Coupling of airway ciliary activity and mucin secretion to mechanical stresses by purinergic signaling

Abstract

The mucociliary clearance system is comprised of three components, ion transport activities controlling the height of airway surface liquid (ASL), mucin secretion, and ciliary activity. These activities in humans are controlled principally by local agonists, extracellular nucleotides and nucleosides released from the epithelium. Importantly, mechanical stresses stimulate goblet cell mucin secretion, ciliary beating, and Cl- and fluid secretion through mechanically induced nucleotide release. Emerging evidence also implicates co-secretion of nucleotides and mucin from goblet cells as a source of extracellular agonist. At rest, ATP is released onto airway surfaces at approximately 370fmol/mincm2, but only approximately 3% of released ATP is recovered in ASL. Secreted UTP meets with a similar fate. A wide variety of hydrolytic and transphosphorylating ecto-enzymes convert the triphosphate nucleotides into ADP, AMP, and adenosine, UDP, UMP, and uridine. Of these, ATP, adenosine, UTP, and UDP act as agonists at apical P2Y2 (ATP, UTP), P2Y6 (UDP), and A2B (adenosine) receptors on ciliated and/or goblet cells to regulate mucociliary clearance.

Cystic fibrosis remodels the regulation of purinergic signaling by NTPDase1 (CD39) and NTPDase3

“…On basolateral surfaces, these enzymes conferred a relatively weak regulation of the P2Y 2 R agonist. These data are consistent with the fact that airway epithelia release nucleotides mainly into the ASL layer on the apical surface (14). The predominant role of NTPDase1 toward physiological nucleotide concentrations suggests that P2Y 2 R activation is regulated more stringently in the nose, whereas bronchi regulate a wider concentration range using both NTPDases.…”

“…Hence, the airway complications emanate from complex interactions between the CF genetic defect and the recurrent episodes of infection and inflammation. Airway clearance is supported by an intricate purinergic network concentrated on the epithelial barrier (14). The rhythmic mechanical stress caused by breathing induces ATP release from the epithelia (10), which binds P2Y 2 receptors (P2Y 2 Rs) to induce fluid secretion via Ca 2ϩ -activated Cl Ϫ channels, and mucin secretion to shield the surface and entrap the pathogens.…”

Vesicular nucleotide transporter regulates the nucleotide content in airway epithelial mucin granules

“…Such a pattern of nucleotide release from goblet cells offers a potential physiological advantage of selectively activating ion/water transport activities on neighboring ciliated cells. Specifically, released ADP/ AMP Ͼ ATP provides an abundant source for the production of extracellular adenosine, which promotes liquid secretion via an A 2b receptor/CFTR-mediated mechanism on ciliated cells (3,11). Such a mechanism maximizes the capacity to hydrate mucins in normal airways while minimizing autocrine feedback on mucin secretion via goblet cell P2Y 2 receptors.…”

Mechanical Forces Impair Alveolar Ion Transport Processes – A Putative Mechanism Contributing to the Formation of Pulmonary Edema

“…On the one hand the PLL is the first physical border that is exposed to the environment and the first line of host defense that absorbs pathogens. This is of particular importance in the airways, where the PLL is part of the innate immune system and crucial for protecting the host from the permanent exposure to pollutions and pathogens due to their removal by the mucociliary clearance (Welsh, 1987;Davis and Lazarowski, 2008 Fig. 1.…”