Transgenic sickle mice have vascular inflammation

Area of Science:

• Hematology
• Immunology
• Molecular Biology

Background:

• Inflammation is implicated in sickle cell disease vaso-occlusion.
• Sickle cell patients display elevated white blood cell counts, C-reactive protein (CRP), cytokines, and adhesion molecules.
• Circulating endothelial cells, leukocytes, and platelets are activated in sickle cell disease.

Purpose of the Study:

• To evaluate transgenic mouse models for their ability to replicate the inflammatory response observed in human sickle cell disease.
• To establish suitable animal models for investigating vascular inflammation and potential anti-inflammatory therapies in sickle cell disease.

Main Methods:

• Four transgenic mouse models expressing human alpha- and sickle beta-globin genes were utilized.
• Measurements included white blood cell counts, serum amyloid P-component (SAP), interleukin-6 (IL-6), and Western blot analysis for adhesion molecules (VCAM, ICAM, PECAM).
• Ribonuclease protection assays (RPAs) assessed VCAM mRNA levels, and nuclear factor kappaB (NF-kappaB) was quantified.

Main Results:

• Transgenic sickle mice (Berk-S(Antilles), NY-S/S(Antilles), Berk-S) showed elevated white blood cell counts (1.4- to 2.1-fold).
• Serum SAP (8.5- to 12.1-fold) and IL-6 (1.6- to 1.9-fold) were significantly increased in transgenic sickle mice.
• Adhesion molecules (VCAM, ICAM, PECAM) and VCAM mRNA were upregulated in the lungs of sickle mice, with elevated NF-kappaB (1.9-fold).

Conclusions:

• Transgenic sickle mouse models effectively mimic the vascular inflammation characteristic of human sickle cell disease.
• These models provide a valuable platform for studying the efficacy of anti-inflammatory therapies aimed at preventing vaso-occlusion.