title: Impact of ozone exposure on the response to glucocorticoid in a mouse model of asthma: involvements of p38 MAPK and MKP-1.
abstract: BACKGROUND
  Molecular mechanisms involved in the oxidative stress induced glucocorticoids insensitivity remain elusive. The mitogen-activated protein kinase phosphatase (MKP) 1 mediates a part of glucocorticoids action and can be modified by exogenous oxidants. Whether oxidant ozone (O3) can affect the function of MKP-1 and hence blunt the response to corticotherapy is not clear.
  
  
  METHODS
  Here we employed a murine model of asthma established with ovalbumin (OVA) sensitization and challenge to evaluate the influence of O3 on the inhibitory effect of dexamethasone on AHR and airway inflammation, and by administration of SB239063, a selective p38 MAPK inhibitor, to explore the underlying involvements of the activation of p38 MAPK and the expression of MKP-1.
  
  
  RESULTS
  Ozone exposure not only aggravated the pulmonary inflammation and AHR, but also decreased the inhibitory effects of dexamethasone, accompanied by the elevated oxidative stress, airway neutrophilia, enhanced phosphorylation of p38 MAPK, and upregulated expression of IL-17. Administration of SB239063 caused significant inhibition of the p38 MAPK phosphorylation, alleviation of the airway neutrophilia, and decrement of the ozone-induced IL-17 expression, and partly restored the ozone-impaired effects of dexamethasone. Ozone exposure not only decreased the protein expression of MKP-1, but also diminished the dexamethasone-mediated induction process of MKP-1 mRNA and protein expression.
  
  
  CONCLUSIONS
  The glucocorticoids insensitivity elicited by ozone exposure on current asthma model may involve the enhanced phosphorylation of p38 MAPK and disturbed expression of MKP-1.
authors.forename: Aihua
authors.initials: A
authors.lastname: Bao
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Pengyu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiao tong University, 100 Haining Road, Shanghai 200080China. xzhou53@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis*; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D019570:Inhalation Exposure / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D010126:Ozone; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse