Department of Genetics, Evolution, Microbiology, and Immunology, Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, University of Campinas, Campinas, Brazil.
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
FASEB J. 2018 Aug;32(8):4470-4481. doi: 10.1096/fj.201700844R. Epub 2018 Mar 20.
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., Câmara, 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.
脑型疟疾（CM）是一种涉及炎症状态加剧、内皮细胞激活、凝血功能障碍、缺氧以及白细胞和寄生虫在脑微血管中积聚的多因素综合征。尽管疟疾控制取得了重大进展，但 CM 病例仍有 15%的死亡率，25%的幸存者会出现终身神经系统后遗症，即使在接受适当的抗疟治疗后也是如此。目前迫切需要一种能够改善 CM 临床症状并实现完全康复的治疗方法。此前，我们发现高压氧（HBO）对实验性 CM 具有保护作用。在此，我们提供了分子证据，表明 HBO 通过降低脑内皮细胞的活性并抑制寄生虫和白细胞的积聚，从而改善脑微循环血流，从而靶向脑内皮细胞。HBO 治疗增加了芳香烃受体的表达，超过了缺氧诱导因子 1-α（HIF-1α），HIF-1α 是一种氧敏感的胞浆受体，同时降低了吲哚胺 2,3-双加氧酶 1 的表达和犬尿氨酸水平。此外，在小鼠内皮细胞中敲除 HIF-1α 表达可对抗 CM 并提高存活率。我们提出，HBO 应该作为 CM 患者的辅助治疗方法，以延长生存期并减轻有害的炎症反应。此外，我们的数据支持将 HBO 用于治疗策略，以改善影响大脑的非 CM 疾病的预后。
