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Title: Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria
Author: Bastos, Marcele F.; 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.; Kayano, Ana Carolina A. V.; Giorgio, Selma; Verinaud, Liana; Epiphanio, Sabrina; Marinho, Claudio R. F.; Lalwani, Pritesh; Amino, Rogerio; Aliberti, Julio; Costa, Fabio T. M.; Silva-filho, João Luiz; Dos-santos, João Conrado K.; Judice, Carla; Blanco, Yara C.; Shryock, Nathaniel; Sercundes, Michelle K.; Ortolan, Luana S.
Year: 2018
Is part of: THE FASEB JOURNAL (ONLINE), v. 32, p. fj.201700844R -
DOI: https://doi.org/10.1096/fj.201700844r

Citation: Bastos, Marcele F.; 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.; Kayano, Ana Carolina A. V.; Giorgio, Selma; Verinaud, Liana; Epiphanio, Sabrina; Marinho, Claudio R. F.; Lalwani, Pritesh; Amino, Rogerio; Aliberti, Julio; Costa, Fabio T. M.; Silva-filho, João Luiz; Dos-santos, João Conrado K.; Judice, Carla; Blanco, Yara C.; Shryock, Nathaniel; Sercundes, Michelle K.; Ortolan, Luana S.; Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria. THE FASEB JOURNAL (ONLINE), v.32, p. fj.201700844R-, 2018

Abstract: 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.



Funding: This work was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) Grants 2012/16525-2 (to F.T.M.C.), 2014/20451-0 (to S.E.), 2016/07030-0 (to C.R.F.M.), and 2016/12855-9 (to J.L.S-F.); FAPESP (http://www.fapesp.br/en/); and U.S. National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant AI118302-02. A.S.F., C.C.W., S.G., L.V., S.E., C.R.F.M., and F.T.M.C. are Conselho Nacional do Desenvolvimento Cientifico e Tecnologico (CNPq) research fellows. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflicts of interest.
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