Study on the Effects of Sitaxsentan on Airway Remodeling in Patients With Severe Asthma

Introduction. Despite adequate steroid therapy, a subpopulation of approximately 10% of asthmatics develops severe persistent airflow obstruction. It is now widely agreed that the latter is the consequence of a remodeling process of the airways, characterized by an increase in airway smooth muscle mass, mucus gland hypertrophy, increased thickness of the subepithelial basement membrane, extracellular matrix protein deposition, angiogenesis, fibroblast and myofibroblast accumulation. These phenomena are responsible for airway wall thickening and for decreased airway caliber leading to persistent airflow obstruction. Endothelin-1 (ET-1) is a small peptide, synthesized in the lung by airway epithelial and smooth muscle cells, as well as inflammatory cells. ET-1 induces bronchoconstriction, mediates eosinophils recruitment during allergic inflammation and contributes to airway remodeling by inducing fibroblasts and smooth muscle cells differentiation and proliferation. In a recent work from Inserm Unit 700, it has been shown that ET-1 was overexpressed in epithelial cells from severe asthmatic patients as compared to patients with less severe disease, and that ET-1 expression was strongly correlated with airway obstruction (measured by FEV1) and on bronchial biopsies with airway smooth muscle areas. In another study, we have shown that a polymorphism of the receptor for ET-1 was strongly associated with the degree of airway obstruction in a population of asthmatic patients. All these data suggest that inhibition of the ET-1 pathway could be a potential therapeutic option in patients with steroids refractory asthma and irreversible airway obstruction. Bosentan, a specific inhibitor of ET-1 receptors which is actually used in patients with pulmonary hypertension, improves survival and inhibits vascular remodeling. Aim and strategy. To study the impact on airway remodeling and clinical status of an antagonist of the endothelin receptors (Sitaxentan 100mg/day) over a 12-m