The Role of Airway Smooth Muscle in the Pathogenesis of Airway Wall Remodeling in Chronic Obstructive Pulmonary Disease

Abstract

Airway wall remodeling processes are present in the small airways of patients with chronic obstructive pulmonary disease, consisting of tissue repair and epithelial metaplasia that contribute to airway wall thickening and airflow obstruction. With increasing disease severity, there is also increased mucous metaplasia and submucosal gland hypertrophy, peribronchial fibrosis, and an increase in airway smooth muscle mass. Apart from its contractile properties, airway smooth muscle produces inflammatory cytokines, proteases, and growth factors, which may contribute to the remodeling process and induce phenotypic changes of the muscle. Airflow limitation responds minimally to ␤-agonists and corticosteroid therapy, unlike asthma, perhaps because of alterations in ␤-receptor or glucocorticoid receptor numbers, alterations in receptor signaling, or the constrictive limitation imposed by peribronchial fibrosis. Better response is observed with the combination of inhaled long-acting ␤-agonists and corticosteroids. This could result from effects at the level of airway smooth muscle. Airway wall remodeling may involve the release of growth factors from inflammatory or resident cells. The influence of smoking cessation or of current therapies on airway wall remodeling is unknown. Specific therapies for airway wall remodeling may be necessary, together with noninvasive methods of imaging small airway wall remodeling to assess responses.

Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction

“…Airway smooth muscle cells not only have contractile properties but also are capable of expressing and releasing cytokines, chemokines, growth factors and proteases [135,136], and can participate in the inflammatory and remodelling process [137]. Airway smooth muscle cells also produce matrix proteins, and their behaviour may depend upon interactions with their own matrix [138].…”

Epidemiology of COPD

“…In addition, cigarette smoke directly stimulates various types of cells, in particular macrophages [40,41] and epithelial cells of the airways [42], thus contributing to increased production of mediators and cytokines that participate in maintaining the inflammatory reaction. Through their interactions with the epithelium and extracellular matrix, the bronchial smooth muscle cells would also appear to play an important role in the remodelling of the airways observed in COPD [43].…”

Muscarinic M3 receptor stimulation increases cigarette smoke-induced IL-8 secretion by human airway smooth muscle cells

“…The airway smooth muscle cell is increasingly recognised as an important cellular source of pro-inflammatory cytokines and growth factors, including interleukins (IL)-6 and -8, monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF) and others (see [15][16][17] for review) and it appears to play an important immunomodulatory role in airways diseases such as asthma and COPD. The immunomodulatory function of airway smooth muscle has mostly been studied in cell culture; these studies have revealed that Gprotein-coupled receptor agonists, growth factors, cytokines and extracellular matrix proteins can induce the release of significant amounts of pro-inflammatory cytokines [15][16][17].…”

“…The immunomodulatory function of airway smooth muscle has mostly been studied in cell culture; these studies have revealed that Gprotein-coupled receptor agonists, growth factors, cytokines and extracellular matrix proteins can induce the release of significant amounts of pro-inflammatory cytokines [15][16][17]. In addition, airway smooth muscle cells exhibit IL-8 release in response to cigarette smoke extract, which is strongly augmented by cytokines such as tumour necrosis factor (TNF)-a [18].…”