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Raised Neutrophil Phospholipase A2 Activity and Defective
Priming of NADPH Oxidase and Phospholipase A2 in Sickle
Cell Disease
Elahe Mollapour,
John B. Porter,
Richard Kaczmarski,
David C. Linch, and
Pamela J. Roberts
From the Departments of Haematology, University College London
Medical School, London; and the North Middlesex Hospital, London,
UK.
Intermittent painful crises due to vasoocclusion are the major
clinical manifestation of sickle cell disease (SCD), but subclinical episodes may also occur. There is sparse evidence for the involvement of neutrophils in the pathophysiology of SCD, but production of cytokines by the damaged endothelium might influence neutrophil function and modulate responses to subsequent cytokine exposure. In
addition, the activation of neutrophils in the microcirculation could
itself exacerbate vasoocclusion. To test whether neutrophil inflammatory responses were altered in SCD, neutrophil phospholipase A2 and NADPH oxidase activity in response to in vitro
priming by granulocyte-macrophage colony-stimulating factor (GM-CSF)
and tumor necrosis factor- (TNF-) were measured both during and between painful crises. Resting levels of neutrophil phospholipase A2 activity in steady-state SCD (4.0% ± 0.5% of total
cell radioactivity) were raised relative to control values
(2.0% ± 0.2%, n = 10, P = .008). There was no
defect of agonist-stimulated phospholipase A2 or NADPH
oxidase activity in steady-state SCD; however, the ability of
phospholipase A2 to respond to priming with GM-CSF was
attenuated to 63% ± 17% of control values (n = 10,
P = .04). Similarly, neutrophil NADPH oxidase activity
after priming with GM-CSF and TNF- was, respectively, 65% ± 11%
(n = 7, P = .03) and 57% ± 7% of control (n = 10, P = .007) in steady-state disease, and was
further reduced during painful vasoocclusive crises to 34% ± 9% and
25% ± 3% of control for GM-CSF and TNF-, respectively. These
data were not explained by poor splenic function or any racial factor,
as normal cytokine responses were seen in splenectomized patients in
remission from Hodgkin's disease and in healthy Afro-Caribbean
subjects. Abnormal neutrophil cytokine priming responses were not
observed in either patients with rheumatoid arthritis or
iron-deficiency anemia. Our findings are indicative of an ongoing
inflammatory state in SCD between painful crises involving neutrophil
activation and an abnormality of cytokine-regulated neutrophil
function, which may compromise the host defenses against certain
microorganisms.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3423-3429
© 1998 by The American Society of Hematology.
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