title: Platelets potentiate brain endothelial alterations induced by Plasmodium falciparum.
abstract: Brain lesions of cerebral malaria (CM) are characterized by a sequestration of Plasmodium falciparum-parasitized red blood cells (PRBC) and platelets within brain microvessels, as well as by blood-brain barrier (BBB) disruption. In the present study, we evaluated the possibility that PRBC and platelets induce functional alterations in brain endothelium. In a human brain endothelial cell line, named HBEC-5i, exhibiting most of the features demanded for a pathophysiological study of BBB, tumor necrosis factor (TNF) or lymphotoxin alpha (LT-alpha) reduced transendothelial electrical resistance (TEER), enhanced the permeability to 70-kDa dextran, and increased the release of microparticles, a recently described indicator of disease severity in CM patients. In vitro cocultures showed that platelets or PRBC can have a direct cytotoxic effect on activated, but not on resting, HBEC-5i cells. Platelet binding was required, as platelet supernatant had no effect. Furthermore, platelets potentiated the cytotoxicity of PRBC for TNF- or LT-alpha-activated HBEC-5i cells when they were added prior to these cells on the endothelial monolayers. This effect was not observed when platelets were added after PRBC. Both permeability and TEER were strongly affected, and the apoptosis rate of HBEC-5i cells was dramatically increased. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM.
authors.affiliation: Laboratory of Immunopathology, Unité des Rickettsies CNRS UMR6020, IFR 48, Faculty of Medicine, Université de la Méditerranée, 27 Boulevard Jean Moulin, F-13385 Marseille Cedex 05, France.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wassmer
authors.forename: Valéry
authors.initials: V
authors.lastname: Combes
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Candal
authors.forename: Irène
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: Georges E
authors.initials: GE
authors.lastname: Grau
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D002199:Capillary Permeability; D002461:Cell Line, Transformed; D016207:Cytokines / Q000502:physiology; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000469:parasitology* / Q000473:pathology* / Q000503:physiopathology; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008233:Lymphotoxin-alpha / Q000502:physiology; D016778:Malaria, Falciparum / Q000097:blood* / Q000469:parasitology / Q000473:pathology; D008833:Microcirculation / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D016207:Cytokines; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha