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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3383-3391
PHAGOCYTES
Cytosolic pH and the inflammatory microenvironment modulate
cell death in human neutrophils after phagocytosis
Raymond J. Coakley,
Clifford Taggart,
Noel G. McElvaney, and
Shane J. O'Neill
From the Division of Respiratory Research, Department
of Medicine, Royal College of Surgeons in Ireland Education and
Research Center, Beaumont Hospital, Dublin, Republic of Ireland.
Following phagocytosis in vivo, acidification of extracellular pH
(pHo) and intracellular metabolic acid generation
contribute to cytosolic proton loading in neutrophils. Cytosolic pH
(pHi) affects neutrophil function, although its
regulation is incompletely understood. Its effect on mechanisms of
neutrophil death is also uncertain. Thus, we investigated
pHi regulation in Escherichia coli-exposed
neutrophils, at various pathogen-to-phagocyte ratios (0:1-50:1), under conditions simulating the inflammatory milieu in vivo and correlated pHi changes with mechanisms of
neutrophil death. Following phagocytosis, proton extrusion was
dominated early by passive proton conductance channels, and later by
Na+/H+ exchange (NHE).
H+-translocating adenosine triphosphatase (V-ATPase)
pHi regulation was evident primarily at lower bacterial
densities. At physiologic pHo, lower pathogen-to-phagocyte
ratios alkalinized pHi and inhibited apoptosis, whereas
higher ratios acidified pHi (despite proton extrusive
mechanisms) and promoted apoptosis. Necrosis was induced by
high-density bacterial exposure at reduced pHo. Following
phagocytosis, targeted inhibition of NHEs, proton conductance channels,
or V-ATPases (amiloride, ZnCl2, or bafilomycin,
respectively) moderately hyperacidified pHi and accelerated
apoptosis. However, in combination they profoundly acidified
pHi and induced necrosis. Proinflammatory mediators in vivo
might affect both pHi regulation and cell death, so we tested the effects of bronchoalveolar lavage (BAL) fluid from patients
with cystic fibrosis (CF) and healthy subjects. Only CF BAL
fluid alkalinized pHi and suppressed apoptosis at
physiologic pHo, but failed to prevent necrosis following
phagocytosis at low pHo. Thus, a precarious balance between
cytosolic proton loading and extrusion after phagocytosis dictates the
mode of neutrophil cell death. pHi/pHo might be
therapeutically targeted to limit neutrophil necrosis and protect
host tissues during necrotizing infections.
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