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Published ahead of print on November 24, 2004, doi:10.1164/rccm.200405-612OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 8, April 2005, 889-898

A more recent version of this article appeared on April 15, 2005
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Submitted on May 16, 2004
Accepted on November 17, 2004

Progressive TGF-{beta}1-induced Lung Fibrosis is Blocked by an Orally Active ALK5 Kinase Inhibitor

Philippe Bonniaud1, Peter J Margetts2, Martin Kolb3, Jane Ann Schroeder2, Ann M Kapoun4, Debby Damm4, Alison Murphy4, Sarvajit Chakravarty4, Sundeep Dugar4, Linda Higgins4, Andrew A Protter4, and Jack Gauldie2*

1 Department of Pathology and Molecular Medicine, McMaster University, Centre for Gene Therapeutics, Hamilton, Ontario, Canada; Service de Pneumologie et Reanimation Respiratoire, CHU du Bocage et Universite de Bourgogne, Dijon, France, 2 Department of Pathology and Molecular Medicine, McMaster University, Centre for Gene Therapeutics, Hamilton, Ontario, Canada, 3 Department of Pathology and Molecular Medicine, McMaster University, Centre for Gene Therapeutics, Hamilton, Ontario, Canada; Medizinische Klinik, Julius-Maximilians-Universitat, Wurzburg, Germany, 4 SCIOS Inc, Fremont, CA, USA

* To whom correspondence should be addressed. 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 is associated with pronounced morbidity and mortality, responds poorly to known therapeutic interventions, and there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor {beta} (TGF{beta}) is known to mediate extracellular matrix gene regulation and appears a major player in both the initiation and progression of IPF. TGF{beta} mediates its biologic effects through members of a family of activin receptor-like kinases (ALK). We have used a gene transfer model of progressive TGF{beta}1 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{beta} receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most importantly, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for Idiopathic Pulmonary Fibrosis and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF{beta} receptor activation.
Key words: interstitial lung fibrosis, matrix, fibrogenesis, TGFbeta receptor




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