A_2B Adenosine Receptors Regulate the Mucus Clearance Component of the Lung's Innate Defense System

Abstract

Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A 2B adenosine receptor (A 2B -R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A 2B -R could treat inflammatory lung diseases. However, stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by ADO may be crucial in permitting the superficial epithelium to maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Our goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia. We used PCR techniques to determine ADO-R expression in bronchial epithelia and used nasal potential difference measurements, Ussing chambers studies, and XZ-confocal microscopy to look at Cl -secretion and ASL volume regulation. The A 2B -R was the most highly expressed ADO-R in donor specimens of human bronchial epithelia, and inhibition of ADO-R in vivo prevented activation of CFTR. A 2B -R was the only ADO-R detected in cultured human bronchial epithelial cells and inhibition of this receptor with specific A 2B -R antagonists resulted in ASL height collapse and a failure to effect ASL height homeostasis. Removal of ADO with ADO deaminase and replacement with 59N-ethylcarboxamide adenosine resulted in dosedependent changes in ASL height, and suggested that the cell surface (ADO) may be in excess of 1 mM, which is sufficient to activate A 2B -R. A 2B -R are required for ASL volume homeostasis in human airways, and therapies directed at inhibiting A 2B -R may lead to a cystic fibrosis-like phenotype with depleted ASL volume and mucus stasis.

UDP-glucose promotes neutrophil recruitment in the lung

“…5). Collectively, these results strongly suggest that UDP-glucose released into CF-like diseased airways acts as a pro-inflammatory mediator, via stimulation of the P2Y 14 R. P2Y 14 R mRNA is expressed in human [45] and murine [46] lungs [17,46] and inflammatory cells [17][18][19][20][21], but the identity of the cell type(s) potentially sensing UDP-glucose in airway surface liquids is not known. We observed no P2Y 14 R mRNA amplification in well-differentiated primary cultures of bronchial epithelial cells (data not shown).…”

Allergic airway inflammation induces a pro-secretory epithelial ion transport phenotype in mice

“…Interestingly, the concept of regional differences in ion and fluid transport in small versus large airways is supported by a previous study that compared primary human bronchial with bronchiolar epithelial cell cultures [32]. The regional differences in native tracheal versus bronchial epithelium may be related to: 1) differences in expression levels of ENaC subunits and genes contributing to basal and agonistinduced Cl -secretion; 2) differences in local concentrations of mediators, such as Th2 cytokines (Il-4 and Il-13), extracellular nucleotides and nucleosides (ATP and adenosine), which are released in allergic inflammation and act as potent modulators of airway ion transport [8,9,[33][34][35]; or 3) local differences in receptor densities, in particular the common IL-4/IL-13 receptor and/or differences in epithelial Stat6 signalling. We predict that further elucidation of the mechanisms underlying these regional differences in basal and regulated airway ion transport may provide novel insights into local (dys)regulation of MCC in response to noxious stimuli in different airway regions of the lung.…”

17β-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia

“…ADO activates CFTR via an A2 B ADO receptor-dependent rise in cAMP (6). ADO addition (100 μM) also elicited a robust increase in ASL height that was unaffected by 10 nM E2 ( Figure 2F).…”

“…The ASL is composed of a periciliary liquid layer (PCL) that lubricates the cell surface and a mucus layer that traps airborne particles and pathogens (3). Adenosine (ADO) and ATP act as physiological ligands that stimulate P1 and P2 subtypes of purinergic receptors to raise cAMP and Ca 2+ levels, respectively, so that Cl -secretion is activated (4)(5)(6). Normal airways can secrete sufficient Cl -to hydrate the mucus layer by raising either cAMP levels to stimulate CFTR or Ca 2+ to stimulate an alternate Cl -channel (7).…”