Affordable Access

Publisher Website

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

  • 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]
Published Article
European journal of pharmacology
Publication Date
Dec 05, 2014
DOI: 10.1016/j.ejphar.2014.10.003
PMID: 25310910


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.

Report this publication


Seen <100 times