Imperial College London
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DrCharalambosMichaeloudes

Faculty of Medicine, National Heart & Lung Institute

Honorary Research Fellow
 
 
 
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c.michaeloudes04

 
 
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Location

 

223Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Chang:2015:10.1164/rccm.201402-0314OC,
author = {Chang, P-J and Michaeloudes, C and Zhu, J and Shaikh, N and Baker, J and Chung, KF and Bhavsar, PK},
doi = {10.1164/rccm.201402-0314OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {54--62},
title = {Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma},
url = {http://dx.doi.org/10.1164/rccm.201402-0314OC},
volume = {191},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Rationale: Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA.Objectives: We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies.Measurements and Main Results: GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10−7 M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α–induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α–induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA.Conclusions: Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB–dependent gene promoters, may underlie CS insensitivity of severe asthma.
AU  - Chang,P-J
AU  - Michaeloudes,C
AU  - Zhu,J
AU  - Shaikh,N
AU  - Baker,J
AU  - Chung,KF
AU  - Bhavsar,PK
DO  - 10.1164/rccm.201402-0314OC
EP  - 62
PY  - 2015///
SN  - 1073-449X
SP  - 54
TI  - Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.201402-0314OC
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000347606500014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/19575
VL  - 191
ER  -
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