@article{Khorasani:2015:10.2147/COPD.S72403,
author = {Khorasani, N and Baker, J and Johnson, M and Chung, KF and Bhavsar, PK},
doi = {10.2147/COPD.S72403},
journal = {International Journal of Chronic Obstructive Pulmonary Disease},
pages = {283--291},
title = {Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD},
url = {http://dx.doi.org/10.2147/COPD.S72403},
volume = {10},
year = {2015}
}

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TY  - JOUR
AB  - Background: Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructivepulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation isincreased in lung macrophages of COPD. We investigated whether p38 MAPK inhibitioncan modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patientswith COPD.Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed tolipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10-10–10-6 M),with dexamethasone (10-10–10-6 M), or with both. Phosphorylated glucocorticoid receptor (GR)was measured by Western blot.Results: Baseline (P,0.01) and LPS-induced (P,0.05) CXCL8 release was greater in PBMCsfrom COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone(10-6 M) was reduced, and baseline and LPS-induced p38 MAPK activation increasedin PBMCs of COPD. GW856553 (10-9 and 10-10 M) synergistically increased the inhibitoryeffect of dexamethasone (10-8 and 10-6 M) on LPS-induced CXCL8 release in COPD. Similarresults were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activatedphosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibitionof p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
AU  - Khorasani,N
AU  - Baker,J
AU  - Johnson,M
AU  - Chung,KF
AU  - Bhavsar,PK
DO  - 10.2147/COPD.S72403
EP  - 291
PY  - 2015///
SN  - 1176-9106
SP  - 283
TI  - Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD
T2  - International Journal of Chronic Obstructive Pulmonary Disease
UR  - http://dx.doi.org/10.2147/COPD.S72403
UR  - http://hdl.handle.net/10044/1/30547
VL  - 10
ER  - 

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