Without CFTR-mediated HCO3secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this timecourse matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNFα and IL-17, two inflammatory cytokines that are elevated in CF airways. TNFα+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl -/HCO3exchanger. Moreover, when CF epithelia were exposed to TNFα+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator-induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cellautonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.

Recent work shows that people with cystic fibrosis (CF) and chronic lung infections generally remain persistently infected after treatment with drugs that target the CF physiological defect (called CFTR modulators). However, changes produced by modulators could increase antibiotic efficacy.

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