Abstract
BackgroundMany asthmatic patients exhibit uncontrolled asthma despite high-dose inhaled corticosteroids (ICS). Airway epithelial cells (AEC) have distinct activation profiles that can influence ICS response.ObjectivesA pilot study to identify gene expression markers of AEC dysfunction and markers of corticosteroid sensitivity in asthmatic and non-asthmatic control children, for comparison with published reports in adults.MethodsAEC were obtained by nasal brushings and primary submerged cultures, and incubated in control conditions or in the presence of 10 ng/ml TNFalpha, 10-8M dexamethasone, or both. RT-PCR-based expression of FKBP51 (a steroid hormone receptor signalling regulator), NF-kB, IL-6, LIF (an IL-6 family neurotrophic cytokine), serpinB2 (which inhibits plasminogen activation and promotes fibrin deposition) and porin (a marker of mitochondrial mass) were determined.Results6 patients without asthma (median age 11yr; min-max: 7–13), 8 with controlled asthma (11yr, 7–13; median daily fluticasone dose = 100 μg), and 4 with uncontrolled asthma (12yr, 7–14; 1000 μg fluticasone daily) were included. Baseline expression of LIF mRNA was significantly increased in uncontrolled vs controlled asthmatic children. TNFalpha significantly increased LIF expression in uncontrolled asthma. A similar trend was observed regarding IL-6. Dexamethasone significantly upregulated FKBP51 expression in all groups but the response was blunted in asthmatic children. No significant upregulation was identified regarding NF-kB, serpinB2 and porin.ConclusionLIF and FKBP51 expression in epithelial cells were the most interesting markers of AEC dysfunction/response to corticosteroid treatment.
Highlights
Asthma is characterized by inflammation of the airways, reversible airflow obstruction and bronchial hyperresponsiveness
Nasal brushings were obtained from male and female asthmatic children aged < 18 years
The study population consisted in 6 control patients without asthma or lung disease, 8 with controlled asthma (11 yr, 7–13), daily inhaled corticosteroids (ICS) dose 140 ±167 μg fluticasone (beclomethasone dose 100 (0–400)) and 4 patients with uncontrolled asthma (12 yr, 7–14), daily ICS dose 560 ± 630 μg fluticasone (beclomethasone dose 1000 (500–2000))
Summary
Asthma is characterized by inflammation of the airways, reversible airflow obstruction and bronchial hyperresponsiveness. Asthma is difficult to manage and remains poorly controlled, despite treatment with high-dose inhaled corticosteroids (ICS) 800 μg/d budesonide)[1,2,3]. Poor treatment supervision, alternative diagnoses and unresponsiveness to corticosteroids (CS) are thought to be the most important influencing factors in difficult asthma [3]. Rare cases of poor glucocorticoid receptor function have been described in children [2], the concept of variable corticoresponsiveness is more interesting to investigate than complete corticoresistance, which is rare [4]. Phenotyping patients according to underlying molecular characteristics may help in determining the prognosis and personalizing treatment regimens [5]
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