Inhibition of p38 MAPK-dependent bronchial contraction after ozone by corticosteroids.
We determined the role of p38 mitogen-activated protein kinase (MAPK) in the increased airway smooth muscle (ASM) contractile responses following ozone and modulation by corticosteroids. Mice were exposed to air or ozone (3 ppm for 3 h) and isometric contractile responses of bronchial rings to acetylcholine (ACh) were measured using a myograph in the presence of p38 MAPK inhibitor, SB239063 (10⁻⁶ M) or dexamethasone (10⁻⁶ M). Because MAPK phosphatase (MKP)-1 is a negative regulator of p38 MAPK, we also studied these effects in MKP-1(-/-) mice. Bronchial rings from ozone-exposed wild-type and MKP-1(-/-) mice showed increased contractile responses, with a leftward shift of the dose-response curve in MKP-1(-/-) mice. SB239063 inhibited bronchial contraction equally in air- and ozone-exposed C57/BL6 and MKP-1(-/-) mice. Dexamethasone inhibited ACh-induced bronchial contraction in both air- and ozone-exposed C57/BL6 mice, but not in air- or ozone-exposed MKP-1(-/-) mice. ACh-stimulated p38 MAPK and heat shock protein (HSP)27 phosphorylation, as measured by Western blotting, and this effect was suppressed by SB239063 in C57/BL6 and MKP-1(-/-) mice, but not by dexamethasone in either air- or ozone-exposed MKP-1(-/-) mice. p38 MAPK plays a role in maximal ACh-induced isometric contractile responses and increased contractility induced by ozone. Dexamethasone inhibits ACh-induced ASM contraction through phosphorylation of p38 MAPK and HSP27.
Li
F
F
Dept Dept of Respiratory Medicine, The Affiliated First People’s Hospital of Shanghai, Jiao Tong University, Shanghai, China.
Zhang
M
M
Hussain
F
F
Triantaphyllopoulos
K
K
Clark
A R
AR
Bhavsar
P K
PK
Zhou
X
X
Chung
K F
KF
D000109:Acetylcholine / Q000494:pharmacology; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology*; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007537:Isometric Contraction; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D010126:Ozone / Q000494:pharmacology*; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000305:Adrenal Cortex Hormones; D055551:HSP27 Heat-Shock Proteins; D007093:Imidazoles; D011743:Pyrimidines; D010126:Ozone; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C406525:SB 239063; D000109:Acetylcholine