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Fibroblast Growth Factor-10 Attenuates H₂O₂-Induced Alveolar Epithelial Cell DNA Damage

Role of MAPK Activation and DNA Repair

Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago; Veterans Administration Chicago Health Care System, Lakeside Division, Chicago, Illinois; and Stanford University Medical Center, Stanford, California

Address correspondence to: David Kamp, Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 303 East Chicago Ave., Tarry Bldg, 14-707, Chicago, IL 60611. E-mail: d-kamp{at}northwestern.edu

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 H₂O₂-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 H₂O₂-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 H₂O₂-induced A549 cell ERK1/2 phosphorylation. Also, FGF-10 and H₂O₂ 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-, -, and -, each blocked the protective effects of FGF-10, suggesting a role for DNA repair. We conclude that FGF-10 attenuates H₂O₂-induced AEC DNA damage by mechanisms that involve activation of Grb2-SOS/Ras/RAF-1/ERK1/2 pathway and DNA repair.

Abbreviations: alveolar epithelial cells, AEC • DNA strand breaks, DNA-SB • extracellular signal-regulated kinases, ERKs • fibroblast growth factor-10, FGF-10 • forskolin, FSK • farnesyl transferase inhibitor, FTI • keratinocyte growth factor, KGF • mitogen-activated protein kinase, MAPK • SH3 binding peptide, SH3b-p

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