This Article Full Text Full Text (PDF) All Versions of this Article: 2004-0158OCv1 31/5/510    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bonniaud, P. Articles by Kolb, M. Search for Related Content PubMed PubMed Citation Articles by Bonniaud, P. Articles by Kolb, M.

Connective Tissue Growth Factor Is Crucial to Inducing a Profibrotic Environment in "Fibrosis-Resistant" Balb/c Mouse Lungs

Departments of Medicine, Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada; Service de Pneumologie et Réanimation Respiratoire, CHU du Bocage et Université de Bourgogne, Dijon, France; Medizinische Klinik, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

Address correspondence to: Dr. Martin Kolb, M.D., P.D., Departments of Medicine, Pathology and Molecular Medicine, McMaster University, Firestone Institute for Respiratory Health, 50 Charlton Ave. East, Room H 325, Hamilton, ON, Canada L8N 4A6. E-mail: kolbm{at}mcmaster.ca

The individual susceptibility to pulmonary fibrosis (PF) remains a mystery, suggesting a role for genetic predisposition. The pathogenesis of PF involves a multitude of factors mediating crosstalk between various tissue components. Some factors, such as transforming growth factor ß, are recognized as key elements in the process, whereas the role of others, such as connective tissue growth factor (CTGF), is unclear. We investigated if Balb/c mice, known to be fibrosis resistant partly due to lack of CTGF induction upon stimulation with bleomycin, can be transformed into fibrosis-sensitive individuals by generation of a CTGF-rich environment using transient overexpression of CTGF by adenoviral gene transfer (AdCTGF). We show that AdCTGF is not sufficient to cause fibrosis, and that bleomycin challenge results in inflammation, but not fibrosis, in Balb/c mouse lungs. This inflammation is accompanied by lower levels of CTGF and tissue inhibitor of metalloproteinase–1 gene expression compared with fibrosis-prone C57BL/6 mice. However, concomitant administration of AdCTGF and bleomycin leads to a persistent upregulation of tissue inhibitor of metalloproteinase–1 gene and a significant fibrotic response in Balb/c similar to that in C57BL/6 mice. We propose that CTGF is an important mediator in the pathogenesis of PF in that it provides a local microenvironment in the lung that causes individual susceptibility. CTGF should be considered as a novel drug target and as a potential marker for identifying individuals at risk.

Abbreviations: connective tissue growth factor ß adenoviral gene transfer, AdCTGF-ß • control vector (no transgene), AdDL • transforming growth factor-ß adenoviral gene transfer, AdTGF-ß • bronchoalveolar lavage, BAL • connective tissue growth factor, CTGF • extracellular matrix, ECM • phosphate-buffered saline, PBS • pulmonary fibrosis, PF • transforming growth factor–ß, TGF-ß • tissue inhibitor of metalloproteinase, TIMP

This article has been cited by other articles:

				E. Rimon, B. Chen, A. L. Shanks, D. M. Nelson, and Y. Sadovsky Hypoxia in Human Trophoblasts Stimulates the Expression and Secretion of Connective Tissue Growth Factor Endocrinology, June 1, 2008; 149(6): 2952 - 2958. [Abstract] [Full Text] [PDF]

				C. T. Migliaccio, M. C. Buford, F. Jessop, and A. Holian The IL-4R{alpha} pathway in macrophages and its potential role in silica-induced pulmonary fibrosis J. Leukoc. Biol., March 1, 2008; 83(3): 630 - 639. [Abstract] [Full Text] [PDF]

				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]

				D. Kass, R. S. Bridges, A. Borczuk, and S. Greenberg Methionine Aminopeptidase-2 as a Selective Target of Myofibroblasts in Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 193 - 201. [Abstract] [Full Text] [PDF]

				K. Pochetuhen, I. G. Luzina, V. Lockatell, J. Choi, N. W. Todd, and S. P. Atamas Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18 Am. J. Pathol., August 1, 2007; 171(2): 428 - 437. [Abstract] [Full Text] [PDF]

				A. Churg, H. Tai, T. Coulthard, R. Wang, and J. L. Wright Cigarette Smoke Drives Small Airway Remodeling by Induction of Growth Factors in the Airway Wall Am. J. Respir. Crit. Care Med., December 15, 2006; 174(12): 1327 - 1334. [Abstract] [Full Text] [PDF]

				A. Leask and D. J. Abraham All in the CCN family: essential matricellular signaling modulators emerge from the bunker J. Cell Sci., December 1, 2006; 119(23): 4803 - 4810. [Abstract] [Full Text] [PDF]

				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]

				S.-H. Wu, X.-H. Wu, C. Lu, L. Dong, and Z.-Q. Chen Lipoxin A4 Inhibits Proliferation of Human Lung Fibroblasts Induced by Connective TissueGrowth Factor Am. J. Respir. Cell Mol. Biol., January 1, 2006; 34(1): 65 - 72. [Abstract] [Full Text] [PDF]

				P. Bonniaud, P. J. Margetts, M. Kolb, J. A. Schroeder, A. M. Kapoun, D. Damm, A. Murphy, S. Chakravarty, S. Dugar, L. Higgins, et al. Progressive Transforming Growth Factor {beta}1-induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 889 - 898. [Abstract] [Full Text] [PDF]