Role of mechanical stress in regulating airway surface hydration and mucus clearance rates

Abstract

Effective clearance of mucus is a critical innate airway defense mechanism, and under appropriate conditions, can be stimulated to enhance clearance of inhaled pathogens. It has become increasingly clear that extracellular nucleotides (ATP and UTP) and nucleosides (adenosine) are important regulators of mucus clearance in the airways as a result of their ability to stimulate fluid secretion, mucus hydration, and cilia beat frequency (CBF). One ubiquitous mechanism to stimulate ATP release is through external mechanical stress. This article addresses the role of physiologicallyrelevant mechanical forces in the lung and their effects on regulating mucociliary clearance (MCC). The effects of mechanical forces on the stimulating ATP release, fluid secretion, CBF, and MCC are discussed. Also discussed is evidence suggesting that airway hydration and stimulation of MCC by stress-mediated ATP release may play a role in several therapeutic strategies directed at improving mucus clearance in patients with obstructive lung diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).

Purinergic Signaling in the Airways

“…The activity of CFTR is required for deformation-induced ATP release from erythrocytes; in CF, where CFTR is normally reduced or absent, ATP was not released from erythrocytes by mechanical deformation (Sprague et al, 1998). Cyclic compressive stress, mimicking normal tidal breathing, results in ATP release and thereby regulates airway surface liquid in normal lungs and improves clearance in the lungs of patients with CF (Button et al, 2007;Button and Boucher, 2008). Dysregulation of extracellular pH regulation is characteristic of CF and involves purinergic signaling (Kaunitz and Akiba, 2009).…”

Human Alveolar Type II Cells Secrete and Absorb Liquid in Response to Local Nucleotide Signaling

“…For example, ATP mediates regulatory responses via P2Y 2 receptor stimulation, and ATP metabolism provides a source of adenosine for stimulation of the A 2b adenosine receptor (18 -20). Recently, the mechanical stresses associated with tidal breathing have been shown to stimulate luminal nucleotide release from airway epithelial cells, providing a link between local stresses and regulation of airway surface liquid (ASL) volume (21). Similarly, purinergic signaling may contribute to the integrated control of ion/liquid homeostasis within the alveolar space.…”

Continuous mucociliary transport by primary human airway epithelial cells in vitro

“…In some cases, cultures have been observed to spontaneously develop regions of coordinated ciliary activity that transport mucus in a circular pattern (29). These "mucus hurricanes" have been especially useful for investigations into the pathogenesis of cystic fibrosis (5,28,42,47). In these cultures, mucus is transported as a sheet, or disk, with a constant angular velocity.…”