International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, Canada.
Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
J Physiol. 2020 Mar;598(5):929-942. doi: 10.1113/JP278451. Epub 2020 Feb 11.
We have developed a novel porcine model of high-thoracic midline contusion spinal cord injury (SCI) at the T2 spinal level. We describe this model and the ensuing cardiovascular and neurohormonal responses, and demonstrate the model is efficacious for studying clinically relevant cardiovascular dysfunction post-SCI. We demonstrate that the high-thoracic SCI model, but not a low-thoracic SCI model, induces persistent hypotension along with a gradual reduction in plasma noradrenaline and increases in plasma aldosterone and angiotensin II. We additionally conducted a proof-of-concept long-term (12 weeks) survival study in animals with T2 contusion SCI demonstrating the potential utility of this model for not only acute experimentation but also long-term drug studies prior to translation to the clinic.
Cardiovascular disease is a leading cause of morbidity and mortality in the spinal cord injury (SCI) population, especially in those with high-thoracic or cervical SCI. With this in mind, we aimed to develop a large animal (porcine) model of high-thoracic (T2 level) contusion SCI and compare the haemodynamic and neurohormonal responses of this injury against a low-thoracic (T10 level) model. Ten Yorkshire pigs were randomly subjected to 20 cm weight drop contusion SCI at either the T2 or the T10 spinal level. Systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were continuously monitored until 4 h post-SCI. Plasma noradrenaline (NA), aldosterone and angiotensin II (ANGII) were measured pre-SCI and at 30, 60, 120 and 240 min post-SCI. Additionally, two Yucatan pigs were subjected to T2-SCI and survived up to 12 weeks post-injury to demonstrate the efficacy of this model for long-term survival studies. Immediately after T2-SCI, SBP, MAP and HR increased (P < 0.0001). Between decompression (5 min post-SCI) and 30 min post-decompression in T2-SCI, SBP and MAP were lower than pre-SCI (P < 0.038). At 3 and 4 h after T2-SCI, SBP remained lower than pre-SCI (P = 0.048). After T10-SCI, haemodynamic indices remained largely unaffected. Plasma NA was lower in T2- vs. T10-SCI post-SCI, whilst aldosterone and ANGII were higher. Both chronically injured pigs demonstrated a vast reduction in SBP at 12 weeks post-SCI. Our model of T2-SCI causes a rapid and sustained alteration in neurohormonal control and cardiovascular function, which does not occur in the T10 model.
我们开发了一种新的猪胸段正中挫伤性脊髓损伤（SCI）模型，损伤部位在 T2 脊髓水平。我们描述了该模型以及随之而来的心血管和神经激素反应，并证明该模型可有效研究 SCI 后与临床相关的心血管功能障碍。我们证明，高胸段 SCI 模型而非低胸段 SCI 模型会导致持续性低血压，同时血浆去甲肾上腺素逐渐减少，血浆醛固酮和血管紧张素 II 增加。我们还在 T2 挫伤性 SCI 动物中进行了为期 12 周的生存能力的概念验证研究，证明了该模型不仅可用于急性实验，还可用于在向临床转化之前进行长期药物研究。
心血管疾病是脊髓损伤（SCI）患者发病率和死亡率的主要原因，尤其是在胸段或颈段 SCI 患者中。有鉴于此，我们旨在开发一种大动物（猪）胸段（T2 水平）挫伤性 SCI 模型，并比较该损伤的血流动力学和神经激素反应与低胸段（T10 水平）模型的反应。10 头约克夏猪随机接受 20cm 重物坠落挫伤性 SCI，损伤部位在 T2 或 T10 脊髓水平。连续监测收缩压（SBP）、平均动脉压（MAP）和心率（HR），直至 SCI 后 4 小时。在 SCI 前和 SCI 后 30、60、120 和 240 分钟测量血浆去甲肾上腺素（NA）、醛固酮和血管紧张素 II（ANGII）。此外，两只尤卡坦猪接受 T2-SCI，并在损伤后存活 12 周，以证明该模型进行长期生存研究的有效性。在 T2-SCI 后，SBP、MAP 和 HR 立即升高（P<0.0001）。在 T2-SCI 的减压（SCI 后 5 分钟）和减压后 30 分钟之间，SBP 和 MAP 低于 SCI 前（P<0.038）。在 T2-SCI 后 3 和 4 小时，SBP 仍低于 SCI 前（P=0.048）。T10-SCI 后，血流动力学指数基本不受影响。SCI 后 T2-SCI 组的血浆 NA 低于 T10-SCI 组，而醛固酮和 ANGII 则高于 T10-SCI 组。慢性损伤的两只猪在 SCI 后 12 周时 SBP 均大幅下降。我们的 T2-SCI 模型导致神经激素控制和心血管功能的快速和持续改变，而 T10 模型则不会出现这种改变。
