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

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.

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.