Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice

Dhananjay K. Kaul, Xiao Du Liu, Stephana Choong, John D Belcher, Gregory M Vercellotti, Robert P Hebbel

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

In sickle cell disease, inflammatory activation of vascular endothelium and increased leukocyte-endothelium interaction may play an important role in the occurrence of vasoocclusion. In sickle mouse models, inflammatory stimuli (e.g., hypoxia-reoxygenation and cytokines) result in increased leukocyte recruitment and can initiate vasoocclusion, suggesting that anti-inflammatory therapy could be beneficial in management of this disease. We have tested the hypothesis that inhibition of endothelial activation in a transgenic mouse model by anti-inflammatory agents would lead to reduced leukocyte recruitment and improved microvascular blood flow in vivo. In transgenic sickle mice, hypoxia-reoxygenation resulted in greater endothelial oxidant production than in control mice. This exaggerated inflammatory response in transgenic mice, characterized by increased leukocyte recruitment and microvascular flow abnormalities, was significantly attenuated by antioxidants (allopurinol, SOD, and catalase). In contrast, control mice exhibited a muted response to antioxidant treatment. In addition, hypoxia-reoxygenation induced activation of NF-κB in transgenic sickle mice but not in control mice. In transgenic sickle mice, sulfasalazine, an inhibitor of NF-κB activation and endothelial activation, attenuated endothelial oxidant generation, as well as NF-κB activation, accompanied by a marked decrease in leukocyte adhesion and improved microvascular blood flow. Thus targeting oxidant generation and/or NF-κB activation may constitute promising therapeutic approaches in sickle cell disease.

Original languageEnglish (US)
Pages (from-to)H293-H301
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number1 56-1
DOIs
StatePublished - Jul 2004

Keywords

  • Antioxidants
  • Endothelium
  • Sickle cell anemia
  • Sulfasalazine

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