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Published ahead of print on April 13, 2006, doi:10.1164/rccm.200512-1930OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 2, July 2006, 134-141

A more recent version of this article appeared on July 15, 2006
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Submitted on December 19, 2005
Accepted on April 13, 2006

Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma

Mark Hew1, Pankaj Bhavsar1, Alfons Torrego1, Sally Meah1, Nadia Khorasani1, Peter J Barnes1, Ian Adcock1, and Kian Fan Chung1*

1 Experimental Studies, Airways Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom

* To whom correspondence should be addressed. E-mail: f.chung{at}imperial.ac.uk.

Rationale & objectives Patients with severe asthma have a poor therapeutic response to corticosteroid therapy, and corticosteroid responsiveness cannot be easily measured in these patients. We hypothesised that this poor response is associated with a reduced effect of corticosteroids to inhibit cytokine release from activated peripheral blood mononuclear cells (PBMCs). Methods Patients with severe asthma were defined by ATS criteria. We compared the suppression of lipopolysaccharide (LPS)-induced cytokine release (MCP-1, MIP-1{alpha}, RANTES, TNF{alpha}, IL-1{beta}, IL-8, IFN-{gamma},IL-6, IL-10 and GM-CSF) by dexamethasone from peripheral blood mononuclear cells (PBMCs) of severe asthma (n=16) and non-severe asthma (n=19) patients and normal volunteers (n=10). Results There was no difference in baseline spontaneous or stimulated release of these cytokines between groups. LPS-induced release of 10 cytokines was less suppressed by dexamethasone (10-6M) in severe asthmatics compared to non-severe asthmatics, with statistical significance achieved for IL-1{beta}(p<0.03), IL-8 (p<0.03) and MIP-1{alpha} (p<0.003), and borderline significance for IL-6 (p=0.054). There was less difference between the 2 groups for dexamethasone at 10-8M. Nuclear histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities were both reduced in severe asthmatics compared to non-severe asthmatics (p<0.01). HDAC activity reduction correlated directly to the degree of steroid insensitivity of GM-CSF (r=0.57, p<0.01) and IFN-{gamma} (r=0.56, p< 0.05) release. Reduction in HAT activity related to corticosteroid use rather than asthma severity. Conclusions Patients with severe asthma have diminished corticosteroid sensitivity of PBMCs when compared to non-severe asthmatics, associated with a reduction in HDAC activity that parallels the impaired corticosteroid sensitivity.
Key words: Severe asthma, corticosteroids, histone deacetylase, histone acetyltransferase




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