Transgenic sickle mice have vascular inflammation

John D. Belcher, Christopher J. Bryant, Julia Nguyen, Paul R. Bowlin, Miroslaw C. Kielbik, John C. Bischof, Robert P Hebbel, Gregory M. Vercellotti

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Inflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human α- and sickle β-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-SAntilles, NY-S/SAntilles (NY-S × Berk-SAntilles), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P ≤ .01) in the Berk-SAntilles, NY-S/SAntilles, and Berk-S mice, but not in the NY-S mice compared with controls. Serum amyloid P-component (SAP), an acute-phase response protein with 60% to 70% sequence homology to CRP, was elevated 8.5- to 12.1-fold (P ≤ .001) in transgenic sickle mice. Similarly, serum interleukin-6 (IL-6) was elevated 1.6- to 1.9-fold (P ≤ .05). Western blots, confirming immunohistochemical staining, showed vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet-endothelial cell adhesion molecule (PECAM) were up-regulated 3- to 5-fold (P ≤ .05) in the lungs of sickle mice. Ribonuclease protection assays (RPAs) demonstrated VCAM mRNA also was elevated in sickle mice 1.2- to 1.4-fold (P ≤ .01). Nuclear factor κB (NF-κB), a transcription factor critical for the inflammatory response, was elevated 1.9-fold (P < .006) in NY-S sickle mouse lungs. We conclude that transgenic sickle mice are good models to study vascular inflammation and the potential benefit of anti-inflammatory therapies to prevent vasoocclusion in sickle cell disease.

Original languageEnglish (US)
Pages (from-to)3953-3959
Number of pages7
JournalBlood
Volume101
Issue number10
DOIs
StatePublished - May 15 2003

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