor ß (TGF-ß) is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-ß mediates its biological effects through members of a family of activin receptor–like kinases (ALK). We have used a gene transfer model of progressive TGF-ß1–induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-ß receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-ß receptor activation.

Key Words: fibrogenesis • interstitial lung fibrosis • matrix • TGF-ß receptor




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