Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism.
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 H(2)O(2)-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.
Upadhyay
Daya
D
Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw 2-2300, Chicago, IL 60611, USA.
Panduri
Vijayalakshmi
V
Kamp
David W
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001194:Asbestos / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats
D002273:Carcinogens; C496465:Fgf10 protein, rat; D051526:Fibroblast Growth Factor 10; D001194:Asbestos; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases