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

Research output: Contribution to journalArticlepeer-review

Authors

  • Mariona Pinart
  • Farhana Hussain
  • Sima Shirali
  • Feng Li
  • Jie Zhu
  • Alaina J. Ammit
  • Kian Fan Chung

Colleges, School and Institutes

External organisations

  • National Heart and Lung Institute
  • Kennedy Institute of Rheumatology
  • University of Sydney

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 dexamethasones 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.

Details

Original languageEnglish
Pages (from-to)108-114
Number of pages7
JournalEuropean Journal of Pharmacology
Volume744
Publication statusPublished - 12 Oct 2014

Keywords

  • Bronchial hyperresponsiveness, Emphysema, Lung inflammation, Mitogen-activated protein kinase, Ozone exposure, phosphatase 1 (MKP-1)

ASJC Scopus subject areas