Abstract
Background and Novel Aspect of this Work: In the light of previous findings that inflammation predisposes to intercellular adhesion and microvascular occlusion in sickle cell disease (SCD), this study investigated the relationship between the number of vaso-occlusive events in SCD, plasma levels of the pro-inflammatory molecules 12-Hydroxyeicosatetraenoic acid (12-HETE), TNF-α and IL-1β; and single nucleotide polymorphisms (SNPs) in the gene 12-Lipooxygenase (ALOX-12), which encodes the enzyme 12-Lipoxygenase that catalyzes the biosynthesis of 12-HETE. Objective: To evaluate the relationship between vaso-occlusion in SCD and plasma concentrations of 12-HETE, TNF-α, and IL-1β; and single nucleotide polymorphisms (SNPs) in ALOX-12 gene. Participants and Methods: In 50 HbSS patients, the numbers of vaso-occlusive crisis requiring hospital treatment in the previous 1 year and the vaso-occlusive complications of SCD developed to date (e.g stroke) were added to obtain the vaso-occlusive events (VOE) score. In the HbSS patients and 30 healthy sibling control persons, plasma concentrations of 12-HETE, TNF-α and IL-1β were measured by ELISA, the ALOX12 SNPs rs2073438 and rs1126667 detected by DNA sequencing, and the accrued data statistically analyzed. Results: Compared to SCD patients with VOE score 0–1, those with scores ≥3 had higher plasma levels of 12-HETE (p < 0.0001) and TNF-α (p = 0.19), but not IL-1β (p = 0.27). VOE score showed strong direct correlation with plasma level of 12-HETE (r = 0.65, p < 0.0001), but not with TNF-α nor IL-1β. Neither VOE score nor plasma concentration of 12-HETE showed any relationship with the ALOX12 SNPs rs2073438 and rs1126667. Conclusion: The strong direct correlation of VOE score with plasma concentration of 12-HETE suggests that the clinical relevance of this pro-inflammatory molecule in SCD-associated vaso-occlusion needs to be evaluated in further studies.
Highlights
Sickle cell disease (SCD) is the most common inherited blood condition in humans. (Davies and Brozovic, 1989; Sergeant, 1997; Escoffery and Suzanne, 1998; Wheatherall and Clegg, 2001; Okpala, 2004a)
Activated endothelial cells increase their expression of the ligands for adhesion molecules on leucocytes, erythrocytes and platelets; such as selectins, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). (Carlos and Harlan, 1994; Springer, 1994; Osarogiagbon, 2001)
These findings suggest that 12HETE could have a role in the pathogenesis of SCD-associated vaso-occlusion
Summary
Sickle cell disease (SCD) is the most common inherited blood condition in humans. (Davies and Brozovic, 1989; Sergeant, 1997; Escoffery and Suzanne, 1998; Wheatherall and Clegg, 2001; Okpala, 2004a). Previous research by Setty and coinvestigators showed that, relative to control individuals, plasma 12-HETE levels are increased in SCD patients in steady state, rising further during vaso-occlusive crises; and that this pro-inflammatory molecule enhances both basal and hypoxia-induced expression of vascular-endothelial cell adhesion molecule (VICAM-1) which mediates sickle erythrocyte adherence to blood vessel endothelium (Setty et al, 1998). These findings suggest that 12HETE could have a role in the pathogenesis of SCD-associated vaso-occlusion. Work: In the light of previous findings that inflammation predisposes to intercellular adhesion and microvascular occlusion in sickle cell disease (SCD), this study investigated the relationship between the number of vasoocclusive events in SCD, plasma levels of the pro-inflammatory molecules 12Hydroxyeicosatetraenoic acid (12-HETE), TNF-α and IL-1β; and single nucleotide polymorphisms (SNPs) in the gene 12-Lipooxygenase (ALOX-12), which encodes the enzyme 12-Lipoxygenase that catalyzes the biosynthesis of 12-HETE
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