Fig 8. Simplified working model of PGE₂-stimulated Cl^- and HCO₃^- secretion and mucociliary clearance in non-CF and CF airway.

A. In the airway, microbial infections cause an increase in PGE₂ through release from infiltrating inflammatory cells (not pictured) and production by airway epithelia via COX-2 activation. H₂O₂ produced by DUOX activates COX-2 and HVCN1 channels provide the H⁺ shunt from H₂O₂ production. PGE₂ exits the cell and activates PGE₂ (EP) receptors. In the current study we did not examine specific EP receptor involvement, however, we propose that EP₄ is the predominant mediator of serosal PGE₂ stimulation in bronchial epithelial cells. Submucosal gland cells may also utilize the EP₃ receptor, or Ca²⁺-activated Cl^- channels (CaCC) may get activated via EP₄-mediated cAMP-Ca²⁺ crosstalk. In bronchial epithelial cells, PGE₂ stimulates Cl^- and HCO₃^- secretion via CFTR, whereas in submucosal glands, both CFTR and CaCC are activated. Cl^- and HCO₃^- secretion will then influence airway pH, mucus properties, hydration, and ultimately, mucociliary clearance. B. In CF airway, lack of CFTR-dependent Cl^- and HCO₃^- secretion in bronchial epithelial cells, coupled with no HCO₃^- secretion and decreased Cl^- secretion from submucosal glands, leads to an acidic airway pH, thick-adherent mucus, and decreased mucociliary clearance. This results in increased microbial infection and rampant inflammation, in part by increased PGE₂ production.