Neutralizing antibody against interleukin-6 attenuates posthemorrhagic vasospasm in the rat femoral artery model
Neutralizing antibody against interleukin-6 attenuates posthemorrhagic vasospasm in the rat femoral artery model
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DOI：
10.1227/01.neu.0000108981.73153.6e
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发表时间：
2004-03-01
期刊：
影响因子：
4.8
通讯作者：
Cockroft, KM
中科院分区：
文献类型：
--
作者：
Bowman, G;Dixit, S;Cockroft, KM
目的：炎症对出血后血管痉挛发生的影响程度存在争议。在本研究中，我们研究了多种炎症细胞因子（肿瘤坏死因子-α、白细胞介素[IL]-1α、IL-1β和IL-6）与实验性血管痉挛发生之间的关系。方法：在大鼠股动脉模型中产生出血后血管痉挛。在每条股动脉周围放置一个乳胶袋，其中一个袋注入自体血液，另一个袋注入生理盐水作为内部对照。在手术后（血液暴露）的不同时间点（1小时至16天）处死动物，并通过动脉横截面积的图像分析来评估血管痉挛的程度。采用酶联免疫吸附法测定炎性细胞因子水平，并检测大鼠IL-6多克隆抗体抑制血管痉挛的能力。 结果：大鼠股动脉模型产生双相血管痉挛反应，最大慢性迟发性血管痉挛发生在出血后8 d。酶联免疫吸附测定显示，在出血后的多个时间点（6、12、24 和 48 小时），暴露于血液的动脉中的 IL-6 浓度相对于暴露于盐水的动脉显着增加（P < 0.0001）。 24 小时时，IL-1α 水平相对增加（P < 0.01）。在暴露于血液和盐水的动脉中，IL-1β 水平同样升高，并且未检测到肿瘤坏死因子-a 水平。在初次手术时，将针对大鼠 IL-6 的中和性多克隆抗体直接注射到血液暴露的动脉周围囊中，与出血后 8 天的媒介物治疗对照相比，血管痉挛程度出现剂量依赖性降低 (P < 0.05)。 结论：这些结果表明，细胞因子介导的炎症在大鼠股动脉产生的出血后血管痉挛的情况下活跃。模型。特别是，暴露于出血后IL-6水平的显着增加以及针对IL-6的多克隆抗体减少血管痉挛的能力表明IL-6可能在该模型中的血管痉挛的发生中发挥重要作用。
OBJECTIVE: The degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-1alpha, IL-1beta, and IL-6) and the development of experimental vasospasm.METHODS: Posthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested.RESULTS: The rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1alpha levels was noted at 24 hours (P < 0.01). IL-1beta levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-a levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05).CONCLUSIONS: These results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.