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Inflammatory targets of therapy in sickle cell disease

  • Amma Owusu-Ansah
    Affiliations
    Division of Hematology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA

    Center for Translational and International Hematology, Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
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  • Chibueze A. Ihunnah
    Affiliations
    Center for Translational and International Hematology, Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA

    Division of Pulmonary Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
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  • Aisha L. Walker
    Affiliations
    Center for Translational and International Hematology, Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA

    Division of Pulmonary Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
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  • Solomon F. Ofori-Acquah
    Correspondence
    Reprint requests: Solomon F. Ofori-Acquah, E 1252 BST, 200 Lothrop Street, Pittsburgh, PA 15261
    Affiliations
    Division of Hematology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA

    Center for Translational and International Hematology, Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA

    Division of Pulmonary Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
    Search for articles by this author
      Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion, and ultimately end-organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident for more than several decades that a more complex disease process contributes to the myriad of clinical complications seen in patients with SCD with inflammation playing a central role. Drugs targeting specific inflammatory pathways therefore offer an attractive therapeutic strategy to ameliorate many of the clinical events in SCD. In addition, they are useful tools to dissect the molecular and cellular mechanisms that promote individual clinical events and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti-inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only Food and Drug Administration–approved drug for SCD.

      Abbreviations:

      ICAM-1 (intercellular adhesion molecule 1), LFA-1 (leukocyte function–associated antigen 1), PECAM (platelet endothelial cell adhesion molecule), VCAM-1 (vascular cell adhesion molecule 1), VLA-4 (very late antigen-4)
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