Abstract
Mucociliary clearance (MCC) is a dominant component of pulmonary host defense. In health, the periciliary layer (PCL) is optimally hydrated, thus acting as an efficient lubricant layer over which the mucus layer moves by ciliary force. Airway surface dehydration and production of hyperconcentrated mucus is a common feature of chronic obstructive lung diseases such as cystic fibrosis (CF) and chronic bronchitis (CB). Mucus hydration is driven by electrolyte transport activities, which in turn are regulated by airway epithelial purinergic receptors. The activity of these receptors is controlled by the extracellular concentrations of ATP and its metabolite adenosine. Vesicular and conducted pathways contribute to ATP release from airway epithelial cells. In this study, we review the evidence leading to the identification of major components of these pathways: (a) the vesicular nucleotide transporter VNUT (the product of the SLC17A9 gene), the ATP transporter mediating ATP storage in (and release from) mucin granules and secretory vesicles; and (b) the ATP conduit pannexin 1 expressed in non-mucous airway epithelial cells. We further illustrate that ablation of pannexin 1 reduces, at least in part, airway surface liquid (ASL) volume production, ciliary beating, and MCC rates.
Highlights
The mucus gel layer covering the airway surface periciliary layer (PCL) traps inhaled materials and acts as a reservoir for water, buffering hydration of the PCL for needed cell surface lubrication and efficient ciliary beating [1]
Cl and Na transport activities in the airways are regulated by airway surface liquid (ASL) concentrations of ATP and its metabolite adenosine acting on Gq-coupled P2Y2 receptors (P2Y2R) and GsGs-coupled
Capitalizing on the availability of Panx1 KO mice, we investigated the contribution of pannexin 1 to mucociliary clearance (MCC) activities
Summary
The mucus gel layer covering the airway surface periciliary layer (PCL) traps inhaled materials and acts as a reservoir for water, buffering hydration of the PCL for needed cell surface lubrication and efficient ciliary beating [1]. When the hydration of the airway surface liquid (ASL) decreases, the mucus becomes hyperconcentrated, the PCL collapses, and the “thickened” mucus layer adheres to the cell surface, causing plaque/plug formation. Gene that result in abnormal CFTR Cl− channel expression/activity are associated with exacerbated Na+ absorption [6] and lead to ASL volume depletion in CF. The processes leading to mucus dehydration in non-CF lung diseases are incompletely described, but recent evidence suggests that prolonged cigarette smoke exposure reduces CFTR expression, induces CFTR internalization, and disrupts CFTR channel function, leading to ASL dehydration. Cigarette smoke-induced CFTR dysfunction likely contributes to the onset of CB [7,8,9]
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