Loss of CFTR Chloride Channels Alters Salt Absorption by Cystic Fibrosis Airway Epithelia In Vitro

Abstract

Cystic fibrosis (CF) is caused by the loss of functional CFTR Cl- channels. However, it is not understood how this defect disrupts salt and liquid movement in the airway or whether it alters the NaCl concentration in the thin liquid film covering the airway surface. Using a new approach, we found that CF airway surface liquid had a higher NaCl concentration than normal. Both CF and non-CF epithelia absorbed salt and liquid; however, expression of CFTR Cl- channels was required for maximal absorption. Thus, loss of CFTR elevates the salt concentration in CF airway surface liquid and in sweat by related mechanisms; the elevated NaCl concentration is due to a block in transcellular Cl- movement. The high NaCl may predispose CF airways to bacterial infections by inhibiting endogenous antibacterial defenses.

The lactoperoxidase system links anion transport to host defense in cystic fibrosis

“…CFTR mutations result in loss of functional anion channel activity on the apical cell surface, although, it is not fully understood how a loss of anion channel activity completely explains defective antibacterial defenses. Several hypotheses have been proposed to relate these two phenomena and focus on: (a) the effects of airway surface liquid (ASL) dehydration that leads to impaired ciliary and cough clearance of mucus [3]; (b) the effects of elevated ASL salt concentration on the activity of antimicrobials in mucus [4][5][6]; or (c) CFTR mediated defective bacterial-epithelial interactions (for reviews see [7][8][9][10][11]). …”

ETCare: a randomized, controlled, masked trial comparing two solutions for upper airway care in the NICU

“…[7][8][9][10][11] Many nosocomial infections in the NICU are with organisms that are of very low virulence in healthy adults, such as C. albicans and coagulasenegative staphylococcus. 21 A low IgG concentration is one factor predisposing preterm neonates to these infections, 22 and disruption of the mucosal barrier by the presence of tubes in the trachea, nose or mouth is likely another predisposing factor.…”

“…6 One problem with using saline for periodic upper airway care in a neonate is that high concentrations of sodium and chloride inactivate natural antimicrobial properties of airway secretions. [7][8][9][10][11][12][13] Tracheal secretions, nasal secretions and saliva all have very low concentrations of sodium and chloride. Moreover, those secretions contain potent natural antibacterial substances that are inhibited by saline.…”

Airway plumbing

“…However, to disprove the salt model one needs to show that airway P f is too high to be compatible with the salt hypothesis, and this discriminating value is not known. Presumably P f could be somewhat higher than in the renal collecting duct, which, during water diuresis, maintains a much larger salt gradient than the one reported for airway epithelia (12). Regardless, demonstrating that transepithelial P f can be studied conveniently in cultured airway epithelia is important and provides hope that conflicting in vitro results will be reconciled.…”