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Am J Physiol Lung Cell Mol Physiol 284: L350-L359, 2003; doi:10.1152/ajplung.00161.2002
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Vol. 284, Issue 2, L350-L359, February 2003

FGF-10 prevents mechanical stretch-induced alveolar epithelial cell DNA damage via MAPK activation

Daya Upadhyay, Eduardo Correa-Meyer, Jacob I. Sznajder, and David W. Kamp

Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Veterans Administration Chicago Health Care System: Lakeside Division and Department of Medicine, Chicago, Illinois 60611

Cyclic stretch of alveolar epithelial cells (AEC) can alter normal lung barrier function. Fibroblast growth factor-10 (FGF-10), an alveolar type II cell mitogen that is critical for lung development, may have a role in promoting AEC repair. We studied whether cyclic stretch induces AEC DNA damage and whether FGF-10 would be protective. Cyclic stretch (30 min of 30% strain amplitude and 30 cycles/min) caused AEC DNA strand break formation, as assessed by alkaline unwinding technique and DNA nucleosomal fragmentation. Pretreatment of AEC with FGF-10 (10 ng/ml) blocked stretch-induced DNA strand break formation and DNA fragmentation. FGF-10 activated AEC mitogen-activated protein kinase (MAPK), and MAPK inhibitors prevented FGF-10-induced AEC MAPK activation and abolished the protective effects of FGF-10 against stretch-induced DNA damage. In addition, a Grb2-SOS inhibitor (SH3b-p peptide), a RAS inhibitor (farnesyl transferase inhibitor 277), and a RAF-1 inhibitor (forskolin) each prevented FGF-10-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in AEC. Moreover, N17-A549 cells that express a RAS dominant/negative protein prevented the FGF-10-induced ERK1/2 phosphorylation and RAS activation in AEC. We conclude that cyclic stretch causes AEC DNA damage and that FGF-10 attenuates these effects by mechanisms involving MAPK activation via the Grb2-SOS/Ras/RAF-1/ERK1/2 pathway.

alveolar epithelial cells; fibroblast growth factor-10; mitogen-activated protein kinase; deoxyribonuclease


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