Journal Article


Shane J O'Neill
Noel G McElvaney
Clifford Taggart
Raymond J Coakley



humans metabolism bronchoalveolar lavage fluid sodium hydrogen antiporter cystic fibrosis vacuolar proton translocating atpases chemistry pathology chlorides neutrophils body fluids inflammation cytosol pharmacology epithelium physiology ion transport amiloride escherichia coli apoptosis cytology drug effects oxidation reduction protons hydrogen ion concentration zinc chloride zinc compounds

Cytosolic pH and the inflammatory microenvironment modulate cell death in human neutrophils after phagocytosis. (2002)

Abstract Following phagocytosis in vivo, acidification of extracellular pH (pH(o)) and intracellular metabolic acid generation contribute to cytosolic proton loading in neutrophils. Cytosolic pH (pH(i)) affects neutrophil function, although its regulation is incompletely understood. Its effect on mechanisms of neutrophil death is also uncertain. Thus, we investigated pH(i) 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 pH(i) 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) pH(i) regulation was evident primarily at lower bacterial densities. At physiologic pH(o), lower pathogen-to-phagocyte ratios alkalinized pH(i) and inhibited apoptosis, whereas higher ratios acidified pH(i) (despite proton extrusive mechanisms) and promoted apoptosis. Necrosis was induced by high-density bacterial exposure at reduced pH(o). Following phagocytosis, targeted inhibition of NHEs, proton conductance channels, or V-ATPases (amiloride, ZnCl(2), or bafilomycin, respectively) moderately hyperacidified pH(i) and accelerated apoptosis. However, in combination they profoundly acidified pH(i) and induced necrosis. Proinflammatory mediators in vivo might affect both pH(i) 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 pH(i) and suppressed apoptosis at physiologic pH(o), but failed to prevent necrosis following phagocytosis at low pH(o). Thus, a precarious balance between cytosolic proton loading and extrusion after phagocytosis dictates the mode of neutrophil cell death. pH(i)/pH(o) might be therapeutically targeted to limit neutrophil necrosis and protect host tissues during necrotizing infections.
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Full list of authors on original publication

Shane J O'Neill, Noel G McElvaney, Clifford Taggart, Raymond J Coakley

Experts in our system

Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 84
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
Clifford C Taggart
Royal College of Surgeons in Ireland
Total Publications: 54