Solovey Anna, Somani Arif, Belcher John D, Milbauer Liming, Vincent Lucile, Pawlinski Rafal, Nath Karl A, Kelm Robert J, Mackman Nigel, O'Sullivan M Gerard, Gupta Kalpna, Vercellotti Gregory M, Hebbel Robert P
Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.
Division of Critical Care, Department of Pediatrics, University of Minnesota Medical School.
Am J Hematol. 2017 Nov;92(11):1119-1130. doi: 10.1002/ajh.24856. Epub 2017 Jul 29.
Elaboration of tumor necrosis factor (TNF) is a very early event in development of ischemia/reperfusion injury pathophysiology. Therefore, TNF may be a prominent mediator of endothelial cell and vascular wall dysfunction in sickle cell anemia, a hypothesis we addressed using NY1DD, S+S , and SS-BERK sickle transgenic mice. Transfusion experiments revealed participation of abnormally activated blood monocytes exerting an endothelial activating effect, dependent upon Egr-1 in both vessel wall and blood cells, and upon NFκB(p50) in a blood cell only. Involvement of TNF was identified by beneficial impact from TNF blockers, etanercept and infliximab, with less benefit from an IL-1 blocker, anakinra. In therapeutic studies, etanercept ameliorated multiple disturbances of the murine sickle condition: monocyte activation, blood biomarkers of inflammation, low platelet count and Hb, vascular stasis triggered by hypoxia/reoxygenation (but not if triggered by hemin infusion), tissue production of neuro-inflammatory mediators, endothelial activation (monitored by tissue factor and VCAM-1 expression), histopathologic liver injury, and three surrogate markers of pulmonary hypertension (perivascular inflammatory aggregates, arteriolar muscularization, and right ventricular mean systolic pressure). In aggregate, these studies identify a prominent-and possibly dominant-role for an abnormal monocyte-TNF-endothelial activation axis in the sickle context. Its presence, plus the many benefits of etanercept observed here, argue that pilot testing of TNF blockade should be considered for human sickle cell anemia, a challenging but achievable translational research goal.
肿瘤坏死因子（TNF）的产生是缺血/再灌注损伤病理生理学发展过程中非常早期的事件。因此，TNF可能是镰状细胞贫血中内皮细胞和血管壁功能障碍的主要介质，我们使用NY1DD、S+S和SS-BERK镰状转基因小鼠对这一假说进行了研究。输血实验表明，异常激活的血液单核细胞参与其中，发挥内皮激活作用，这依赖于血管壁和血细胞中的早期生长反应蛋白-1（Egr-1），以及仅在血细胞中的核因子κB（p50）。通过TNF阻滞剂依那西普和英夫利昔单抗的有益影响确定了TNF的参与，而白细胞介素-1阻滞剂阿那白滞素的益处较少。在治疗研究中，依那西普改善了小鼠镰状状态的多种紊乱：单核细胞激活、炎症的血液生物标志物、低血小板计数和血红蛋白、缺氧/复氧引发的血管淤滞（但血红素输注引发的则不然）、神经炎症介质的组织产生、内皮激活（通过组织因子和血管细胞黏附分子-1表达监测）、组织病理学肝损伤以及肺动脉高压的三个替代标志物（血管周围炎性聚集物、小动脉肌化和右心室平均收缩压）。总体而言，这些研究确定了在镰状细胞环境中异常单核细胞-TNF-内皮激活轴的突出且可能占主导的作用。它的存在，加上此处观察到的依那西普的诸多益处，表明对于人类镰状细胞贫血应考虑进行TNF阻断的初步试验，这是一个具有挑战性但可实现的转化研究目标。
