Le remodelage bronchique dans l’asthme: mécanismes et enjeux thérapeutiques Airway remodeling in asthma: mechanisms and therapeutical perspectives

Résumé

Les remaniements de la paroi bronchique, connus sous le nom de « remodelage des voies aériennes », touchent une partie des sujets asthmatiques. Ces altérations sont responsables d’un déclin progressif et irréversible de la fonction respiratoire et de la constitution d’un trouble ventilatoire obstructif irréversible et résistant aux thérapies conventionnelles, notamment aux corticoïdes. Le remodelage des voies aériennes se caractérise, entre autres, par des lésions épithéliales et une hyperplasie/hypertrophie/métaplasie des fibroblastes et des cellules musculaires lisses bronchiques. L’étude des mécanismes cellulaires et moléculaires qui gouvernent ces altérations tissulaires est l’étape indispensable à l’identification de nouvelles stratégies thérapeutiques préventives et/ou curatives.

Summary

Although asthma is classically defined as reversible airflow obstruction and often remits in younger subjects with milder disease, a proportion of asthmatics experience chronic symptoms, episodic exacerbations and persistent airway obstruction, despite the continuous use of β2-agonists, associated with high doses of inhaled/oral corticosteroids. These patients contribute to the majority of asthma costs through hospitalization, emergency visits, absence from work or school and use of medication. Although the mechanisms behind irreversible airflow obstruction in asthma are unclear, a prominent role has been attributed to persistent structural changes of the bronchial wall, defined as airway remodeling. Studies conducted on endobronchial biopsy samples have led to the histopathological characterization of these tissue alterations, which include chronic mucosal inflammation, extensive epithelial damage, collagen deposition, subepithelial fibrosis, increased mucous glands and airway smooth muscle hypertrophy and/or hyperplasia. Several factors, such as polypeptide growth factors and their receptors, matrix metalloproteases, intracellular molecules controlling cell death and survival, adhesion molecules and their ligands, as well a large variety of cytotoxic pro-inflammatory mediators are likely to contribute to the onset and maintenance of these tissue abnormalities. However, to date, the cellular and molecular events driving specifically these phenomena and allowing asthmatics with persistent airflow limitation to be distinguished from patients who normalize their bronchial obstruction upon adequate therapeutic management have not been identified yet. Accordingly, airway remodeling represents a major research challenge, particularly in view of the development of new therapeutic strategies specifically addressed at alleviating persistent bronchial obstruction in these otherwise intractable patients.