TY - JOUR
T1 - Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury
AU - Pinart, Mariona
AU - Hussain, Farhana
AU - Shirali, Sima
AU - Li, Feng
AU - Zhu, Jie
AU - Clark, Andrew R.
AU - Ammit, Alaina J.
AU - Chung, Kian Fan
PY - 2014/10/12
Y1 - 2014/10/12
N2 - 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.
AB - 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.
KW - Bronchial hyperresponsiveness
KW - Emphysema
KW - Lung inflammation
KW - Mitogen-activated protein kinase
KW - Ozone exposure
KW - phosphatase 1 (MKP-1)
UR - http://www.scopus.com/inward/record.url?scp=84918783953&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2014.10.003
DO - 10.1016/j.ejphar.2014.10.003
M3 - Article
C2 - 25310910
AN - SCOPUS:84918783953
SN - 0014-2999
VL - 744
SP - 108
EP - 114
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -