Upadhyay Daya, Panduri Vijayalakshmi, Kamp David W
Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw 2-2300, Chicago, IL 60611, USA.
Am J Respir Cell Mol Biol. 2005 Mar;32(3):232-8. doi: 10.1165/rcmb.2004-0242OC. Epub 2004 Dec 23.
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.
石棉通过线粒体调控的死亡途径和氧化应激诱导肺泡上皮细胞（AEC）DNA损伤和凋亡。成纤维细胞生长因子10（FGF-10）是一种肺泡II型上皮细胞有丝分裂原，是肺发育所必需的，它通过有丝分裂原激活蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）依赖性机制防止H₂O₂诱导的AEC DNA损伤。在本研究中，我们表明FGF-10可减轻石棉诱导的AEC DNA链断裂形成和凋亡。MAPK/ERK激酶（MEK）抑制剂U0126或PD98059均可阻断FGF-10对石棉诱导的DNA损伤和凋亡的保护作用，而p38-MAPK抑制剂的作用可忽略不计，这表明MEK/ERK激活在介导FGF-10的保护作用中起关键作用。此外，我们表明FGF-10可减轻石棉诱导的AEC线粒体膜电位变化和半胱天冬酶9激活，而这两者均被U0126阻断。我们得出结论，FGF-10部分通过涉及MEK/ERK依赖性信号传导的机制减少石棉诱导的AEC DNA损伤和凋亡，该机制影响线粒体调控的死亡途径。
