Rehman T, Karp PH, Tan P, et al. - Inflammation plays an important role in the regulation of HCO3– secretion in cystic fibrosis (CF) airways. As a result, the authors explain previous observations that ASL pH rises after birth and show that, for comparable levels of inflammation, the pH of CF ASL is abnormally acidic. Such findings also indicate that a non-cell-autonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.

• In order to learn whether inflammation alters CF ASL pH, they treated CF epithelia with TNF-α and IL-17 (TNF-α+IL-17), 2 inflammatory cytokines that are elevated in CF airways.

• TNF-α+IL-17 increased ASL pH significantly by upregulating pendrin, an apical Cl–/HCO3– exchanger.

• Furthermore, when CF epithelia were exposed to TNF-α+IL-17, clinically approved CFTR modulators alkalinized ASL pH even more.

• In vivo studies demonstrated a favourable connection between airway inflammation and CFTR modulator–induced improvement in lung function, as predicted by these findings.