Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 186, Issue 11, Pages 2957-2969Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.07.020
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Funding
- NIH Interhemispheric Research/Training in Infectious Disease training grant [D43-TW007129]
- Geographic Medicine and Emerging Infections training grant [T32-AI070117]
- NIH National Institute of Allergy and Infectious Diseases [R01-AI076248, R01-AI93220]
- Burroughs-Wellcome Fund's Career Awards for Medical Scientists
- Einstein-Montefiore Institute for Clinical and Translational Research Career Development Award
- NIH National Institute of Neurological Disorders and Stroke grant [R01-NS0695771]
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Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10(6) PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed Leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM.
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