Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia
Abstract
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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Selectins interact with sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other interactions, ultimately contributing to vascular occlusion and sickle cell crisis.
“selectins interact with sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other interactions (924 -927) ultimately contributing to vascular occlusion and ' sickle cell crisis ' (928).”
From Biological roles of glycans (2017) · cites this paper as [924]
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References 59 · Cited by 110
- Authors
- Benkerrou, M., Delarche, C., Brahimi, L., Fay, M., Vilmer, E., Elion, J., Gougerot-Pocidalo, M.-A., & Elbim, C.
- Affiliations
- Inserm (FR)
- 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.
- ORCID
- Benkerrou, Malika
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2002-04-01
- Volume
- 99
- Issue
- 7
- Pages
- 2297-2303
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2080441809
- Cited by
- 110
- References
- 59
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 8 · 2015: 7 · 2014: 3 · 2013: 4 · 2012: 1
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- sickle cell disease, hydroxyurea, neutrophils, L-selectin, soluble E-selectin, soluble L-selectin, hydrogen peroxide production, respiratory burst, neutrophil activation, vasoocclusion, fMLP stimulation, TNF-α, endothelial activation, adhesion molecules, children
- MeSH terms
- Adolescent, Anemia, Sickle Cell, Antisickling Agents, Child, Child, Preschool, Hemoglobin, Sickle, Humans, Hydrogen Peroxide, Hydroxyurea, Infant, Newborn, Leukocyte Count, Neutrophils, Platelet Count, Tumor Necrosis Factor-alpha, Cell Adhesion Molecules, Cytokines, Africa South of the Sahara, L-Selectin, Black People
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