Hydroxyurea attenuates activated neutrophil-mediated sickle erythrocyte membrane phosphatidylserine exposure and adhesion to pulmonary vascular endothelium.
Activated neutrophils increase erythrocyte phosphatidylserine (PS) exposure. PS-exposed sickle red blood cells (SSRBCs) are more adhesive to vascular endothelium than non-PS-exposed cells. An increase in SSRBC fetal hemoglobin (HbF) concentration has been associated with improved rheology and decreased numbers of vasoocclusive episodes. This study examined the effects of HbF, PS-exposed SSRBCs, and chronic hydroxyurea (HU) treatment on activated neutrophil-mediated SSRBC retention/adherence in isolated-perfused rat lungs. Lungs were perfused with erythrocyte suspensions from 1) individuals homozygous for hemoglobin S with 0-7% HbF (SS), 2) with > or =8% HbF (SS + F), and 3) individuals homozygous for hemoglobin S treated with HU therapy for > or =1 yr (SS + HU). Retention of SSRBCs from the SS + HU group was significantly less than that seen in both the SS and SS + F groups. No difference was observed between the SS and SS + F groups. The percentage of HbF and F-cells did not differ between the SS + F and SS + HU groups. At baseline, the proportion of PS-exposed SSRBCs was not different between the SS and SS + HU groups. However, SSRBC treatment with activated neutrophil supernatant caused a twofold increase in PS-exposed SSRBCs in the SS control and no change in the SS + HU group. We conclude that 1) HU attenuates SSRBC retention/adherence in the pulmonary circulation seen in response neutrophil activation, 2) HU stabilizes SSRBC membrane PS, and 3) HU attenuation SSRBC retention/adherence in the pulmonary circulation occurs through a mechanism(s) independent of HbF.
Haynes
Johnson
J
Comprehensive Sickle Cell Center, Department of Medicine, University of South Alabama Medical Center, 2451 Fillingim Street, Mobile, AL 36617, USA. jhaynes@usouthal.edu
Obiako
Boniface
B
Hester
Raymond B
RB
Baliga
B Surendra
BS
Stevens
Troy
T
D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D008297:Male; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D010477:Perfusion; D010718:Phosphatidylserines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000986:Antisickling Agents; D006451:Hemoglobin, Sickle; D018836:Inflammation Mediators; D010718:Phosphatidylserines; D005319:Fetal Hemoglobin; D006918:Hydroxyurea