Mechanosensitive ATP Release Maintains Proper Mucus Hydration of Airways

Abstract

The clearance of mucus from the airways protects the lungs from inhaled noxious and infectious materials. Proper hydration of the mucus layer enables efficient mucus clearance through beating of cilia on airway epithelial cells, and reduced clearance of excessively concentrated mucus occurs in patients with chronic obstructive pulmonary disease and cystic fibrosis. Key steps in the mucus transport process are airway epithelia sensing and responding to changes in mucus hydration. We reported that extracellular adenosine triphosphate (ATP) and adenosine were important luminal auto-crine and paracrine signals that regulated the hydration of the surface of human airway epithelial cultures through their action on apical membrane purinoceptors. Mucus hydration in human airway epithelial cultures was sensed by an interaction between cilia and the overlying mucus layer: Changes in mechanical strain, proportional to mucus hydration, regulated ATP release rates, adjusting fluid secretion to optimize mucus layer hydration. This system provided a feedback mechanism by which airways maintained mucus hydration in an optimum range for cilia propulsion. Understanding how airway epithelia can sense and respond to changes in mucus properties helps us to understand how the mucus clearance system protects the airways in health and how it fails in lung diseases such as cystic fibrosis.

Continuous mucociliary transport by primary human airway epithelial cells in vitro

“…In general, measurements of CBF and MCT in this study were similar to values obtained in other studies of cultured HBE cells (6,25,29,38). For example, Matsui et al (29) reported mucus transport velocities of 20 -80 m/s, and Liu et al (25) reported a CBF of 9 -10 Hz in cultured HBE cells.…”

Mitochondria in lung disease

“…Normal lung function requires ATP release by AECs to optimize airway surface layer hydration, mucus composition, and mucociliary clearance (93). However, excessive ATP release from dying or damaged cells acts as a DAMP and is recognized by the purinergic receptor P2X7, which is expressed specifically on cells of the immune system and is involved in the release of IL-1β (94).…”

The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis

“…ADO was significant reduced in the subjects with CB as compared with the CS-N (P = 0.03). Because ATP and ADO are the two active nucleotides/nucleosides regulating airway surface liquid (ASL) volume and mucus concentration, the sum of ATP and ADO concentrations across groups was compared ( Figure 2B) (18,26). The combined ATP/ADO concentrations were significantly lower in the CB group (566 6 73 mM) than the NS control group (2,003 6 495 mM; P = 0.0006) or the CS-N group (1,588 6 355 mM; P = 0.02).…”

“…Human airway epithelial cultures (HBE) were left unwashed for 2-3 weeks to produce mucus with greater than 10% solids (16,29). To measure MCC, fluorescent microspheres were added to the apical surface of HBE cultures approximately 16 hours before study (18,30). MCC rates were calculated from time-lapse fluorescent images (30).…”

“…Healthy airways sense and maintain normal mucus concentrations (hydration) via interactions of cilia with the mucus layer during cilial propulsion of mucus (18). Mucus concentration-dependent cilial strain governs the rate of ATP release onto airway surfaces, which regulates, via P2Y 2 R, the balance between liquid absorption from versus liquid secretion onto airway surfaces.…”