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Am J Physiol Heart Circ Physiol (March 4, 2004). doi:10.1152/ajpheart.01150.2003
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Submitted on December 4, 2003
Accepted on February 25, 2004

Anti-inflammatory Therapy Ameliorates Leukocyte Adhesion and Microvascular Flow Abnormalities in Transgenic Sickle Mice

Dhananjay K. Kaul1*, Xiao-du Liu1, Stephana Choong2, John D. Belcher2, Gregory M. Vercellotti2, and Robert P. Hebbel2

1 Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
2 Vascular Biology Center, Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA

* To whom correspondence should be addressed. E-mail: kaul{at}aecom.yu.edu.

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 vaso-occlusion, suggesting that anti-inflammatory therapy could be beneficial in the management of this disease. Here, 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 as compared with control mice. This exaggerated inflammatory response in the transgenic mice, characterized by increased leukocyte recruitment and microvascular flow abnormalities, was significantly attenuated by anti-oxidants (allopurinol, superoxide dismutase and catalase). In contrast, control mice exhibited a muted response to antioxidant treatment. In addition, hypoxia/reoxygenation induced activation of nuclear factor- {kappa}B (NF-{kappa}B) in transgenic sickle mice, but not in control mice. In transgenic sickle mice, sulfasalazine, an inhibitor of NF-{kappa}B activation and endothelial activation, attenuated endothelial oxidant generation, as well as NF-{kappa}B activation, accompanied by a marked decrease in leukocyte adhesion and improved microvascular blood flow. Thus, targeting oxidant generation and/or NF-{kappa}B activation may constitute promising therapeutic approaches in sickle cell disease.




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