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Published ahead of print on July 15, 2004, doi:10.1165/rcmb.2004-0158OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 5, November 2004, 510-516

A more recent version of this article appeared on November 1, 2004
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Submitted on May 11, 2004
Revised on July 14, 2004

CTGF is crucial to induce a profibrotic environment in "fibrosis resistant" Balb/c mouse lungs

Philippe Bonniaud1, Gail Martin2, Peter J Margetts2, Kjetil Ask2, Jennifer Robertson2, Jack Gauldie2, and Martin Kolb3*

1 Departments of Medicine, Pathology and Molecular Medicine, McMaster University, Center for Gene Therapeutics, Hamilton, Ontario, Canada; Service de Pneumologie et Reanimation Respiratoire, CHU du Bocage et Universite de Bourgogne, Dijon, France, 2 Departments of Medicine, Pathology and Molecular Medicine, McMaster University, Center for Gene Therapeutics, Hamilton, Ontario, Canada, 3 Departments of Medicine, Pathology and Molecular Medicine, McMaster University, Center for Gene Therapeutics, Hamilton, Ontario, Canada; Medizinische Klinik, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany

* To whom correspondence should be addressed. E-mail: kolbm{at}mcmaster.ca.

The individual susceptibility to pulmonary fibrosis remains a mystery suggesting a role for genetic predisposition. The pathogenesis of pulmonary fibrosis involves a multitude of factors mediating crosstalk between various tissue components. Some factors, such as transforming growth factor (TGF) {beta} 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 is accompanied by lower levels of CTGF and TIMP-1 gene expression, compared to fibrosis prone C57BL/6 mice. However, concomitant administration of AdCTGF and bleomycin leads to a persistent upregulation of TIMP-1 gene and a significant fibrotic response in Balb/c similar to C57BL/6 mice. We propose that CTGF is an important mediator in the pathogenesis of pulmonary fibrosis by providing a local microenvironment in the lung that causes individual susceptibility. CTGF should be considered as novel drug target and as a potential marker to identify individuals at risk.




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