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 metalloproteinases, 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 FEV(1) value (r(2) >or= 0.193, P <or= .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).


CONCLUSIONS
Increased EDN1 synthesis by the bronchial epithelium characterizes severe refractory asthma and correlates with airway remodeling and airflow obstruction.


CONCLUSIONS
Targeting EDN1 might represent a novel therapeutic strategy for severe steroid-refractory asthma.
Pégorier
Sophie
S
Inserm U700, Paris, and Université Paris 7, Faculté de Médecine Denis Diderot, site Xavier Bichat, Paris, France.
Arouche
Nassim
N
Dombret
Marie-Christine
MC
Aubier
Michel
M
Pretolani
Marina
M
D000276:Adjuvants, Immunologic / Q000096:biosynthesis* / Q000235:genetics*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004417:Dyspnea / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013256:Steroids / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D019332:Endothelin-1; D013256:Steroids