Cystic fibrosis (CF) is a condition characterized by neutrophil-mediated lu
ng damage and bacterial colonization. The physiological basis for reported
functional alterations in CF neutrophils, including increased release of ne
utrophil elastase, myeloperoxidase, and oxidants, is unknown. These process
es are, however, regulated by intracellular pH (pH(i)). We demonstrate here
that pH(i) regulation is altered in neutrophils from CF patients. Although
resting pH(i) is similar, pH(i) after acid loading and activation (N-formy
l-methionyl-leucyl-phenylalanine and phorbol 12-myristate 13-acetate) is mo
re acidic in CF cells than in normal cells. Furthermore, patients with non-
CF-related bronchiectasis handle acid loading and activation in a fashion s
imilar to subjects with normal neutrophils, suggesting that chronic pulmona
ry inflammation alone does not explain the difference in pH(i). This is fur
ther supported by data showing that normal neutrophils exposed to the CF pu
lmonary milieu respond by increasing pH(i) as opposed to decreasing pH(i) a
s seen in activated CF neutrophils. These pH(i) differences in activated or
acid-loaded CF neutrophils are abrogated by ZnCl2 but not by amiloride and
bafilomycin A(1), suggesting that passive proton conductance is abnormal i
n CF. In addition, DIDS, which inhibits HCO3-/Cl- exchange, causes alkalini
zation of control but not of CF neutrophils, suggesting that anion transpor
t is also abnormal in CF neutrophils. In summary, we have shown that pH(i)
regulation in CF neutrophils is intrinsically abnormal, potentially contrib
uting to the pulmonary manifestations of the condition.