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Inhibition of neutrophil oxidative metabolism by lysosomotropic weak bases
B Styrt and MS Klempner
Maintenance of an acidic intralysosomal compartment may be relevant to
multiple aspects of neutrophil function. The effect of lysosomal
alkalinization on the neutrophil respiratory burst was studied by measuring
cytochrome c reduction in response to soluble stimuli in the presence of
lysosomotropic weak bases. The weak bases chloroquine, ammonium chloride,
methylamine, and clindamycin all raised the intralysosomal pH and inhibited
neutrophil oxidative metabolism at concentrations ranging from 0.1 to 100
mmol/L. Inhibition was dose dependent for each base and correlated
significantly with the degree of lysosomal alkalinization. Concentrations
that did not alkalinize the lysosome did not inhibit the respiratory burst.
Inhibition by weak bases was seen when oxidative metabolism was stimulated
by phorbol myristate acetate, calcium ionophore A23187,
formyl-methionyl-leucyl- phenylalanine, opsonized zymosan, or sodium
fluoride. Increasing the stimulus concentration (from 5 ng/mL to 5
micrograms/mL phorbol myristate acetate and from 0.5 to 1 mumol/L A23187)
diminished or abolished inhibition by weak bases. Washing the cells after
incubation with bases and before stimulation substantially reversed the
inhibition. None of the bases impaired detection of superoxide in a
cell-free xanthine-xanthine oxidase assay. Other indexes of oxidative
metabolism, including oxygen consumption and hydrogen peroxide release,
were also inhibited by weak bases. Analysis of particulate NADPH oxidase
activity from neutrophils stimulated in the presence of bases suggested
that these cells assemble a subnormal amount of an enzyme complex with
normal kinetic characteristics. Lysosomotropic weak bases alkalinized the
neutrophil lysosome and produced inhibition of oxidative metabolism that
was dose related, was not stimulus specific, and was largely reversed by
washing the cells before stimulation. A possible explanation would be
altered assembly of the enzyme complex involved in respiratory burst
activation as a consequence of impaired granule/plasma membrane fusion in
the presence of diminished transmembrane pH gradients.
Volume 67,
Issue 2,
pp. 334-342,
02/01/1986
Copyright © 1986 by The American Society of Hematology
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