CONNECTIVE-TISSUE GROWTH-FACTOR MESSENGER-RNA EXPRESSION IS UP-REGULATED IN BLEOMYCIN-INDUCED LUNG FIBROSIS

Connective tissue growth factor (CTGF) is a newly described 38-kDa pep tide mitogen for fibroblasts and a promoter of connective tissue depos ition in the skin. The CTGF gene promotor contains a transforming grow th factor-beta 1 (TGF-beta 1) response element. Because TGF-beta 1 exp ression is upregulated in several models of fibroproliferative lung di sease, we asked whether CTGF is also upregulated in a murine lung fibr osis model and whether CTGF could mediate some of the fibrogenic effec ts associated with TGF-beta 1. A portion of the rat CTGF gene was clon ed and used to show that primary isolates of both murine and human lun g fibroblasts express CTGF mRNA in vitro. There was a greater than two fold increase in CTGF expression in both human and murine lung fibrobl asts 2, 4, and 24 h after the addition of TGF-beta 1 in vitro. A bleom ycin-sensitive mouse strain (C57BL/6) and a bleomycin-resistant mouse strain (BALB/c) were given bleomycin, a known lung fibrogenic agent. C TGF mRNA expression was upregulated in the sensitive, but not in the r esistant, mouse strain after administration of bleomycin. In vivo diff erences in the CTGF expression between the two mouse strains were not due to an inherent inability of BALB/c lung fibroblasts to respond to TGF-beta 1 because fibroblasts from untreated BALB/c mouse lung upregu lated their CTGF message when treated with TGF-beta 1 in vitro. These data demonstrate that CTGF is expressed in lung fibroblasts and may pl ay a role in the pathogenesis of lung fibrosis.