Mai Nguyen, Prifti Landa, Rininger Aric, Bazarian Hannah, Halterman Marc W
Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States.
Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States; Department of Neurology, University of Rochester, Rochester, NY 14642, United States.
Exp Neurol. 2017 Nov;297:82-91. doi: 10.1016/j.expneurol.2017.07.016. Epub 2017 Jul 28.
Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50μg/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions.
缺血后神经变性仍然是心脏复苏后死亡的主要原因。最近的研究表明，胃肠道缺血与心脏骤停后综合征（PCAS）相关的脓毒症样反应有关。然而，高达86%的复苏患者中存在的低度内毒素血症对脑缺血再灌注损伤的影响程度尚未得到研究。在此我们报告，与单纯缺血相比，在全脑缺血（GCI）后单次注射低剂量脂多糖（50μg/kg，腹腔注射）会在体内诱导血脑屏障通透性、小胶质细胞激活、皮质损伤和功能衰退。虽然GCI足以诱导中性粒细胞（PMN）激活并募集到缺血后的中枢神经系统，但最低限度的内毒素血症对全身炎症标志物表现出协同作用，包括PMN预激活、肺损伤以及肺和包括肾脏和肝脏在内的其他非缺血器官中的PMN负荷。我们的研究结果预测，针对阻断心脏骤停幸存者中血清学隐匿性内毒素血症影响的急性干预措施将限制延迟性神经变性、多器官功能障碍以及PCAS的潜在其他特征。这项工作还引入了肺-脑耦合作为一个新的治疗靶点，对心脏骤停及相关脑血管疾病后的先天免疫预激活和缺血后神经变性具有广泛影响。
