PDF(Pubmed)
Abstract：
BACKGROUND: A sepsis-like syndrome is known to occur after cardiac arrest, leading to cerebral infiltration by white blood cells (WBC). We hypothesized that pharmacological sequestration of WBC, and more specifically lymphocytes within lymphoid tissues, could reduce the cerebral infiltration by these inflammatory cells and subsequent acute brain injury in a porcine model of cardiac arrest. Lymphocyte sequestration was induced by the sphingosine-1 phosphate receptors agonist fingolimod.
METHODS: In a first set of experiments, anesthetized pigs underwent a sham instrumentation with no cardiac arrest (n = 4). They received an administration of fingolimod (1 mg/kg, i.v.) in order to confirm its effect on WBC. In a second set of experiments, animals randomly received fingolimod or saline two hours prior to an episode of ventricular fibrillation (14 min) with subsequent resuscitation (n = 6 in each group). Neurological injury was assessed 24 h after resuscitation.
RESULTS: In the first set of experiments, WBC and blood lymphocyte counts were significantly reduced by - 61 ± 10% and - 75 ± 6% two hours after fingolimod administration. In the second set of experiments, blood lymphocyte counts, but not WBC, were also significantly reduced after cardiac arrest in Fingolimod vs Control group. However, most cytokine blood levels were not different among groups, including Interleukin (IL)-1ra, IL-8 or IL-18 blood levels. A difference was only observed for IL-6, which decreased in Fingolimod vs Control (e.g., 5.6 ± 4.8 vs 59.4 ± 20.6 pg/ml at 2 h after cardiac arrest, respectively; p = 0.126). Neurofilament light chain (NFL) blood levels were not different among groups (57 ± 25 vs 84 ± 41 pg/ml in Fingolimod vs Control at 6 h after resuscitation, respectively). After awakening, 3 and 2 animals were prematurely euthanized for ethical reasons due to recurrent seizures in Fingolimod and Control groups, respectively. At Day 1, neurological dysfunction score was not different between groups (87 ± 7 vs 87 ± 5% in Fingolimod vs Control, respectively). Conversely, a decrease in the number of CD3 + cells was observed in the brain of surviving animals in Fingolimod vs Control group (3.10 ± 0.50 vs 7.53 ± 0.57 CD3 + cells/field, respectively; p = 0.0286).
CONCLUSIONS: Fingolimod-induced WBC sequestration, and more specifically lymphocytes sequestration, did not improve clinical neurological dysfunction following cardiac arrest although it reduced cerebral infiltration by lymphocytes.
METHODS: In a first set of experiments, anesthetized pigs underwent a sham instrumentation with no cardiac arrest (n = 4). They received an administration of fingolimod (1 mg/kg, i.v.) in order to confirm its effect on WBC. In a second set of experiments, animals randomly received fingolimod or saline two hours prior to an episode of ventricular fibrillation (14 min) with subsequent resuscitation (n = 6 in each group). Neurological injury was assessed 24 h after resuscitation.
RESULTS: In the first set of experiments, WBC and blood lymphocyte counts were significantly reduced by - 61 ± 10% and - 75 ± 6% two hours after fingolimod administration. In the second set of experiments, blood lymphocyte counts, but not WBC, were also significantly reduced after cardiac arrest in Fingolimod vs Control group. However, most cytokine blood levels were not different among groups, including Interleukin (IL)-1ra, IL-8 or IL-18 blood levels. A difference was only observed for IL-6, which decreased in Fingolimod vs Control (e.g., 5.6 ± 4.8 vs 59.4 ± 20.6 pg/ml at 2 h after cardiac arrest, respectively; p = 0.126). Neurofilament light chain (NFL) blood levels were not different among groups (57 ± 25 vs 84 ± 41 pg/ml in Fingolimod vs Control at 6 h after resuscitation, respectively). After awakening, 3 and 2 animals were prematurely euthanized for ethical reasons due to recurrent seizures in Fingolimod and Control groups, respectively. At Day 1, neurological dysfunction score was not different between groups (87 ± 7 vs 87 ± 5% in Fingolimod vs Control, respectively). Conversely, a decrease in the number of CD3 + cells was observed in the brain of surviving animals in Fingolimod vs Control group (3.10 ± 0.50 vs 7.53 ± 0.57 CD3 + cells/field, respectively; p = 0.0286).
CONCLUSIONS: Fingolimod-induced WBC sequestration, and more specifically lymphocytes sequestration, did not improve clinical neurological dysfunction following cardiac arrest although it reduced cerebral infiltration by lymphocytes.
摘要：
背景：已知败血症样综合征在心脏骤停后发生，导致白细胞（WBC）的脑浸润。我们假设WBC的药理隔离，更具体地说是淋巴组织内的淋巴细胞，可以减少这些炎症细胞的脑浸润以及随后在猪心脏骤停模型中的急性脑损伤。鞘氨醇-1磷酸受体激动剂芬戈莫德诱导淋巴细胞隔离。
方法：在第一组实验中，麻醉猪接受了假器械治疗,无心脏骤停(n=4).他们接受了芬戈莫德（1mg/kg，i.v.)以确认其对WBC的影响。在第二组实验中，动物在室颤发作前2小时(14分钟)随机接受芬戈莫德或生理盐水,随后进行复苏(每组n=6).复苏后24小时评估神经损伤。
结果：在第一组实验中，在芬戈莫德给药后两小时，WBC和血液淋巴细胞计数显着降低了-61±10％和-75±6％。在第二组实验中,血液淋巴细胞计数，但不是WBC,与对照组相比，芬戈莫德在心脏骤停后也显着降低。然而,大多数细胞因子血液水平在组间没有差异，包括白细胞介素（IL）-1ra，IL-8或IL-18血液水平。仅观察到IL-6的差异，其在芬戈莫德与对照组中降低（例如，心脏骤停后2小时5.6±4.8vs59.4±20.6pg/ml，分别为；p=0.126)。各组之间的神经丝轻链（NFL）血液水平没有差异（复苏后6小时，芬戈莫德与对照组的57±25vs84±41pg/ml，分别)。觉醒后,由于芬戈莫德和对照组的反复发作，出于伦理原因，将3只和2只动物过早安乐死。分别。在第1天，两组之间的神经功能障碍评分没有差异（芬戈莫德与对照组的87±7对87±5％，分别)。相反，在芬戈莫德与对照组的存活动物的大脑中观察到CD3+细胞数量的减少（3.10±0.50vs7.53±0.57CD3+细胞/场，分别为；p=0.0286)。
结论：芬戈莫德诱导的白细胞隔离，更具体地说是淋巴细胞隔离，尽管减少了淋巴细胞的脑浸润，但并未改善心脏骤停后的临床神经功能障碍。
方法：在第一组实验中，麻醉猪接受了假器械治疗,无心脏骤停(n=4).他们接受了芬戈莫德（1mg/kg，i.v.)以确认其对WBC的影响。在第二组实验中，动物在室颤发作前2小时(14分钟)随机接受芬戈莫德或生理盐水,随后进行复苏(每组n=6).复苏后24小时评估神经损伤。
结果：在第一组实验中，在芬戈莫德给药后两小时，WBC和血液淋巴细胞计数显着降低了-61±10％和-75±6％。在第二组实验中,血液淋巴细胞计数，但不是WBC,与对照组相比，芬戈莫德在心脏骤停后也显着降低。然而,大多数细胞因子血液水平在组间没有差异，包括白细胞介素（IL）-1ra，IL-8或IL-18血液水平。仅观察到IL-6的差异，其在芬戈莫德与对照组中降低（例如，心脏骤停后2小时5.6±4.8vs59.4±20.6pg/ml，分别为；p=0.126)。各组之间的神经丝轻链（NFL）血液水平没有差异（复苏后6小时，芬戈莫德与对照组的57±25vs84±41pg/ml，分别)。觉醒后,由于芬戈莫德和对照组的反复发作，出于伦理原因，将3只和2只动物过早安乐死。分别。在第1天，两组之间的神经功能障碍评分没有差异（芬戈莫德与对照组的87±7对87±5％，分别)。相反，在芬戈莫德与对照组的存活动物的大脑中观察到CD3+细胞数量的减少（3.10±0.50vs7.53±0.57CD3+细胞/场，分别为；p=0.0286)。
结论：芬戈莫德诱导的白细胞隔离，更具体地说是淋巴细胞隔离，尽管减少了淋巴细胞的脑浸润，但并未改善心脏骤停后的临床神经功能障碍。
