Acidic fibroblast growth factor induces an antifibrogenic phenotype in human lung fibroblasts

Acidic fibroblast growth factor (FGF-1), a prototype member of the heparin- binding growth factor family, influences proliferation, differentiation, an d protein synthesis in different cell types. However, its possible role on lung extracellular matrix (ECM) metabolism has not been evaluated. In this study we examined the effects of FGF-1 and FGF-1 plus heparin on type I col lagen, collagen-binding stress protein HSP47, interstitial collagenase (mat rix metalloproteinase [MMP]-1), gelatinase A, and tissue inhibitor of metal loproteinase (TIMP)-1 and TIMP-2 expression by normal human lung fibroblast s. Heparin was used because it enhances the biologic activities of FGF-1. F ibroblasts were exposed either to 20 ng/ml FGF-1 plus 100 mu g/ml heparin f or 48 h or to FGF-1 or heparin alone. Messenger RNA (mRNA) expression was a nalyzed by Northern blot. Collagen synthesis was evaluated by digestion of [H-3]collagen with bacterial collagenase, MMP-1 by Western blot, and gelati nolytic activities by zymography. Our results show that FGF-1 induced colla genase mRNA expression, which was strongly enhanced when FGF-1 was used wit h heparin. Likewise, both FGF-1 and FGF-1 plus heparin reduced by 70 to 80% the expression of type I collagen transcript, in part through effect on pr o-alpha 1(I) collagen mRNA stability. A downregulation of HSP47 gene expres sion was also observed. Synthesis of collagen and collagenase proteins para lleled gene expression results. FGF-1 activities were abolished with genist ein, a tyrosine kinase inhibitor. Neither FGF-1 nor FGF-1 plus heparin affe cted the expression of TIMP-1, TIMP-2, and gelatinase A. These findings dem onstrate that FGF-1, mostly in the presence of heparin, upregulates collage nase and downregulates type I collagen expression that might have a protect ive role in avoiding collagen accumulation during lung ECM remodeling.