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Inhibition of hypoxia‐associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria
Author(s) -
Bastos Marcele F.,
Kayano Ana Carolina A. V.,
SilvaFilho João Luiz,
DosSantos João Conrado K.,
Judice Carla,
Blanco Yara C.,
Shryock Nathaniel,
Sercundes Michelle K.,
Ortolan Luana S.,
Francelin Carolina,
Leite Juliana A.,
Oliveira Rafaella,
Elias Rosa M.,
Câmara Niels O. S.,
Lopes Stefanie C. P.,
Albrecht Letusa,
Farias Alessandro S.,
Vicente Cristina P.,
Werneck Claudio C.,
Giorgio Selma,
Verinaud Liana,
Epiphanio Sabrina,
Marinho Claudio R. F.,
Lalwani Pritesh,
Amino Rogerio,
Aliberti Julio,
Costa Fabio T. M.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700844r
Subject(s) - cerebral malaria , proinflammatory cytokine , hypoxia (environmental) , kynurenine , medicine , aryl hydrocarbon receptor , pharmacology , endothelial activation , immunology , indoleamine 2,3 dioxygenase , malaria , inflammation , biology , chemistry , oxygen , plasmodium falciparum , biochemistry , tryptophan , organic chemistry , amino acid , transcription factor , gene
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 life—even 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‐α (HIF‐1α), an oxygen‐sensitive cytosolic receptor, along with decreased indoleamine 2, 3‐dioxygenase 1 expression and kynurenine levels. Moreover, ablation of HIF‐1α 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. FASEB J . 32, 4470–4481 (2018). www.fasebj.org