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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2297-2303
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Hydroxyurea corrects the dysregulated L-selectin expression and
increased H2O2 production of polymorphonuclear
neutrophils from patients with sickle cell anemia
Malika Benkerrou,
Charlotte Delarche,
Lamia Brahimi,
Michèle Fay,
Etienne Vilmer,
Jacques Elion,
Marie-Anne Gougerot-Pocidalo, and
Carole Elbim
From INSERM U479 and Service d'Immunologie et
d'Hématologie, CHU X Bichat; and Centre de la
Drépanocytose and INSERM U458, Hôpital Robert-Debré;
both of Paris, France.
Impaired polymorphonuclear neutrophil (PMN) functions during sickle
cell anemia (SCA) may have a pathogenic role in the onset of
vasoocclusive events. We used flow cytometry to study, in whole blood,
the adhesion molecule expression and respiratory burst of PMNs from
children with SCA. Three different clinical groups were studied: (1)
patients with no history of vasoocclusive events (n = 15); (2)
patients with a history of vasoocclusive events (n = 17); and (3)
patients receiving hydroxyurea therapy for severe vasoocclusive events
(n = 9). Unstimulated PMNs showed decreased L selectin expression and
increased H2O2 production whatever the severity
of the disease, reflecting PMN activation. This could contribute to
endothelial activation reflected by abnormal plasma levels of soluble
adhesion molecules (soluble intercellular adhesion molecule-1, sE
selectin, and sL selectin). After stimulation with bacterial N-formyl
peptides (N-formyl-methionyl-leucyl-phenylalanine [fMLP]), PMNs from
untreated patients with a history of vasoocclusive events showed
dysregulated L selectin shedding and increased
H2O2 production. Furthermore, in these
patients, tumor necrosis factor priming followed by fMLP stimulation
induced an H2O2 production significantly higher
than in the other patient groups and controls. These impairments could
immobilize PMNs on the endothelium, thereby inducing reduced blood flow
and fostering microvascular occlusion and vascular damage. In contrast,
children treated with hydroxyurea showed near-normal basal and
poststimulation H2O2 production as well as
normal L selectin shedding after stimulation but no change in plasma
levels of soluble adhesion molecules. To our knowledge, this is the
first report showing major qualitative changes of PMN abnormalities
upon hydroxyurea treatment in SCA patients. This strongly suggests that
PMNs are a primary target of this drug.
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