Defining the Mechanism of Subarachnoid Hemorrhage-Induced Pyrexia
Defining the Mechanism of Subarachnoid Hemorrhage-Induced Pyrexia
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DOI：
10.1007/s13311-020-00866-x
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发表时间：
2020-05-05
影响因子：
5.7
通讯作者：
Hanafy, Khalid A.
中科院分区：
文献类型：
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作者：
Thomas, Ajith J.;Ascanio-Cortez, Luis;Hanafy, Khalid A.
发热可以影响大多数蛛网膜下腔出血（SAH）患者，并且很多时候没有发现发热的可识别来源，无论是感染性还是无菌性，如深静脉血栓形成。我们假设SAH中的发热是由非环加氧酶依赖性机制介导的，我们将其新命名为蛛网膜下腔出血诱导的发热（SAHiP）。使用转基因小鼠、药理学操作、SAH患者的脑脊液和一个大的SAH患者队列研究了这一假设。神经元前列腺素EP 3受体、整体Toll样受体4（TLR 4）、髓样TLR 4和小胶质细胞TLR 4缺失的小鼠在植入温度计后进行SAH。确定了SAHiP所需的途径。用流式细胞术检测SAH患者脑脊液中SAHiP的含量并进行相关性分析。从一个大的SAH患者队列中，使用逻辑回归分析确定与SAHiP的独立关联。在我们的SAH小鼠模型中，小胶质细胞TLR 4是SAHiP所必需的，但独立于神经元前列腺素EP 3受体、环氧合酶和肾上腺素。SAH合并SAHiP患者脑脊液中的巨噬细胞TLR 4共受体表达高于SAH不合并SAHiP患者。在一个大的SAH患者队列中，发现SAHiP与对乙酰氨基酚给药独立相关，但呈负相关。SAHiP不依赖于神经元前列腺素EP 3受体、环氧合酶和前列腺素，但依赖于小胶质细胞/巨噬细胞TLR 4，这一证据来自SAH小鼠模型和SAH患者。
Fever can affect the majority of patients with subarachnoid hemorrhage (SAH) and many times no identifiable source is found for the fever whether infectious or sterile, like deep vein thrombosis. We hypothesized that fever in SAH is mediated by a NON-cyclo-oxygenase-dependent mechanism, which we neologized as subarachnoid hemorrhage-induced pyrexia (SAHiP). This hypothesis was investigated using genetically modified mice, pharmacological manipulation, cerebrospinal fluid from SAH patients, and a large cohort of SAH patients. Mice with deletions of neuronal prostaglandin EP3 receptor, global toll-like receptor 4 (TLR4), myeloid TLR4, and microglial TLR4 were subjected to SAH after being implanted with thermometers. Pathways necessary for SAHiP were identified. In SAH patients, cerebrospinal fluid was examined by flow cytometry and correlated with SAHiP. From a large cohort of SAH patients, independent associations with SAHiP were determined using logistic regression analysis. In our mouse model of SAH, microglial TLR4 is necessary for SAHiP, but independent of the neuronal prostaglandin EP3 receptor, cyclo-oxygenase, and prostaglandins. Macrophages from the cerebrospinal fluid of SAH patients with SAHiP expressed more TLR4-co-receptor than SAH patients without SAHiP. In a large cohort of SAH patients, SAHiP was found to be independently, yet inversely, associated with acetaminophen administration. SAHiP is independent of the neuronal prostaglandin EP3 receptor, cyclo-oxygenase, and prostaglandins, but dependent on microglial/macrophage TLR4 with evidence from both SAH mouse models and SAH patients.