help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
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
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200405-612OCv1
171/8/889    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bonniaud, P.
Right arrow Articles by Gauldie, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bonniaud, P.
Right arrow Articles by Gauldie, J.

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




This article has been cited by other articles:


Home page
 Antimicrob. Agents Chemother.Home page
M. C. Waghabi, E. M. de Souza, G. M. de Oliveira, M. Keramidas, J.-J. Feige, T. C. Araujo-Jorge, and S. Bailly
Pharmacological Inhibition of Transforming Growth Factor {beta} Signaling Decreases Infection and Prevents Heart Damage in Acute Chagas' Disease
Antimicrob. Agents Chemother., November 1, 2009; 53(11): 4694 - 4701.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
W. D. Hardie, S. W. Glasser, and J. S. Hagood
Emerging Concepts in the Pathogenesis of Lung Fibrosis
Am. J. Pathol., July 1, 2009; 175(1): 3 - 16.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
L. Long, A. Crosby, X. Yang, M. Southwood, P. D. Upton, D.-K. Kim, and N. W. Morrell
Altered Bone Morphogenetic Protein and Transforming Growth Factor-{beta} Signaling in Rat Models of Pulmonary Hypertension: Potential for Activin Receptor-Like Kinase-5 Inhibition in Prevention and Progression of Disease
Circulation, February 3, 2009; 119(4): 566 - 576.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. J. Ellmers, N. J. A. Scott, S. Medicherla, A. P. Pilbrow, P. G. Bridgman, T. G. Yandle, A. M. Richards, A. A. Protter, and V. A. Cameron
Transforming Growth Factor-{beta} Blockade Down-Regulates the Renin-Angiotensin System and Modifies Cardiac Remodeling after Myocardial Infarction
Endocrinology, November 1, 2008; 149(11): 5828 - 5834.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
S. Fineschi, M. Bongiovanni, Y. Donati, S. Djaafar, F. Naso, L. Goffin, C. Barazzone Argiroffo, J.-C. Pache, J.-M. Dayer, S. Ferrari-Lacraz, et al.
In Vivo Investigations on Anti-Fibrotic Potential of Proteasome Inhibition in Lung and Skin Fibrosis
Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 458 - 465.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
A. L. Zaiman, M. Podowski, S. Medicherla, K. Gordy, F. Xu, L. Zhen, L. A. Shimoda, E. Neptune, L. Higgins, A. Murphy, et al.
Role of the TGF-{beta}/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension
Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 896 - 905.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
K. Fu, M. J. Corbley, L. Sun, J. E. Friedman, F. Shan, J. L. Papadatos, D. Costa, F. Lutterodt, H. Sweigard, S. Bowes, et al.
SM16, an Orally Active TGF-{beta} Type I Receptor Inhibitor Prevents Myofibroblast Induction and Vascular Fibrosis in the Rat Carotid Injury Model
Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 665 - 671.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
J. F. Santibanez, F. J. Blanco, E. M. Garrido-Martin, F. Sanz-Rodriguez, M. A. del Pozo, and C. Bernabeu
Caveolin-1 interacts and cooperates with the transforming growth factor-{beta} type I receptor ALK1 in endothelial caveolae
Cardiovasc Res, March 1, 2008; 77(4): 791 - 799.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. F. Alcorn, L. M. Rinaldi, E. F. Jaffe, M. van Loon, J. H. T. Bates, Y. M. W. Janssen-Heininger, and C. G. Irvin
Transforming Growth Factor-beta1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease
Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 974 - 982.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
N. Decologne, M. Kolb, P. J. Margetts, F. Menetrier, Y. Artur, C. Garrido, J. Gauldie, P. Camus, and P. Bonniaud
TGF-beta1 Induces Progressive Pleural Scarring and Subpleural Fibrosis
J. Immunol., November 1, 2007; 179(9): 6043 - 6051.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
C. J. Scotton and R. C. Chambers
Molecular Targets in Pulmonary Fibrosis: The Myofibroblast in Focus
Chest, October 1, 2007; 132(4): 1311 - 1321.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
H. Zhang, W. E. Lawson, V. V. Polosukhin, A. Pozzi, T. S. Blackwell, Y. Litingtung, and C. Chiang
Inhibitor of Differentiation 1 Promotes Endothelial Survival in a Bleomycin Model of Lung Injury in Mice
Am. J. Pathol., October 1, 2007; 171(4): 1113 - 1126.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
M. C. Waghabi, M. Keramidas, C. M. Calvet, M. Meuser, M. d. N. C. Soeiro, L. Mendonca-Lima, T. C. Araujo-Jorge, J.-J. Feige, and S. Bailly
SB-431542, a Transforming Growth Factor {beta} Inhibitor, Impairs Trypanosoma cruzi Infection in Cardiomyocytes and Parasite Cycle Completion
Antimicrob. Agents Chemother., August 1, 2007; 51(8): 2905 - 2910.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
N. I. Chaudhary, G. J. Roth, F. Hilberg, J. Muller-Quernheim, A. Prasse, G. Zissel, A. Schnapp, and J. E. Park
Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis
Eur. Respir. J., May 1, 2007; 29(5): 976 - 985.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. Khan, A. Agrotis, and A. Bobik
Understanding the role of transforming growth factor-{beta}1 in intimal thickening after vascular injury
Cardiovasc Res, May 1, 2007; 74(2): 223 - 234.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. Suzuki, S. Kim, H.-K. Cheung, M. J. Corbley, X. Zhang, L. Sun, F. Shan, J. Singh, W.-C. Lee, S. M. Albelda, et al.
A Novel Small-Molecule Inhibitor of Transforming Growth Factor {beta} Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection
Cancer Res., March 1, 2007; 67(5): 2351 - 2359.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
J. Gauldie, M. Kolb, K. Ask, G. Martin, P. Bonniaud, and D. Warburton
Smad3 Signaling Involved in Pulmonary Fibrosis and Emphysema
Proceedings of the ATS, November 1, 2006; 3(8): 696 - 702.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
S. Y. Leung, A. Niimi, A. Noble, T. Oates, A. S. Williams, S. Medicherla, A. A. Protter, and K. F. Chung
Effect of Transforming Growth Factor-beta Receptor I Kinase Inhibitor 2,4-Disubstituted Pteridine (SD-208) in Chronic Allergic Airway Inflammation and Remodeling
J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 586 - 594.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. M. Kapoun, N. J. Gaspar, Y. Wang, D. Damm, Y.-W. Liu, G. O'Young, D. Quon, A. Lam, K. Munson, T.-T. Tran, et al.
Transforming Growth Factor-beta Receptor Type 1 (TGFbetaRI) Kinase Activity but Not p38 Activation Is Required for TGFbetaRI-Induced Myofibroblast Differentiation and Profibrotic Gene Expression
Mol. Pharmacol., August 1, 2006; 70(2): 518 - 531.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Ge, V. Rajeev, P. Ray, E. Lattime, S. Rittling, S. Medicherla, A. Protter, A. Murphy, J. Chakravarty, S. Dugar, et al.
Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-{beta} Type I Receptor Kinase In vivo.
Clin. Cancer Res., July 15, 2006; 12(14): 4315 - 4330.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
F. J. Martinez and M. P. Keane
Update in diffuse parenchymal lung diseases 2005.
Am. J. Respir. Crit. Care Med., May 15, 2006; 173(10): 1066 - 1071.
[Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
S. I. Rennard
Chronic Obstructive Pulmonary Disease: Linking Outcomes and Pathobiology of Disease Modification
Proceedings of the ATS, May 1, 2006; 3(3): 276 - 280.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
G. R. S. Budinger, G. M. Mutlu, J. Eisenbart, A. C. Fuller, A. A. Bellmeyer, C. M. Baker, M. Wilson, K. Ridge, T. A. Barrett, V. Y. Lee, et al.
Proapoptotic Bid is required for pulmonary fibrosis
PNAS, March 21, 2006; 103(12): 4604 - 4609.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
K. Ask, G. E. M. Martin, M. Kolb, and J. Gauldie
Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls.
Proceedings of the ATS, January 1, 2006; 3(4): 389 - 393.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
Y. Chen, X. Shi-wen, J. van Beek, L. Kennedy, M. McLeod, E. A. Renzoni, G. Bou-Gharios, S. Wilcox-Adelman, P. F. Goetinck, M. Eastwood, et al.
Matrix Contraction by Dermal Fibroblasts Requires Transforming Growth Factor-{beta}/Activin-Linked Kinase 5, Heparan Sulfate-Containing Proteoglycans, and MEK/ERK: Insights into Pathological Scarring in Chronic Fibrotic Disease
Am. J. Pathol., December 1, 2005; 167(6): 1699 - 1711.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. Bonniaud, P. J. Margetts, K. Ask, K. Flanders, J. Gauldie, and M. Kolb
TGF-{beta} and Smad3 Signaling Link Inflammation to Chronic Fibrogenesis
J. Immunol., October 15, 2005; 175(8): 5390 - 5395.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2004 American Thoracic Society 		  Red In Translatin