SA McKenzie’s research while affiliated with Barts Health NHS Trust and other places

Previous studies have suggested that low glucocorticoid receptor (GR) numbers and reduced OR binding affinity may play a role in the development of corticosteroid insensitive (CI) asthma. We investigated GR number and binding affinity in peripheral blood mooonudear cells (PBMC) in a group of children with CI asthma. We also examined markers of airway inflammation, as reduced GR binding affinity is thought to be induced by persistent airway inflammation. Methods: 21 children, (6-16 years), with a proven diagnosis of asthma and treated with ≥ 800mcg/day of inhaled budesonide or equivalent were included. Corticosteroid insensitivity was defined as an increase in prebronchodilator FEV1 <190ml following two weeks of oral prednisolone (40mg/day). An increase of >190ml indicates reversibility and is independent of the magnitude of the baseline FEV1. Airway inflammation was measured by exhaled nitric oxide (NO) before prednisolone and by NO and bronchial biopsy after prednisolone. GR number and binding affinity were measured in PBMC after prednisolone. Results: 13 children were corticosteroid sensitive (CS) and 8 CI. Median age was 11(CS) and 10(CI). Median baseline FEV1 (percent predicted) was 69.5(CS) and 80.5(CI), (p>0.05). Median NO levels, in parts per billion, fell from 11.7 to 6.3(CS), (p>0.05) and 9.9 to 7.2(CI), (p>0.05) after prednisolone. There was no significant difference between the groups for levels of eosinophils, T cells and macrophages in bronchial biopsy. Median values for the dissociation constant, a measure of GR binding affinity, were 6.35nM(CS) and 20.95nM(CI), (p>0.05). Median GR number/cell was 2043(CS) and 2243(CI) (p>0.05). 2 CI patients had very low levels of GR/cell (<750). Conclusions: Children with CI asthma appear to have a similar pattern of airway inflammation to those with CS asthma. There is no difference in GR binding affinity or GR number between the groups, although reduced GR number may be important in some children with CI asthma.