[Severe asthma: new therapeutic targets]

Severe asthma is a highly incapacitating disease with no effective preventive or curative treatment. The 10% of patients with "refractory" or "difficult" asthma have chronic symptoms, episodic exacerbations and persistent airway obstruction, despite chronic? 2-agonist and steroid therapy. A major objective of current asthma research is to identify the underlying cellular and molecular mechanisms and thus to develop new treatments. Persistent airway eosinophilia is a hallmark of severe asthma. IL-5 is essential for terminal differentiation of committed eosinophil precursors and is also involved in eosinophily degranulation and priming. By releasing cytokines and cationic proteins, eosinophils contribute to airway inflammation and damage the bronchial mucosa. A monoclonal antibody against IL-5 has been shown to reduce exacerbations of refractory asthma. Interventions targeting eosinophil cationic proteins might have therapeutic potential. Structural changes in the bronchial wall, collectively known as airway remodeling, are believed to play a prominent role in the persistent airflow obstruction associated with severe asthma. In this setting the airway epithelium shows major abnormalities, including loss of barrier function, phenotypic changes, and functional disorders. The abnormal respiratory epithelium is believed to orchestrate airway remodeling through aberrant production of extracellular matrix components, fibrogenic cytokines and chemokines, and growth factors responsible for the proliferation, migration and activation of smooth muscle cells and fibroblasts. Recently, increased ET-1 synthesis by the bronchial epithelium was observed in severe refractory asthma, and was found to correlate with airway remodeling and airway obstruction. ET-1 might represent a novel therapeutic target in severe steroid-refractory asthma.