Eicosanoids in sickle cell disease: Potential relevance of neutrophil leukotriene B₄ to disease pathophysiology

Neutrophil activation with the release of intracellular granule contents has been observed in sickle cell disease (SCD). Because leukotriene B₄(LTB₄), a 5-lipoxy-genase metabolite of arachidonic acid in neutrophils, is a chemoattractant and enhances neutrophil adhesion to endothelium, we assessed plasma levels of this metabolite in controls (n = 9) and individuals with SCD, SS genotype, both in basal "steady state" (n = 37) and during episodes of vaso-occlusion (n = 10) and acute chest syndrome (n = 5). Thirteen patients with SCD, SC genotype, in steady state were also studied. Although no significant differences were noted between the control (136 ± 32 fmol/mL) and SC genotype (177 ± 83 fmol/mL, P> .15), LTB₄ levels were markedly increased in patients with SS genotype in basal steady state (207 ± 64 fmol/mL, P < .003) compared with those in controls. Values were further increased during vaso-occlusion (264 ± 94 fmol/mL) and acute chest syndrome (363 ± 124 fmol/mL). These levels were significantly different from measurements taken during steady state (P < .04 and P < .0001, respectively). No correlation was noted between LTB₄ level and total white cell or neutrophil count. Additionally, the significant correlation noted in SCD between increased levels of plasma LTB₄ and soluble L-selectin (P < .03) reflects neutrophil activation. We also observed an effect of LTB₄ on red cell-endothelial adhesion at concentrations that appear clinically relevant (1-10 pmol/mL) with concomitant up-regulation of mRNA for the endothelial vitronectin receptor. These properties of LTB₄ are relevant to disease pathophysiology, providing further evidence of the contribution of the neutrophil to the proinflammatory and proadhesive phenotype in SCD.