Native Small Airways Secrete Bicarbonate

Since the discovery of Cl-impermeability in cystic fibrosis (CF) and the cloning of the responsible channel, CF pathology has been widely attributed to a defect in epithelial Cl-transport. However, loss of bicarbonate (HCO3-) transport also plays a major, possibly more critical role in CF pathogenesis. Even though HCO3-transport is severely affected in the native pancreas, liver, and intestines in CF, we know very little about HCO3 2 secretion in small airways, the principle site of morbidity in CF. We used a novel, mini-Ussing chamber system to investigate the properties of HCO3 2 transport in native porcine small airways (similar to 1 mm phi). We assayed HCO3-transport across small airway epithelia as reflected by the transepithelial voltage, conductance, and equivalent short-circuit current with bilateral 25-mM HCO3 -plus 125-mM NaGlu Ringer's solution in the presence of luminal amiloride (10 mM). Under these conditions, because no major transportable anions other than HCO3 2 were present, we took the equivalent short-circuit current to be a direct measure of active HCO3 2 secretion. Applying selective agonists and inhibitors, we show constitutive HCO3 2 secretion in small airways, which can be stimulated significantly by beta-adrenergic-(cAMP) and purinergic (Ca2+) -mediated agonists, independently. These results indicate that two separate components for HCO3 2 secretion, likely via CFTR and calcium-activated chloride channel-dependent processes, are physiologically regulated for likely roles in mucus clearance and antimicrobial innate defenses of small airways.