Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Chronic persistent asthma is characterized by poorly reversible airflow obs truction and airways inflammation and remodelling, Histopathological studie s of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result o f hyperplastic and/or hypertrophic growth, is believed to be one of the pri ncipal contributors to airway wall thickening, In recent years, significant advances have been made in elucidating the med iators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent air flow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversi ble phenotypic modulation and increased heterogeneity of airway smooth musc le function may also be a feature of the asthmatic airway, This review focuses on possible mechanisms controlling smooth muscle phenot ype heterogeneity as well as on the mediators and intracellular pathways im plicated in its cellular proliferation. Particular attention Is paid to mec hanisms involving activation of the extracellular signal regulated kinase-, protein kinase C- acid phosphoinositide 3-kinase-dependent pathways, since these appear to be the major candidate second messenger pathways for G pro tein- and tyrosine? kinase-coupled receptor-stimulated proliferation.