Published ahead of print on December 23, 2004, doi:10.1165/rcmb.2004-0242OC Am. J. Respir. Cell Mol. Biol., Volume 32, Number 3, March 2005, 232-238 A more recent version of this article appeared on March 1, 2005
Submitted on August 2, 2004 FGF-10 PREVENTS ASBESTOS-INDUCED AEC APOPTOSIS BY A MAPK-DEPENDENT MECHANISMDaya Upadhyay1,1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA; Stanford University Medical Center, Palo Alto, CA, USA, 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA * To whom correspondence should be addressed. 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 while 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.
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