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INFECTION

Endothelin in a Murine Model of Cerebral Malaria

Fabiana S. Machado^*,,,1, Mahalia S. Desruisseaux^,||,1,2, Nagajyothi, Richard P. Kennan^||,¶,#, Hoby P. Hetherington^¶,#, Murray Wittner, Louis M. Weiss^,||, Sunhee C. Lee, Philipp E. Scherer^||,**, Moriya Tsuji^*, and Herbert B. Tanowitz^,||

^* Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10016; Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York 10016; Department of Immunology, Duke University School of Medicine, Durham, North Carolina 27710; Department of Pathology, ^|| Department of Medicine, ^¶ Gruss Magnetic Resonance Research Center, ^# Department of Physiology and Biophysics, and ^** Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

To whom requests for reprints should be addressed at ² Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail: mdesruis{at}montefiore.org

Abstract

Cerebral malaria (CM) remains a deadly complication of Plasmodium falciparum infection, and children are at high risk of developing encephalopathy as a result of CM. This is probably a consequence of the activation of many of the inflammatory cytokines as well as the glial cells and the vascular endothelium in the brain. We have previously demonstrated that there is a striking reduction in cerebral blood flow by magnetic resonance imaging when mice are infected with Plasmodium berghei ANKA (PbA), and we now demonstrate a possible role for endothelin (ET-1) in the pathogenesis of CM. The brains of female C57BL/6 mice with PbA infection were examined at Day 5 for the expression of ET-1, endothelin converting enzyme (ECE), and the endothelin receptors A and B (ET_A and ET_B) by both reverse transcription–polymerase chain reaction (RT-PCR) and quantitative real-time PCR. ET-1 and ECE mRNA expression was markedly increased by RT-PCR in PbA-infected mice. Real-time quantitative PCR demonstrated a 3-fold increase in ET-1 (P < 0.05) and a significant increase in ET_A and ET_B expression (P < 0.05) in PbA-infected mice. Histopathology bof PbA-infected mice demonstrated a transformation in the morphology of microglial cells and clustering of these cells consistent with activation. Though the full impact of ET-1 on CM remains to be elucidated, these findings demonstrate that in the murine model, there is a significant increase in ET-1 and its components, which is associated with the vasculopathy and immunopathology of CM.

Key Words: endothelin • cerebral malaria • cerebral blood flow • magnetic resonance imaging

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