Fibroblast growth factor-10 attenuates H₂O₂-induced alveolar epithelial cell DNA damage: Role of MAPK activation and DNA repair

Fibroblast growth factor-10 (FGF-10), an alveolar epithelial cell (AEC) mitogen that is critical for lung development, may promote AEC repair. We determined whether FGF-10 attenuates H₂O₂-induced, A549 and rat alveolar type II cell DNA damage. We show that FGF-10 prevents H ₂O₂-induced DNA damage assessed by an alkaline elution, ethidium bromide fluorescence as well as by a comet assay. Mitogen-activated protein kinase inhibitors abolished the protective effect of FGF-10 against H₂O₂-induced DNA damage yet had no effect on H ₂O₂-induced DNA damage. A Grb2-SOS inhibitor (SH3 binding peptide), an Ras inhibitor (farnesyl transferase inhibitor 277), and an Raf-1 inhibitor (forskolin) each prevented FGF-10- and H₂O ₂-induced A549 cell ERK1/2 phosphorylation. Also, FGF-10 and H ₂O₂ each induced negligible ERK1/2 phosphorylation in Ras dominant-negative (N17) cells. Inhibitors of Ras and Raf-1 blocked the protective effect of FGF-10 against H₂O₂-induced DNA damage but had no effect on H₂O₂-induced DNA damage. Furthermore, cold conditions and aphidicolin, an inhibitor of DNA polymerase-α, -δ, and -ε, each blocked the protective effects of FGF-10, suggesting a role for DNA repair. We conclude that FCF-10 attenuates H₂O₂-induced AEC DNA damage by mechanisms that involve activation of Grb2-SOS/Ras/RAF-1/ERK1/2 pathway and DNA repair.