title: Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury.
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.
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Mariona
authors.initials: M
authors.lastname: Pinart
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Farhana
authors.initials: F
authors.lastname: Hussain
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Sima
authors.initials: S
authors.lastname: Shirali
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, London, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.affiliation: Respiratory Research Group, Faculty of Pharmacy, University of Sydney, NSW, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: f.chung@imperial.ac.uk.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D055370:Lung Injury / Q000378:metabolism*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010126:Ozone / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D018793:Interleukin-13; D016877:Oxidants; D010126:Ozone; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D053508:Matrix Metalloproteinase 12
keywords: Bronchial hyperresponsiveness; Emphysema; Lung inflammation; Mitogen-activated protein kinase phosphatase 1 (MKP-1); Ozone exposure