Purinergic receptors in airway hydration

Abstract

Airway epithelial purinergic receptors control key components of the mucociliary clearance (MCC), the dominant component of pulmonary host defense. In healthy airways, the periciliary liquid (PCL) is optimally hydrated, thus acting as an efficient lubricant layer over which the mucus layer moves by ciliary force. When the hydration of the airway surface decreases, the mucus becomes hyperconcentrated, the PCL collapses, and the "thickened" mucus layer adheres to cell surfaces, causing plaque/plug formation. Mucus accumulation is a major contributing factor to the progression of chronic obstructive lung diseases such as cystic fibrosis (CF) and chronic bronchitis (CB). Mucus hydration is regulated by finely tuned mechanisms of luminal Cl^- secretion and Na⁺ absorption with concomitant osmotically driven water flow. These activities are regulated by airway surface liquid (ASL) concentrations of adenosine and ATP, acting on airway epithelial A_2B and P2Y₂ receptors, respectively. The goal of this article is to provide an overview of our understanding of the role of purinergic receptors in the regulation of airway epithelial ion/fluid transport and the mechanisms of nucleotide release and metabolic activities that contribute to airway surface hydration in healthy and chronically obstructed airways.

Keywords: ATP hydrolysis; Airway epithelia; Airway hydration; Nucleotide release; Purinergic receptors.

Figure 1.. Regulation of mucus hydration in airway epithelia.

A, airway surface hydration is maintained by water fluxes mainly driven by active Cl⁻ and Na⁺ transport. When the hydration of the airway surface decreases, e.g., secondary to CFTR dysfunction, Na⁺ absorption increases, the mucus becomes hyperconcentrated, the PCL collapses, and the “thickened” mucus layer adheres to the cell surface, causing plaque/plug formation, as seen in CF and CB. B, ATP and adenosine (Ado) acting on airway epithelial P2Y₂R and A_2BR, respectively, promote Cl⁻ secretion and inhibition of Na⁺ absorption.

Figure 2.. Purinergic regulation of mucus hydration and clearance.

ATP is released from non-mucous cells via the plasma membrane channel pannexin 1 (PANX1). Goblet cell mucin granules release ATP and, to a greater extent, ADP and AMP. A subset of ecto-enzymes (not shown for clarity) convert released ATP to ADP, AMP, and adenosine (Ado). The A_2BR and the P2Y₂R on non-mucous cells are major regulators of ASL volume production, via activation of the CFTR and CACC, and promote inhibition of Na⁺ absorption. P2Y₂RS expressed on goblet cells promote mucin secretion.

Figure 3.. Inhibition of ATP hydrolysis improves ASL volume regulation in CF HBE cells.

CF HBE cells were maintained at an air-liquid interface overnight under phasic motion (0.5 dynes/cm2, 14 cycles/min) [62]. Afterwards, PBS or PBS containing 1 mM POM-5 were applied via an Aeroneb Lab Nebulizer (final [POM-5] = 100 μM; volume applied =100 nl) and ASL height was measured by confocal microscopy, as in [62]. A, representative confocal microscopy image taken at 60 min in the absence (PBS) or presence of 100 μM POM-5; bar =10 μm. B, quantification of ASL height in CF HBE cells. The data represent the mean ± SD (4 cultures / condition; *, p < 0.05) and are representative of two independent experiments. Reproduced from van Heusden et al. 2020. Am J Physiol Lung Cell Mol Physiol 318, L356-L365A [23].