Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor.
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 beta (TGF-beta) is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta 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-beta1-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 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-beta receptor activation.
Bonniaud
Philippe
P
Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Room 2N16, Hamilton, ON, Canada.
Margetts
Peter J
PJ
Kolb
Martin
M
Schroeder
Jane Ann
JA
Kapoun
Ann M
AM
Damm
Debby
D
Murphy
Alison
A
Chakravarty
Sarvajit
S
Dugar
Sundeep
S
Higgins
Linda
L
Protter
Andrew A
AA
Gauldie
Jack
J
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000502:physiology; D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011621:Pteridines / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D047428:Protein Kinase Inhibitors; D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; C511004:SD-208; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat