title: Lipoxin A4 attenuates endothelial dysfunction during experimental cerebral malaria.
abstract: A breakdown of the brain-blood barrier (BBB) due to endothelial dysfunction is a primary feature of cerebral malaria (CM). Lipoxins (LX) are specialized pro-resolving mediators that attenuate endothelial dysfunction in different vascular beds. It has already been shown that LXA4 prolonged Plasmodium berghei-infected mice survival by a mechanism that depends on inhibiting IL-12 production and CD8(+)IFN-γ(+) T cells in brain tissue; however, the effects of this treatment on endothelial dysfunction induced during experimental cerebral malaria (ECM) remains to be elucidated. Herein, we investigate the role of LXA4 on endothelial dysfunction during ECM. The treatment of P. berghei-infected mice with LXA4 prevented BBB breakdown and ameliorated behavioral symptoms but did not modulate TNF-α production. In addition, microcirculation analysis showed that treatment with LXA4 significantly increased functional capillary density in brains of P. berghei-infected C57BL/6 mice. Furthermore, histological analyses of brain sections demonstrated that exogenous LXA4 reduced capillary congestion that was accompanied by reduced ICAM-1 expression in the brain tissue. In agreement, LXA4 treatment of endothelial cells stimulated by Plasmodium berghei (Pb)- or Plasmodium falciparum (Pf)-parasitized red blood cells (RBCs) inhibited ICAM-1 expression. Additionally, LXA4 treatment restored the expression of HO-1 that is reduced during ECM. As well, LXA4 treatment inhibits PbRBC and PfRBC adhesion to endothelial cells that was reversed by the use of an HO-1 inhibitor (ZnPPIX). Our results demonstrate for the first time that LXA4 ameliorates endothelial dysfunction during ECM by modulating ICAM-1 and HO-1 expression in brain tissue.
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Souza
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Pádua
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Natália D
authors.initials: ND
authors.lastname: Torres
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Souza Costa
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: André P
authors.initials: AP
authors.lastname: Candéa
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Thadeu
authors.initials: T
authors.lastname: Maramaldo
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Leonardo Noboru
authors.initials: LN
authors.lastname: Seito
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Carmen
authors.initials: C
authors.lastname: Penido
authors.affiliation: Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Estato
authors.affiliation: Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Barbara
authors.initials: B
authors.lastname: Antunes
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Silva
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Ana Acácia
authors.initials: AA
authors.lastname: Pinheiro
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Celso
authors.initials: C
authors.lastname: Caruso-Neves
authors.affiliation: Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tibiriçá
authors.affiliation: Laboratory of Malaria Research, Instituto Oswaldo Cruz, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Carvalho
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil. Electronic address: gracahenriques@fiocruz.br.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Henriques
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D044045:Lipoxins / Q000494:pharmacology*; D016779:Malaria, Cerebral / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D044045:Lipoxins; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D018799:Intercellular Adhesion Molecule-1; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Brain–blood barrier breakdown; Endothelial dysfunction; Lipoxin; Malaria