p38 MAPK activation as the basis for corticosteroid insensitivity in severe asthma

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Severe asthma affects only ~5% of all asthmatics, but these unfortunate patients are the most difficult group to treat because they do not get the same amount of benefit from corticosteroid medicines as other patients whose asthma remains well-controlled. These patients therefore desperately need newer treatments to control their asthma. Severe asthmatics suffer from persistent asthma symptoms and attacks and suffer from more side-effects of corticosteroid treatment because they need higher doses than usual. We have been studying how the steroids do not seem to provide more beneficial effects on patients with severe asthma and how cells from their lung (alveolar macrophages) and blood (blood mononuclear cells) are not responding to steroids in the test-tub, as those cells from a mild type of asthma. We have found that there is a protein that determines the release of a chemical from lung cells (called p38 MAPK for short, an enzyme that accelerates reactions in many cells) that is increased in severe asthma. We now wish to study how this protein gets to be active in severe asthma, and how it causes the steroids to be less effective in these cells in the test-tube. This work may provide more effective medicines that patients with severe asthma desperately need such as those medicines that block the effect of the p38 MAPK.

Technical Summary

Patients with severe asthma do not respond adequately to currently-available treatments including corticosteroids, and have been also labelled as having asthma refractory to treatment. An urgent unmet need for severe asthma is an effective treatment. We have recently found a reduction on corticosteroid (CS) responsiveness in blood mononuclear cells and alveolar macrophages (AMs) of severe asthma patients by studying the effect of dexamethasone in inhibiting cytokine release induced by lipopolysaccharide (LPS). In addition, we found that an inhibitor of p38 mitogen-activated protein kinase (MAPK) reversed CS insensitivity in the macrophages of patients with severe asthma.
In this research, we will determine the mechanisms by which AMs and blood monocytes from severe asthma patients are less well suppressed by CS. We will focus on the activation signalling of the MAPK, particularly p38, which we have found to be overactivated in AMs of severe asthma patients. Patients with severe and non-severe asthma will be recruited. Our aims are (i) to evaluate the activation of monocytes/macrophages in bronchial biopsies and in bronchoalveolar lavage fluid (ii) to determine whether CS insensitivity is also replicated with IL-1b as with lipopolysaccharide (LPS) stimulation of AMs and blood monocytes (ii) pursue the role of p38 MAPK activation in determining the accessibility of NF-kB to its cognate DNA binding sites of inflammatory genes (iii) investigate the mechanisms of p38 MAPK activation on CS receptor activation status, nuclear translocation and ability to recruit cofactors and (iv) investigate the effects of p38 MAPK activation on histone phosphorylation, NF-kB activity and accessibility of its DNA-binding sites at promoters of CS-insensitive genes and (v) examine the role of played by MAPK phosphatase-1 in regulating p38 MAPK activity and CS insensitivity.
This research aims at finding out how the inflammation in patients suffering from severe asthma is different from that with non-severe asthma, and how it may prevent CS from working efficiently in severe asthma. It will uncover specific targets such as p38 MAPK from which more efficient therapies for severe asthma could be developed.

Publications

10 25 50

 
Description Analysis of epigenetic factors in macrophages from severe asthma
Amount £50,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2010 
End 01/2011
 
Description ERS, Travel Fellowship
Amount £12,000 (GBP)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2008 
End 07/2009
 
Description MRC ABPI COPD Consortium
Amount £130,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2011 
End 01/2014
 
Description Collaboration with Professor TH Lee at Kings College on role of SERCA in severe asthma 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of biopsies from severe asthma patients for analysis of SERCA
Collaborator Contribution Examined the role of SERCA in steroid insensitivity
Impact Paper published: Mahn K, Hirst SJ, Ying S, Holt MR, Lavender P, Ojo OO, Siew L, Simcock DE, McVicker CG, Kanabar V, Snetkov VA, O'Connor BJ, Karner C, Cousins DJ, Macedo P, Chung KF, Corrigan CJ, Ward JP, Lee TH. Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma. Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10775-80. Epub 2009 Jun 16.
Start Year 2008
 
Title p38 MAPK inhibitors 
Description Use of p38 MAPK inhibitors in corticosteroid insensitivity 
IP Reference WO2008087437 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact Nil