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Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, CA 94143
Oxidative stress has been implicated in the pathogenesis
of inflammatory diseases of airways. Here we show that oxidative stress
causes ligand-independent activation of epidermal growth factor
receptors (EGFR) and subsequent activation of mitogen-activated protein
kinase kinase (MEK)-p44/42 mitogen-activated protein kinase
(p44/42mapk), resulting in mucin synthesis in NCI-H292
cells. Exogenous hydrogen peroxide and neutrophils activated by IL-8,
FMLP, or TNF-
increased EGFR tyrosine phosphorylation and subsequent
activation of p44/42mapk and up-regulated the expression of
MUC5AC at both mRNA and protein levels in NCI-H292 cells. These effects
were blocked by selective EGFR tyrosine kinase inhibitors (AG1478,
BIBX1522) and by a selective MEK inhibitor (PD98059), whereas a
selective platelet-derived growth factor receptor tyrosine kinase
inhibitor (AG1295), a selective p38 MAPK inhibitor (SB203580), and a
negative compound of tyrosine kinase inhibitors (A1) were without
effect. Neutrophil supernatant-induced EGFR tyrosine phosphorylation,
activation of p44/42mapk, and MUC5AC synthesis were
inhibited by antioxidants
(N-acetyl-L-cysteine, DMSO, dimethyl
thiourea, or superoxide dismutase); neutralizing Abs to EGFR ligands
(EGF and TGF-) were without effect, and no TGF- protein was found
in the neutrophil supernatant. In contrast, the EGFR ligand, TGF-,
increased EGFR tyrosine phosphorylation, activation of
p44/42mapk, and subsequent MUC5AC synthesis, but these
effects were not inhibited by antioxidants. These results implicate
oxidative stress in stimulating mucin synthesis in airways and provide
new therapeutic approaches in airway hypersecretory
diseases.
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 J. Aarbiou, M. Ertmann, S. van Wetering, P. van Noort, D. Rook, K. F. Rabe, S. V. Litvinov, J. H. J. M. van Krieken, W. I. de Boer, and P. S. Hiemstra Human neutrophil defensins induce lung epithelial cell proliferation in vitro J. Leukoc. Biol., July 1, 2002; 72(1): 167 - 174. [Abstract] [Full Text] [PDF]
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J. L. Lordan, F. Bucchieri, A. Richter, A. Konstantinidis, J. W. Holloway, M. Thornber, S. M. Puddicombe, D. Buchanan, S. J. Wilson, R. Djukanovic, et al. Cooperative Effects of Th2 Cytokines and Allergen on Normal and Asthmatic Bronchial Epithelial Cells J. Immunol., July 1, 2002; 169(1): 407 - 414. [Abstract] [Full Text] [PDF]
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R A O'Donnell and A J Frew Is there more than one inflammatory phenotype in asthma? Thorax, July 1, 2002; 57(7): 566 - 568. [Full Text] [PDF]
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S. Kim, J. J. Shim, P.-R. Burgel, I. F. Ueki, T. Dao-Pick, D. C.-W. Tam, and J. A. Nadel IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L67 - L75. [Abstract] [Full Text] [PDF]
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 C. Northcott, J. A. Florian, A. Dorrance, and S. W. Watts Arterial Epidermal Growth Factor Receptor Expression in Deoxycorticosterone Acetate-Salt Hypertension Hypertension, December 1, 2001; 38(6): 1337 - 1341. [Abstract] [Full Text] [PDF]
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P.-R. Burgel, S. C. Lazarus, D. C.-W. Tam, I. F. Ueki, K. Atabai, M. Birch, and J. A. Nadel Human Eosinophils Induce Mucin Production in Airway Epithelial Cells Via Epidermal Growth Factor Receptor Activation J. Immunol., November 15, 2001; 167(10): 5948 - 5954. [Abstract] [Full Text] [PDF]
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Y. Saito, J. Haendeler, Y. Hojo, K. Yamamoto, and B. C. Berk Receptor Heterodimerization: Essential Mechanism for Platelet-Derived Growth Factor-Induced Epidermal Growth Factor Receptor Transactivation Mol. Cell. Biol., October 1, 2001; 21(19): 6387 - 6394. [Abstract] [Full Text] [PDF]
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J. J. Shim, K. Dabbagh, I. F. Ueki, T. Dao-Pick, P.-R. Burgel, K. Takeyama, D. C.-W. Tam, and J. A. Nadel IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L134 - L140. [Abstract] [Full Text] [PDF]
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K. Takeyama, B. Jung, J. J. Shim, P.-R. Burgel, T. Dao-Pick, I. F. Ueki, U. Protin, P. Kroschel, and J. A. Nadel Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L165 - L172. [Abstract] [Full Text] [PDF]
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K. Chen, J. A. Vita, B. C. Berk, and J. F. Keaney Jr. c-Jun N-terminal Kinase Activation by Hydrogen Peroxide in Endothelial Cells Involves Src-dependent Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., May 4, 2001; 276(19): 16045 - 16050. [Abstract] [Full Text] [PDF]
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