In
sickle cell disease, deoxygenation of intra-erythrocytic
hemoglobin S leads to
hemoglobin polymerization, erythrocyte rigidity,
hemolysis, and microvascular occlusion.
Ischemia-reperfusion injury, plasma
hemoglobin-mediated
nitric oxide consumption, and
free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state
sickle cell disease (10 patients treated and 17 patients untreated with
hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with
sickle cell disease demonstrated differential gene expression of 112 genes involved in
heme metabolism, cell-cycle regulation,
antioxidant and stress responses,
inflammation, and angiogenesis. Inducible
heme oxygenase-1 and downstream
proteins biliverdin reductase and p21, a
cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of
atherosclerosis in patients with
sickle cell disease despite endothelial dysfunction and vascular
inflammation.
Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such
therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense
oxidant and inflammatory nature of steady-state
sickle cell disease and provides insight into the broad compensatory responses to
vascular injury.