Published ahead of print on February 19, 2004, doi:10.1165/rcmb.2003-0064OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 1, July 2004, 107-113 A more recent version of this article appeared on July 1, 2004
Submitted on February 28, 2003 FGF-10 ATTENUTES H2O2-INDUCED AEC DNA DAMAGE: ROLE OF MAPK ACTIVATION AND DNA REPAIRDaya Upadhyay1,1 Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA, USA, 2 Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Medicine, Veterans Administration Chicago Health Care System: Lakeside Division, Chicago, IL, USA, 3 Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA * To whom correspondence should be addressed. 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-b-p peptide), a RAS inhibitor (Farnesyl transferase inhibitor- 277), and a 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-
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, 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.
