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Adenoviral Gene Transfer of Connective Tissue Growth Factor in the Lung Induces Transient Fibrosis

Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Service de Pneumologie et Réanimation Respiratoire, CHU du Bocage et Université de Bourgogne, Dijon, France; Medizinische Klinik, Julius-Maximilians-Universitat, Wurzburg, Germany; and FibroGen, Inc., South San Francisco, California

Correspondence and requests for reprints should be addressed to Jack Gauldie, Ph.D., Department of Pathology and Molecular Medicine, Room 2N16, McMaster University, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. E-mail: gauldie{at}mcmaster.ca

Connective tissue growth factor (CTGF) is felt to be one of the key profibrotic factors and is a downstream effector molecule mediating the action of transforming growth factor (TGF)–ß1, a cytokine known to induce severe and progressive fibrosis. However, the in vivo fibrogenic effect of isolated CTGF expression is not well described. We used adenoviral gene transfer to transiently overexpress CTGF in rat lungs after intratracheal administration and compared it with transient overexpression of active TGF-ß1 delivered by a similar adenovirus vector. This high expression of CTGF over 6–10 days induced a moderate but reversible fibrosis. We observed an increase of fibronectin, procollagen 1a2, and endogenous CTGF gene expression at 14 days, which suggested an indirect activation by CTGF. Tissue inhibitor of metalloproteinase–1 was weakly and transiently upregulated after CTGF exposure. These same genes were robustly and persistently stimulated by TGF-ß1 from Day 3 to Day 21. This data suggested that CTGF may act as a TGF-ß1 cofactor rather than a direct fibrogenic factor. We demonstrate that CTGF overexpression can initiate fibrogenic activity but likely requires the presence of additional factors, such as tissue inhibitor of metalloproteinase–1, to maintain a nonfibrolytic environment and to cause progression of fibrosis.

Key Words: extracellular matrix • pulmonary • transforming growth factor–ß • tissue inhibitor of metalloproteinase • fibrotic

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