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.