Augmented epithelial endothelin-1 expression in refractory asthma

Background: Airway remodeling in patients with severe steroid-refractory asthma might result from a reduced ability of steroid therapy to limit the transcription of remodeling factors by the bronchial epithelium. Objective: We sought to compare the levels of transcripts encoding remodeling factors in bronchial epithelium of healthy volunteers and of asthmatic patients with either steroid-sensitive or steroid-refractory disease and to correlate these levels with hallmarks of airway remodeling. Methods: By means of real-time quantitative PCR, we assessed the levels of 14 transcripts encoding remodeling factors, matrix metalolproteinases, and extracellular matrix proteins in laser-capture microdissected bronchial epithelium of healthy volunteers, patients with mild steroid-untreated asthma, and patients with steroid-sensitive and steroid-refractory asthma (n = 8-10 in each group). Histologic features of airway remodeling and endothelin-1 (EDN1) immunolocalization were determined by using frozen specimens. Results: Patients with steroid-refractory asthma had greater levels of EDN1 transcripts (4.1-fold increase, P = .026) and protein (P = .0009) in their bronchial epithelium compared with patients with steroid-sensitive asthma. EDN1 mRNA levels and protein expression in asthmatic patients were negatively correlated with prebronchodilator and postbronchodilator FEV1 value (r(2) >= 0.193, P <= .03), and they were positively related to airway smooth muscle areas (r(2) = 0.253, P = .01 and r(2) = 0.281, P = .005 for EDN1 mRNA and protein expression, respectively). Conclusion: Increased EDN1 synthesis by the bronchial epithelium characterizes severe refractory asthma and correlates with airway remodeling and airflow obstruction. Clinical implications: Targeting EDN1 might represent a novel therapeutic strategy for severe steroid-refractory asthma.