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Am J Physiol Lung Cell Mol Physiol 279: L66-L74, 2000;
1040-0605/00 $5.00
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Vol. 279, Issue 1, L66-L74, July 2000

Altered intracellular pH regulation in neutrophils from patients with cystic fibrosis

Raymond J. Coakley1, Clifford Taggart1, Gerry Canny2, Peter Greally2, Shane J. O'Neill1, and Noel G. McElvaney1

1 Pulmonary Research Division, Beaumont Hospital, Dublin 9; and 2 Our Lady's Hospital for Sick Children, Crumlin, Dublin 10, Ireland

Cystic fibrosis (CF) is a condition characterized by neutrophil-mediated lung damage and bacterial colonization. The physiological basis for reported functional alterations in CF neutrophils, including increased release of neutrophil elastase, myeloperoxidase, and oxidants, is unknown. These processes are, however, regulated by intracellular pH (pHi). We demonstrate here that pHi regulation is altered in neutrophils from CF patients. Although resting pHi is similar, pHi after acid loading and activation (N-formyl-methionyl-leucyl-phenylalanine and phorbol 12-myristate 13-acetate) is more acidic in CF cells than in normal cells. Furthermore, patients with non-CF-related bronchiectasis handle acid loading and activation in a fashion similar to subjects with normal neutrophils, suggesting that chronic pulmonary inflammation alone does not explain the difference in pHi. This is further supported by data showing that normal neutrophils exposed to the CF pulmonary milieu respond by increasing pHi as opposed to decreasing pHi as seen in activated CF neutrophils. These pHi differences in activated or acid-loaded CF neutrophils are abrogated by ZnCl2 but not by amiloride and bafilomycin A1, suggesting that passive proton conductance is abnormal in CF. In addition, DIDS, which inhibits HCO3-/Cl- exchange, causes alkalinization of control but not of CF neutrophils, suggesting that anion transport is also abnormal in CF neutrophils. In summary, we have shown that pHi regulation in CF neutrophils is intrinsically abnormal, potentially contributing to the pulmonary manifestations of the condition.

human; inflammation; acid load; anion exchanger; passive proton conductance


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