Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
PLoS One. 2021 Feb 24;16(2):e0246601. doi: 10.1371/journal.pone.0246601. eCollection 2021.
To test in mice with a double mutation of the ApoE gene (ApoE-/-) whether spinal cord injury (SCI) hastens the native trajectory of, and established component risks for, atherosclerotic disease (AD), and whether Salsalate anti-inflammatory pharmacotherapy attenuates the impact of SCI.
ApoE-/- mice were anesthetized and underwent a T9 laminectomy. Exposed spinal cords were given a contusion injury (70 k-dynes). Sham animals underwent all surgical procedures, excluding injury. Injured animals were randomized to 2 groups: SCI or SCI+Salsalate [120 mg/Kg/day i.p.]. Mice were serially sacrificed at 20-, 24-, and 28-weeks post-SCI, and body mass was recorded. At sacrifice, heart and aorta were harvested intact, fixed in 10% buffered formalin, cleaned and cut longitudinally for en face preparation. The aortic tree was stained with oil-red-O (ORO). AD lesion histomorphometry was calculated from the proportional area of ORO. Plasma total cholesterol, triglycerides and proatherogenic inflammatory cytokines (PAIC's) were analyzed.
AD lesion in the aortic arch progressively increased in ApoE-/-, significant at 24- and 28-weeks. AD in SCI is significantly greater at 24- and 28-weeks compared to time-controlled ApoE-/-. Salsalate treatment attenuates the SCI-induced increase at these time points. Body mass in all SCI groups are significantly reduced compared to time-controlled ApoE-/-. Cholesterol and triglycerides are significantly higher with SCI by 24- and 28-weeks, compared to ApoE-/-, and Salsalate reduces the SCI-induced effect on cholesterol. PAIC's interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (CCL-5) are significantly greater with SCI compared to ApoE-/- at varying timepoints. Salsalate confers a marginal reducing effect on PAIC's by 28-weeks compared to SCI. Regression models determine that each PAIC is a significant and positive predictor of lesion. (p's <0.05).
SCI accelerates aortic AD and associated risk factors, and anti-inflammatory treatment may attenuate the impact of SCI on AD outcomes. PAIC's IL-1β, IL-6, TNFα, MCP-1, and CCL-5 may be effective predictors of AD.
在载脂蛋白 E 基因（ApoE-/-）双重突变的小鼠中测试脊髓损伤（SCI）是否会加速动脉粥样硬化疾病（AD）的自然病程和已确立的危险因素，以及水杨酸盐抗炎药物治疗是否会减弱 SCI 的影响。
用麻醉剂麻醉 ApoE-/-小鼠，并进行 T9 椎板切除术。暴露的脊髓受到挫伤（70 k-dynes）。假手术动物接受所有手术程序，但不包括损伤。受伤动物随机分为 2 组：SCI 或 SCI+Salsalate [120 mg/Kg/天腹腔内注射]。伤后 20、24 和 28 周时，动物连续处死，并记录体重。处死时，完整采集心脏和主动脉，用 10%缓冲福尔马林固定，清洗并沿长轴切开进行全面准备。主动脉树用油红-O（ORO）染色。AD 病变组织形态计量学通过 ORO 的比例面积计算。分析血浆总胆固醇、甘油三酯和促动脉粥样硬化炎症细胞因子（PAIC）。
ApoE-/--主动脉弓中的 AD 病变逐渐增加，在 24 周和 28 周时明显。与时间对照的 ApoE-/--相比，SCI 中的 AD 在 24 周和 28 周时显著增加。Salsalate 治疗可减轻这些时间点 SCI 引起的增加。所有 SCI 组的体重与时间对照的 ApoE-/--相比均明显降低。与 ApoE-/--相比，24 周和 28 周时 SCI 导致胆固醇和甘油三酯显著升高，Salsalate 降低了 SCI 对胆固醇的影响。SCI 时白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子α（TNFα）、单核细胞趋化蛋白-1（MCP-1）和趋化因子（C-C 基序）配体 5（CCL-5）与 ApoE-/--相比，在不同时间点均显著升高。与 SCI 相比，Salsalate 在 28 周时对 PAIC 的减少作用略有降低。回归模型确定每个 PAIC 都是病变的显著正预测因子（p<0.05）。
SCI 加速主动脉 AD 及其相关危险因素，抗炎治疗可能减弱 SCI 对 AD 结局的影响。PAIC 的白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子α（TNFα）、单核细胞趋化蛋白-1（MCP-1）和趋化因子（C-C 基序）配体 5（CCL-5）可能是 AD 的有效预测因子。
