Endothelin in a murine model of cerebral malaria.
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.
Machado
Fabiana S
FS
Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10016, USA.
Desruisseaux
Mahalia S
MS
Nagajyothi
Kennan
Richard P
RP
Hetherington
Hoby P
HP
Wittner
Murray
M
Weiss
Louis M
LM
Lee
Sunhee C
SC
Scherer
Philipp E
PE
Tsuji
Moriya
M
Tanowitz
Herbert B
HB
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D007274:Injections, Intraperitoneal; D016779:Malaria, Cerebral / Q000209:etiology / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000473:pathology; D018512:Parasitemia; D010962:Plasmodium berghei; D012333:RNA, Messenger / Q000032:analysis; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes