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Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury.

Authors
  • Pinart, Mariona1
  • Hussain, Farhana1
  • Shirali, Sima1
  • Li, Feng1
  • Zhu, Jie1
  • Clark, Andrew R2
  • Ammit, Alaina J3
  • Chung, Kian Fan4
  • 1 Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
  • 2 Kennedy Institute of Rheumatology Division, Imperial College London, London, UK.
  • 3 Respiratory Research Group, Faculty of Pharmacy, University of Sydney, NSW, Australia. , (Australia)
  • 4 Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: [email protected]
Type
Published Article
Journal
European journal of pharmacology
Publication Date
Dec 05, 2014
Volume
744
Pages
108–114
Identifiers
DOI: 10.1016/j.ejphar.2014.10.003
PMID: 25310910
Source
Medline
Keywords
License
Unknown

Abstract

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and in the induction of corticosteroid (CS) insensitivity. Chronic ozone exposure leads to a model of COPD with lung inflammation and emphysema. Mitogen-activated protein kinase phosphatase-1 (MKP-1) may underlie CS insensitivity in COPD. We determined the role played by MKP-1 by studying the effect of corticosteroids in wild-type C57/BL6J and MKP-1(-/-) mice after chronic ozone exposure. Mice were exposed to ozone (3 ppm, 3 h) 12 times over 6 weeks. Dexamethasone (0.1 or 2 mg/kg; intraperitoneally) was administered before each exposure. Mice were studied 24 h after final exposure. In ozone-exposed C57/BL6J mice, bronchial hyperresponsiveness (BHR) was not inhibited by both doses of dexamethasone, but in MKP-1(-/-) mice, there was a small inhibition by high dose dexamethasone (2 mg/kg). There was an increase in mean linear intercept after chronic ozone exposure in both strains which was CS-insensitive. There was lesser inflammation after low dose of dexamethasone in MKP-1(-/-) mice compared to C57/Bl6J mice. Epithelial and collagen areas were modulated in ozone-exposed MKP-1(-/-) mice treated with dexamethasone compared to C57/Bl6J mice. MKP-1 regulated the expression of MMP-12, IL-13 and KC induced by ozone but did not alter dexamethasone׳s effects. Bronchial hyperresponsiveness, lung inflammation and emphySEMa after chronic exposure are CS-insensitive, and the contribution of MKP-1 to CS sensitivity in this model was negligible.

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