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Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease.

Abstract
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.
AuthorsMaria L Jison, Peter J Munson, Jennifer J Barb, Anthony F Suffredini, Shefali Talwar, Carolea Logun, Nalini Raghavachari, John H Beigel, James H Shelhamer, Robert L Danner, Mark T Gladwin
JournalBlood (Blood) Vol. 104 Issue 1 Pg. 270-80 (Jul 01 2004) ISSN: 0006-4971 [Print] United States
PMID15031206 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Membrane Proteins
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Cyclin-Dependent Kinases
Topics
  • Adult
  • Anemia, Sickle Cell (blood, genetics, pathology)
  • Case-Control Studies
  • Cluster Analysis
  • Cyclin-Dependent Kinases (genetics, metabolism)
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Heme Oxygenase (Decyclizing) (genetics, metabolism)
  • Heme Oxygenase-1
  • Hemolysis
  • Humans
  • Inflammation (blood)
  • Leukocyte Count
  • Leukocytes, Mononuclear (cytology, metabolism)
  • Male
  • Membrane Proteins
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Oxidative Stress (physiology)

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