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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Coakley, R. J. Articles by O'Neill, S. J. Search for Related Content PubMed PubMed Citation Articles by Coakley, R. J. Articles by O'Neill, S. J. Related Collections Phagocytes Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Morgan, M. Capasso, B. Musset, V. V. Cherny, E. Rios, M. J. S. Dyer, and T. E. DeCoursey Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis PNAS, October 20, 2009; 106(42): 18022 - 18027. [Abstract] [Full Text] [PDF] D G Downey, S C Bell, and J S Elborn Neutrophils in cystic fibrosis Thorax, January 1, 2009; 64(1): 81 - 88. [Abstract] [Full Text] [PDF] F. M. Lasorsa, P. Pinton, L. Palmieri, P. Scarcia, H. Rottensteiner, R. Rizzuto, and F. Palmieri Peroxisomes as Novel Players in Cell Calcium Homeostasis J. Biol. Chem., May 30, 2008; 283(22): 15300 - 15308. [Abstract] [Full Text] [PDF] L. R. Prince, S. M. Bianchi, K. M. Vaughan, M. A. Bewley, H. M. Marriott, S. R. Walmsley, G. W. Taylor, D. J. Buttle, I. Sabroe, D. H. Dockrell, et al. Subversion of a Lysosomal Pathway Regulating Neutrophil Apoptosis by a Major Bacterial Toxin, Pyocyanin J. Immunol., March 1, 2008; 180(5): 3502 - 3511. [Abstract] [Full Text] [PDF] B. E. Steinberg and S. Grinstein Unconventional Roles of the NADPH Oxidase: Signaling, Ion Homeostasis, and Cell Death Sci. Signal., March 27, 2007; 2007(379): pe11 - pe11. [Abstract] [Full Text] [PDF] J. L. Bankers-Fulbright, G. M. Kephart, K. R. Bartemes, H. Kita, and S. M. O'Grady Platelet-activating factor stimulates cytoplasmic alkalinization and granule acidification in human eosinophils J. Cell Sci., November 15, 2004; 117(24): 5749 - 5757. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020