Figure 1. Role of the A2b signaling pathway in ASL hydration. ATP is secreted from cells basally or following shear stress and is hydrolyzed by ecto-enzymes to AMP. The 5’ ecto-nucleotidase (5’NT; 1) then degrades AMP to ADO, which activates A2b receptors (A2b-R, 2) that are coupled to G-proteins (Gs) and adenylyl cyclase (AC) to raise local concentrations of intracellular cAMP, resulting in activation of CFTR and inactivation of ENaC. ADO is then degraded to inosine by adenosine deaminase (ADA, 3) and taken up into the cell by nucleotide transporters (eNT1, 4).

Figure 2. Schematic model of early pathogenic events in CF airways. Left, on normal airway epithelia, a thin mucus layer resides atop the periciliary liquid layer (PCL), which is maintained by active ion transport (e.g. Na+ & Cl- channels). The presence of the low viscosity PCL facilitates efficient mucociliary clearance and allows free movement of neutrophils which engulf inhaled bacteria. Right, excessive CF volume depletion caused by abnormal ion transport removes the PCL, mucus becomes adherent to epithelial surfaces, and mucus transport slows/stops. Due to the concentration of mucus, neutrophil movement also becomes impaired and natural antibactierial agents such as lactoferrin and lysozyme are insufficient to kill bacteria.