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 (r² ≥ 0.193, P ≤ .03), and they were positively related to airway smooth muscle areas (r² = 0.253, P = .01 and r² = 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.

Key words: Endothelin-1, severe asthma, laser microdissection, fibrosis, airway smooth muscle

Abbreviations used: ASM, Airway smooth muscle, CCL2, Chemokine (C-C motif) ligand 2, CXCL8, Chemokine (C-X-C motif) ligand 8, ECM, Extracellular matrix, EDN1, Endothelin-1, MCP, Monocyte chemotactic protein, MMP, Matrix metalloproteinase, SBM, Subepithelial basement membrane