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The Role of Nox4 in Oxidative Stress–Induced MUC5AC Overexpression in Human Airway Epithelial Cells

¹ Department of Otolaryngology—Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, Korea; ² Department of Otorhinolaryngology, ³ The Airway Mucus Institute, ⁴ BK 21 Project for Medical Science, ⁵ Research Center for Natural Human Defense System, ⁶ Department of Medicine the Graduate School, Yonsei University College of Medicine, Seoul, Korea; ⁷ The Center for Cell Signaling Research, Division of Molecular Life Sciences, and Department of Biological Science, Ewha Womans University, Seoul, Korea

Correspondence and requests for reprints should be addressed to Joo-Heon Yoon, M.D., Ph.D., Department of Otorhinolaryngology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, Korea 120-752. E-mail: jhyoon{at}yuhs.ac

Mucus hypersecretion is a prominent manifestation in patients with chronic inflammatory airway diseases, and MUC5AC is a major airway mucin. It is well known that reactive oxygen species (ROS) may be involved in the pathogenesis of various inflammatory airway diseases. The purpose of this study was to identify which secreted mucin genes are induced by exogenous hydrogen peroxide and the mechanism by which these genes are up-regulated in normal human nasal epithelial (NHNE) cells. Exogenous H₂O₂ induced the ligand-independent activation of epidermal growth factor receptors (EGFR) and the subsequent activation of ERK1 mitogen-activated protein kinase, resulting in the induction of intracellular ROS generation. Through this signal pathway, exogenous H₂O₂ markedly induced overexpression of the MUC5AC gene alone. In addition, Nox4, a subtype of nonphagocytic NADPH oxidase, was found to play a key role in intracellular ROS generation and exogenous H₂O₂–induced MUC5AC gene expression in NHNE cells.

Key Words: hydrogen peroxide • MUC5AC • epidermal growth factor receptor • Nox4

CLINICAL RELEVANCE Exogenous H2O2 induces intracellular reactive oxygen species (ROS) generation via a signal pathway involving EGFR-ERK1 mitogen-activated protein kinase and Nox4, resulting in MUC5AC gene expression in normal human nasal epithelial (NHNE) cells, and Nox4 plays a key role in intracellular ROS generation in NHNE cells.

 

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