Introduction Corticosteroid (CS) insensitivity contributes to the difficulty in managing children with severe asthma.1 A better understanding of the molecular mechanisms driving this defective response could provide novel therapeutic options for these patients. Peripheral blood mononuclear cells (PBMCs) from adults with severe asthma have been used to demonstrate an impaired sensitivity to CS, enabling the delineation of potential underlying mechanisms. Whether CS insensitivity exists in PBMCs from severely asthmatic children, however, requires further validation.
Objective To determine whether PBMCs from children with severe asthma have an impaired in vitro responsiveness to corticosteroids.
Methods We conducted an observational feasibility study comparing the corticosteroid sensitivity of PBMCs from asthmatic children on British Thoracic Society treatment step 4–5 (n = 7) with healthy controls (n = 5). PBMCs from 5 ml of venous blood were plated in the presence of 100 ng/ml of lipopolysaccharide (LPS), and in the absence or presence of either 10–8 M or 10–6 M of dexamethasone (DEX). ELISA assays were used to determine the levels of TNF-α and IL-8, and the% suppression of these by DEX. Pearson product-moment correlation tests were conducted to determine the correlation between in vitro CS sensitivity and different clinical parameters.
Results There was no difference in baseline or LPS-induced cytokine release from PBMCs between the two groups. The inhibition of TNF-α release by DEX was significantly diminished in children with asthma compared to healthy controls at 10–8 M concentration (p = 0.018) but no differences were noticed at 10–6 M concentration, or on LPS-induced IL-8 production. A significant inverse correlation between% inhibition of TNF-α and body mass index (BMI) at 10–8 M (r=-0.84, p = 0.02) and 10–6 M DEX (r=-0.82, p = 0.02) was found.
Conclusions Our results show the existence of an impaired CS sensitivity in PBMCs from children with severe asthma, suggesting that these cells can be used for mechanistic investigations. Interestingly, we observed a negative correlation between CS sensitivity and BMI, a novel in vitro finding which supports the association between overweight/obese asthmatic children and a decreased clinical response to CS therapy. Together, these results merit further studies with a larger sample size.
Chung KF et al. ERJ 2014;43:343–373