Airway Epithelial Nucleotide Release Contributes to Mucociliary Clearance

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.

Intercellular Communication in Airway Epithelial Cell Regeneration: Potential Roles of Connexins and Pannexins

“…Interestingly, ATP released from Panx1 channels triggered LXA4 production via activation of the purinergic receptor P2RY11 [40]. In fact, Panx1 KO mice exhibit ASL dehydration and deficient mucociliary clearance [41]. In airway epithelial cells from COPD patients and in cell models mimicking viral infection with dsRNA, the release of ATP via Panx1 channels and subsequent P2Y2R activation was found to stimulate the expression and release of MUC5AC in an autocrine manner [42].…”

Cough in non-cystic fibrosis bronchiectasis

“…Mechanical stress, such as shear and compression, triggers ATP release, which, when excessive, leads to purinoceptor desensitisation, inhibiting fluid secretion and preventing airway flooding [33,34].…”

Pannexin1 channels in the liver: an open enemy

“…This deletion of Panx1 goes hand in hand with disturbed myoblast functioning, which is reflected by deficits in muscle regeneration ( Suarez-Berumen et al, 2021 ). Moreover, Panx1 channel activity promotes mucociliary lung clearance ( Seminario-Vidal et al, 2011 ; van Heusden et al, 2021 ). Panx1 channel-mediated ATP release contributes to normal lung physiology, since ciliary beat frequencies and mucociliary clearance activities are lower upon deletion of Panx1 in mice ( van Heusden et al, 2021 ).…”

“…Moreover, Panx1 channel activity promotes mucociliary lung clearance ( Seminario-Vidal et al, 2011 ; van Heusden et al, 2021 ). Panx1 channel-mediated ATP release contributes to normal lung physiology, since ciliary beat frequencies and mucociliary clearance activities are lower upon deletion of Panx1 in mice ( van Heusden et al, 2021 ). Collectively, these data show that Panx1 channel activity underlies various physiological functions.…”