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Effect of age on second messenger generation in neutrophils
DA Lipschitz, KB Udupa, SR Indelicato and M Das
Department of Medicine, University of Arkansas for Medical Sciences, Little
Rock.
Neutrophils from healthy elderly donors generate significantly less
diacylglycerol (DAG) and inositol triphosphate (IP3) than neutrophils from
young donors, following stimulation by the chemotactic peptide,
formyl-methionyl-leucylphenylalanine (FMLP). The defect in signal
transduction occurred at a point proximal to the generation of IP3 and DAG,
since the reduction in FMLP-induced superoxide generation was corrected if
the intervening signal transduction steps were bypassed, either by priming
with a substimulatory dose (1.62 nmol/L) of phorbol myristate acetate
(PMA), by ionophore elevation of cytosolic calcium, or by using a
stimulatory dose of PMA (1.62 mumol/L). FMLP receptor number and affinity
were unaffected by aging. On FMLP activation, neutrophils from old, as
compared with young, volunteers showed significantly greater and more
long-lasting decreases in the concentrations of phosphatidylinositol (PI),
phosphatidylinositol 4- monophosphate (PIP), and phosphatidylinositol
4,5-bisphosphate (PIP2). This indicates a reduction with age in the
metabolically active precursor pools responsible for the generation of IP3
and DAG. In contrast, aging had little effect on the production of
phosphatidic acid (PA), which has recently been suggested to serve as a
major activator of the NADPH oxidase. This may explain why the decrease in
IP3 and DAG production was not accompanied by a comparable decrement in
superoxide generation, which was only 17% lower in the old than in young
donor neutrophils. Thus, aging is associated with reductions in the
concentration of critically important phosphoinositides, resulting in
diminution in the ability to produce key second messengers. Although the
aged neutrophil is largely able to compensate for the decrements in signal
transduction, its reserve capacity is compromised, making it particularly
vulnerable to external insults that also impair function.
Volume 78,
Issue 5,
pp. 1347-1354,
09/01/1991
Copyright © 1991 by The American Society of Hematology
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