Airway acidification initiates host defense abnormalities in cystic fibrosis mice

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF.

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

“…CF mucus has altered properties that impair mucociliary transport (31). Recent studies showed that CF ASL has an increased viscosity due to a reduced ASL pH (32,35). In epithelia composed of mixtures of CFTR −/− and CFTR +/+ cells, the relationship between the percentage of WT cells and ASL viscosity (τ ASL /τ saline ) approximately paralleled that of ASL pH (Fig.…”

“…Loss of HCO 3 − secretion in the face of continued proton secretion contributes to the abnormally reduced pH of CF ASL (35). Although increasing HCO 3 − secretion increased ASL pH, pH reached a maximum at ∼7.50.…”

“…The * indicates the difference from epithelia with 100% WT cells by repeated measures ANOVA, P < 0.05. epithelium are WT or overexpress CFTR, Cl − secretion rises to the level of WT epithelia (10)(11)(12)(13)(14). However, knowledge that CFTR conducts HCO 3 − (48), that HCO 3 − is the major pH buffer of ASL (49), and that HCO 3 − secretion plays a key role in airway host defense (31)(32)(33)(34)(35)50) led us to test the relationship between CFTR expression and HCO 3 − secretion. We found that, unlike Cl − secretion, HCO 3 − secretion was directly proportional to CFTR expression.…”

“…CF ASL has an abnormally low pH, which reduces the activity of ASL antimicrobials and increases the viscosity of ASL. The abnormally acidic ASL pH results from loss of CFTR-mediated HCO 3 − secretion in the presence of continued H + secretion (35). CFTR is also key for HCO 3 − secretion and alkalization of ASL pH in small airways (36).…”

Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep

“…At the beginning of the year, Shah et al 65 helped our understanding of early airway infection in CF by examining the differences between CF pigs and humans that both have early airway infection and CF mice that do not. 65 CF pigs and humans both have abnormal airway acidification related to the H + secretion by the non-gastric H + /K + ATP12A which acidifies the airway surface liquid, and CF mice that have little ATP12A and secrete little H + and consequently have less airway infection suggesting that ATP12A may be an important therapeutic target for CF.…”