HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/1/H293    most recent 01150.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (22) Citing Articles via Google Scholar Google Scholar Articles by Kaul, D. K. Articles by Hebbel, R. P. Search for Related Content PubMed PubMed Citation Articles by Kaul, D. K. Articles by Hebbel, R. P.

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

¹Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461; and ²Vascular Biology Center, Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55454

Submitted 4 December 2003 ; accepted in final form 25 February 2004

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-B in transgenic sickle mice but not in control mice. In transgenic sickle mice, sulfasalazine, an inhibitor of NF-B activation and endothelial activation, attenuated endothelial oxidant generation, as well as NF-B activation, accompanied by a marked decrease in leukocyte adhesion and improved microvascular blood flow. Thus targeting oxidant generation and/or NF-B activation may constitute promising therapeutic approaches in sickle cell disease.

endothelium; antioxidants; sulfasalazine; sickle cell anemia

This article has been cited by other articles:

				J. D. Beckman, J. D. Belcher, J. V. Vineyard, C. Chen, J. Nguyen, M. O. Nwaneri, M. G. O'Sullivan, E. Gulbahce, R. P. Hebbel, and G. M. Vercellotti Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1243 - H1253. [Abstract] [Full Text] [PDF]

				N. Patel, C. S. Gonsalves, M. Yang, P. Malik, and V. K. Kalra Placenta growth factor induces 5-lipoxygenase-activating protein to increase leukotriene formation in sickle cell disease Blood, January 29, 2009; 113(5): 1129 - 1138. [Abstract] [Full Text] [PDF]

				D. R. Archer, J. K. Stiles, G. W. Newman, A. Quarshie, L. L. Hsu, P. Sayavongsa, J. Perry, E. M. Jackson, and J. M. Hibbert C-Reactive Protein and Interleukin-6 Are Decreased in Transgenic Sickle Cell Mice Fed a High Protein Diet J. Nutr., June 1, 2008; 138(6): 1148 - 1152. [Abstract] [Full Text] [PDF]

				L. L. Hsu, H. C. Champion, S. A. Campbell-Lee, T. J. Bivalacqua, E. A. Manci, B. A. Diwan, D. M. Schimel, A. E. Cochard, X. Wang, A. N. Schechter, et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability Blood, April 1, 2007; 109(7): 3088 - 3098. [Abstract] [Full Text] [PDF]

				M. J. Telen Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease Hematology, January 1, 2007; 2007(1): 84 - 90. [Abstract] [Full Text] [PDF]

				D. K. Kaul, X.-d. Liu, X. Zhang, L. Ma, C. J. C. Hsia, and R. L. Nagel Inhibition of sickle red cell adhesion and vasoocclusion in the microcirculation by antioxidants Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H167 - H175. [Abstract] [Full Text] [PDF]

				J. D. Belcher, H. Mahaseth, T. E. Welch, A. E. Vilback, K. M. Sonbol, V. S. Kalambur, P. R. Bowlin, J. C. Bischof, R. P. Hebbel, and G. M. Vercellotti Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2715 - H2725. [Abstract] [Full Text] [PDF]

				G. R. Buchanan, M. R. DeBaun, C. T. Quinn, and M. H. Steinberg Sickle Cell Disease Hematology, January 1, 2004; 2004(1): 35 - 47. [Abstract] [Full Text] [PDF]