Higgins Sarah J, Purcell Lisa A, Silver Karlee L, Tran Vanessa, Crowley Valerie, Hawkes Michael, Conroy Andrea L, Opoka Robert O, Hay John G, Quaggin Susan E, Thurston Gavin, Liles W Conrad, Kain Kevin C
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Regeneron Pharmaceuticals Inc, Tarrytown, NY 10591, USA.
Sci Transl Med. 2016 Sep 28;8(358):358ra128. doi: 10.1126/scitranslmed.aaf6812.
Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)-Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang-Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang-Tie-2-based interventions as potential adjunctive therapies for treating severe malaria.
脑型疟疾是全球发病和死亡的主要原因。与仅用抗疟药治疗相比，针对脑型疟疾潜在病理生理学的干预措施可能会改善治疗结果。微血管渗漏在脑型疟疾的发病机制中起重要作用。血管生成素（Ang）-Tie-2系统是血管功能的关键调节因子。我们在一项对乌干达重症疟疾儿童的前瞻性研究以及实验性脑型疟疾的临床前小鼠模型中表明，Ang-1表达和可溶性Tie-2表达与疾病严重程度和预后相关。在脑型疟疾小鼠模型中，Ang-1是维持血管完整性和生存所必需的。Ang-1的治疗性给药可保持血脑屏障的完整性，并且与青蒿琥酯联合治疗相比单独使用青蒿琥酯可提高生存率。这些数据确定了Ang-Tie-2轴失调在脑型疟疾发病机制中的作用，并支持评估基于Ang-Tie-2的干预措施作为治疗重症疟疾的潜在辅助疗法。
