FGF-2 induces surfactant protein gene expression in foetal rat lung epithelial cells through a MAPK-independent pathway

Fibroblast growth factors (FGFs) play important roles in diverse aspects of animal development including mammalian lung epithelial cell proliferation, differentiation, and branching morphogenesis. We developed an in vitro lun g epithelial cell culture system to study functions and mechanisms of FGFs in regulating growth and differentiation of primary foetal rat lung epithel ial cells. In comparison with other growth factors such as IGF-I, EGF, and HGF, FGFs were the most potent mitogens in stimulating lung epithelial cell proliferation. In the presence of FGF-1, 2, or 7, the primary lung epithel ial cells could be propagated for generations and grown for more than two m o in vitro. Among the three FGFs tested, FGF 7 showed the strongest stimula tion in cell growth. FGF-2, on the other hand, is the most effective induce r of lung epithelial cell-specific surfactant protein gene expression (SP-A , -B, and -C). FGF-2 upregulated SP-C expression in a dose-dependent manner . More interestingly, the induction of surfactant protein gene expression b y FGF-2 appeared to be independent of MAPK pathway, since the SP-C expressi on was not inhibited but rather augmented by MEK1 inhibitor which inhibited MAPK activation and cell proliferation. Similar effects were observed for the expressions of surfactant protein genes SP-A and SP-B. In contrast to M APK, FGF-2-induced SP-C expression was partially inhibited by PI 3-kinase i nhibitor wortmannin. These data suggest dynamic roles and complex signallin g mechanisms of FGFs in regulating lung epithelial cell proliferation and d ifferentiation While a MAPK-dependent pathway is essential for ail three FG Fs to stimulate cell proliferation,a MAPK-independent pathway may be respon sible for the FGF-2-induced surfactant protein gene expression. PI 3-kinase may play an important role in mediating FGF-2-induced lung epithelial cell differentiation during development. CELL SIGNAL 11;3:221-228, 1999. (C) 19 99 Elsevier Science Inc.