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Fibroblast Growth Factor-10 Prevents Asbestos-Induced Alveolar Epithelial Cell Apoptosis by a Mitogen-Activated Protein Kinase–Dependent Mechanism

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

Correspondence and requests for reprints should be addressed to David W. Kamp, Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron St., McGaw 2-2300, Chicago, IL 60611. E-mail: d-kamp{at}northwestern.edu

Asbestos induces alveolar epithelial cell (AEC) DNA damage and apoptosis by the mitochondria-regulated death pathway and oxidative stress. Fibroblast growth factor-10 (FGF-10), an alveolar epithelial type II cell mitogen that is required for the lung development, prevents H₂O₂-induced AEC DNA damage by a mitogen activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK)-dependent mechanism. In this study, we show that FGF-10 attenuates asbestos-induced AEC DNA strand break formation and apoptosis. MAPK/ERK kinase (MEK) inhibitors, U0126 or PD98059, each blocked the protective effect of FGF-10 against asbestos-induced DNA damage and apoptosis, whereas a p38-MAPK inhibitor had a negligible effect, suggesting a crucial role for MEK/ERK activation in mediating the protective effects of FGF-10. Further, we show that FGF-10 attenuates asbestos-induced change in AEC mitochondrial membrane potential and caspase 9 activation, both of which are blocked by U0126. We conclude that FGF-10 decreases asbestos-induced AEC DNA damage and apoptosis in part by mechanisms involving MEK/ERK-dependent signaling that affects the mitochondria-regulated death pathway.

Key Words: asbestos • growth factors • signal transduction • cell death • pulmonary epithelium

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