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(-) 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(-) transport in native porcine small airways (∼ 1 mm φ). 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 μM). Under these conditions, because no major transportable anions other than HCO3(-) were present, we took the equivalent short-circuit current to be a direct measure of active HCO3(-) secretion. Applying selective agonists and inhibitors, we show constitutive HCO3(-) secretion in small airways, which can be stimulated significantly by β-adrenergic- (cAMP) and purinergic (Ca(2+)) -mediated agonists, independently. These results indicate that two separate components for HCO3(-) 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.
1 Department of Pediatrics, University of California San Diego, La Jolla, California; and.
A K M
AK
Shamsuddin
Paul M
PM
Quinton
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004553:Electric Conductivity; D005260:Female; D017136:Ion Transport; D008168:Lung / Q000033:anatomy & histology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D058913:Purinergic Agonists / Q000494:pharmacology; D013552:Swine; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D001639:Bicarbonates; D018118:Chloride Channels; D058913:Purinergic Agonists; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D002118:Calcium