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Prepublished online as a Blood First Edition Paper on January 23, 2003; DOI 10.1182/blood-2002-10-3313.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3953-3959
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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, and
Gregory M. Vercellotti
From the Department of Medicine, Division of
Hematology, Oncology and Transplantation, and Department of Mechanical
Engineering, University of Minnesota, Minneapolis.
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  - and sickle  -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  B (NF-B), 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 vaso-occlusion in sickle cell disease.
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