期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 744, 期 -, 页码 108-114出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2014.10.003
关键词
Ozone exposure; Emphysema; Lung inflammation; Bronchial hyperresponsiveness; Mitogen-activated protein kinase; phosphatase 1 (MKP-1)
资金
- Wellcome Trust [083905]
- European Respiratory Society/Marie Curie Joint Postdoctoral Research Fellowship through the European Respiratory Society [MC [0935]-2009]
- European Community's Seventh Framework Programme FP7-Marie Curie Actions [PCOFUND-GA-2008-229571]
- European Respiratory Society long-term fellowship
- University of Sydney
- Versus Arthritis [19614] Funding Source: researchfish
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. (C) 2014 The Authors. Published by Elsevier B.V.
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