Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells.

  • Papaiahgari S
  • Zhang Q
  • Kleeberger S
 et al. 
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Nuclear factor erythroid 2-related factor (Nrf2) confers protection against cell death induced by hyperoxia and other proapoptotic stimuli. Because phosphoinositide-3-kinase (PI3K)/Akt signaling promotes cell survival, the significance of this pathway in mediating reactive oxygen species (ROS)-dependent hyperoxia-induced Nrf2 activation was investigated in the murine pulmonary epithelial cell line, C10. Inhibition of the PI3K pathway markedly attenuated hyperoxia-induced Nrf2 translocation and ARE (antioxidant response element)-mediated transcription. Consistent with this, hyperoxia markedly stimulated the activation of PI3K pathway, while an NADPH oxidase inhibitor and an antioxidant prevented such activation. The inhibition of Akt activity using a pharmacological inhibitor markedly attenuated Nrf2 translocation and ARE-driven expression. Moreover, overexpression of a dominant-negative Akt mutant attenuated the transcription, whereas a constitutively active mutant stimulated it. These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia. Inhibition of the PI3K pathway prevented hyperoxia-stimulated Akt and ERK1/2 kinase activation, which is critical for Nrf2-mediated transcription. Likewise, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, blocked hyperoxia-stimulated Akt and ERK1/2 phosphorylation, Nrf2 nuclear accumulation, and ARE-driven transcription. Consistent with this result, an NADPH oxidase inhibitor blocked hyperoxia- stimulated EGFR phosphorylation, which was correlated with the attenuation of Akt and ERK activation. Collectively, our data suggest that EGFR-PI3K signaling through Akt and ERK kinases regulates ROS-dependent, hyperoxia-induced Nrf2 activation in pulmonary epithelial cells.

Author-supplied keywords

  • Animals
  • Biological
  • Cell Line
  • Epidermal Growth Factor
  • Epidermal Growth Factor: physiology
  • Genetic
  • Hyperoxia
  • Hyperoxia: physiopathology
  • Hyperoxia: prevention & control
  • Immunohistochemistry
  • MAP Kinase Signaling System
  • MAP Kinase Signaling System: physiology
  • Mice
  • Models
  • NF-E2-Related Factor 2
  • NF-E2-Related Factor 2: metabolism
  • Oxidative Stress
  • Oxidative Stress: physiology
  • Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol 3-Kinases: metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-akt: metabolism
  • Pulmonary Alveoli
  • Pulmonary Alveoli: physiology
  • Receptor
  • Respiratory Mucosa
  • Respiratory Mucosa: physiology
  • Transcription

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  • Srinivas Papaiahgari

  • Qin Zhang

  • Steven R Kleeberger

  • Hye-Youn Cho

  • Sekhar P Reddy

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