A Nod and a WNK (Kinase): Understanding Airway Surface Liquid pH

Cystic fi brosis (CF) is a progressive disease with high morbidity and mortality caused by mutations in the CFTR (CF Transmembrane Conductance Regulator) gene encoding for a cAMP-activated anionic channel, known to mainly secrete chloride (Cl 2 ) and bicarbonate (HCO 3 2 ) at the apical surface of epithelia. A key pathophysiological feature of cystic fi brosis is a reduction in HCO 3 2 secretion, which in turn acidi fi es the airway surface liquid (ASL) acting as a thin fl uid barrier on the luminal side of airway epithelia. Recent studies have revealed that there is reduced antimicrobial activity in CF ASL as a result of the decreased pH (1, 2), a defect that can be rescued with ASL alkalinization (2, 3). To date, the mechanisms regulating ASL pH remain poorly understood. Given the role pH homeostasis plays in CF disease pathogenesis, understanding the mechanisms that regulate HCO 3 2 secretion in human airways may reveal new therapeutic targets in CF, including for those CFTR mutations where highly effective CFTR modulator therapy (HEMT) is not available.

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