Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria

Autor(es):Mostrar menos -

Bastos, Marcele F. ^[1] ; Kayano, Ana Carolina A. V. ^[1] ; Silva-Filho, Joao Luiz ^[1] ; Dos-Santos, Joao Conrado K. ^[1] ; Judice, Carla ^[1] ; Blanco, Yara C. ^[1] ; Shryock, Nathaniel ^[2] ; Sercundes, Michelle K. ^[3] ; Ortolan, Luana S. ^[3] ; Francelin, Carolina ^[4] ; Leite, Juliana A. ^[1] ; Oliveira, Rafaella ^[5] ; Elias, Rosa M. ^[6] ; Camara, Niels O. S. ^[6] ; Lopes, Stefanie C. P. ^{[1, 5]} ; Albrecht, Letusa ^{[7, 1]} ; Farias, Alessandro S. ^[1] ; Vicente, Cristina P. ^[3] ; Werneck, Claudio C. ^[8] ; Giorgio, Selma ^[9] ; Verinaud, Liana ^[4] ; Epiphanio, Sabrina ^[3] ; Marinho, Claudio R. F. ^[10] ; Lalwani, Pritesh ^[5] ; Amino, Rogerio ^[11] ; Aliberti, Julio ^{[2, 12]} ; Costa, Fabio T. M. ^[1]

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^[1] Univ Estadual Campinas, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, Campinas, SP - Brazil

^[2] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 - USA

^[3] Univ Sao Paulo, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

^[4] Univ Estadual Campinas, Dept Funct & Struct Biol, Campinas, SP - Brazil

^[5] Fundacao Oswaldo Cruz, Inst Leonidas & Maria Deane, Manaus, Amazonas - Brazil

^[6] Univ Sao Paulo, Dept Immunol, Sao Paulo - Brazil

^[7] Fundacao Oswaldo Cruz, Inst Carlos Chagas, Curitiba, Parana - Brazil

^[8] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

^[9] Univ Estadual Campinas, Dept Anim Biol, Campinas, SP - Brazil

^[10] Univ Sao Paulo, Dept Parasitol, Sao Paulo - Brazil

^[11] Inst Pasteur, Unit Malaria Infect & Immun, Paris - France

^[12] NIAID, Div Extramural Act, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

• Tipo de documento: Artigo Científico
• Fonte: FASEB JOURNAL; v. 32, n. 8, p. 4470-4481, AUG 2018.
• Citações Web of Science: 2

Resumo

Cerebral malaria (CM) is a multifactorial syndrome involving an exacerbated proinflammatory status, endothelial cell activation, coagulopathy, hypoxia, and accumulation of leukocytes and parasites in the brain microvasculature. Despite significant improvements in malaria control, 15% of mortality is still observed in CM cases, and 25% of survivors develop neurologic sequelae for lifeeven after appropriate antimalarial therapy. A treatment that ameliorates CM clinical signs, resulting in complete healing, is urgently needed. Previously, we showed a hyperbaric oxygen (HBO)-protective effect against experimental CM. Here, we provide molecular evidence that HBO targets brain endothelial cells by decreasing their activation and inhibits parasite and leukocyte accumulation, thus improving cerebral microcirculatory blood flow. HBO treatment increased the expression of aryl hydrocarbon receptor over hypoxia-inducible factor 1- (HIF-1), an oxygen-sensitive cytosolic receptor, along with decreased indoleamine 2,3-dioxygenase 1 expression and kynurenine levels. Moreover, ablation of HIF-1 expression in endothelial cells in mice conferred protection against CM and improved survival. We propose that HBO should be pursued as an adjunctive therapy in CM patients to prolong survival and diminish deleterious proinflammatory reaction. Furthermore, our data support the use of HBO in therapeutic strategies to improve outcomes of non-CM disorders affecting the brain.Bastos, M. F., Kayano, A. C. A. V., Silva-Filho, J. L., Dos-Santos, J. C. K., Judice, C., Blanco, Y. C., Shryock, N., Sercundes, M. K., Ortolan, L. S., Francelin, C., Leite, J. A., Oliveira, R., Elias, R. M., Camara, N. O. S., Lopes, S. C. P., Albrecht, L., Farias, A. S., Vicente, C. P., Werneck, C. C., Giorgio, S., Verinaud, L., Epiphanio, S., Marinho, C. R. F., Lalwani, P., Amino, R., Aliberti, J., Costa, F. T. M. Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria. (AU)

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