小鼠劳力性中暑的临床前模型
Summary
该协议描述了在没有不利外部刺激（如电击）的小鼠中劳力性中暑（EHS）的标准化，可重复，临床前模型的发展。该模型为机械、预防和治疗研究提供了一个平台。
Abstract
中暑是热相关疾病最严重的表现。经典中暑 （CHS），也称为被动性中暑，发生在休息时，而劳力性中暑 （EHS） 发生在体力活动期间。EHS 与 CHS 在多器官功能障碍的病因、临床表现和后遗症方面的不同。直到最近，只有CHS的模型已经建立起来。该协议旨在为EHS的精制临床前小鼠模型提供指南，该模型不受主要限制因素的影响，例如使用麻醉，约束，直肠探头或电击。在该模型中使用了雄性和雌性C57Bl / 6小鼠，用核心温度（Tc）遥测探针进行检测。为了熟悉跑步模式，小鼠使用自愿和强制跑步轮进行3周的训练。此后，小鼠在设置为37.5°C和40%-50%相对湿度（RH）的气候室内用力轮子运行，直到在Tc为42.1-42.5°C时表现出症状限制（例如，意识丧失），尽管可以在34.5-39.5°C和湿度在30%-90%之间的腔室温度下获得合适的结果。根据所需的严重程度，立即将小鼠从腔室中取出以在环境温度下恢复或在加热室中停留更长时间，从而诱导更严重的暴露和更高的死亡率。将结果与假匹配运动对照（EXC）和/或朴素对照（NC）进行比较。该模型反映了在人类EHS中观察到的许多病理生理学结果，包括意识丧失，严重体温过高，多器官损伤以及炎症细胞因子释放和免疫系统的急性期反应。该模型非常适合假设驱动的研究，以测试可能延缓EHS发作或减少该表现特征的多器官损伤的预防和治疗策略。
Introduction
中暑的特征是中枢神经系统功能障碍和随后的器官损伤在高热受试者1。中暑有两种表现。经典中暑（CHS）在热浪期间主要影响老年人群或在炎热的夏季留在阳光照射的车辆中的儿童1。劳力性中暑（EHS）发生在体力消耗期间无法充分调节体温时，通常（但并非总是）在高环境温度下导致神经系统症状，体温过高以及随后的多器官功能障碍和损伤2。EHS发生在娱乐和精英运动员以及军事人员以及伴有和没有伴随脱水的工人中3，4。事实上，EHS是运动员在身体活动期间死亡的第三大原因5。研究人类的EHS极具挑战性，因为该事件可能是致命的或导致长期负面的健康结果6，7。因此，可靠的EHS临床前模型可以作为克服人类EHS患者回顾性和关联性临床观察的局限性的宝贵工具。CHS在啮齿动物和猪中的临床前模型已经得到了很好的表征8，9，10。然而，CHS的临床前模型并不直接转化为EHS病理生理学，因为体育锻炼对体温调节谱和先天免疫反应有独特的影响11。此外，以前在啮齿动物中开发临床前EHS模型的尝试带来了重大限制，包括电击引起的叠加应力刺激，直肠探头的插入以及预定义的最高核心体温与高死亡率12，13，14，15，16 与当前的流行病学数据不符。这些代表了可能混淆数据解释并提供不可靠的生物标志物指数的重大局限性。因此，该协议旨在表征和描述小鼠EHS的标准化，高度可重复和可翻译的临床前模型的步骤，该模型在很大程度上不受上述限制。描述了对模型的调整，这些调整可能导致从中度到致命性中暑的分级生理结果。据作者所知，这是唯一具有此类特征的EHS临床前模型，使得以假设驱动的方式进行相关的EHS研究成为可能11，17，18。
Protocol
Representative Results
Discussion
本技术综述旨在为小鼠EHS临床前模型的性能提供指导。提供了执行可重复的可变严重程度的EHS事件所需的详细步骤和材料。重要的是，该模型在很大程度上模仿了在人类EHS受害者中观察到的体征，症状和多器官功能障碍11，19。此外，该模型允许检查短期和长期EHS恢复19，20，22，23以及干预措施对体温调节，热量性能测量，中风后温度降低率的影响，以?…
Declarações
The authors have nothing to disclose.
Acknowledgements
这项工作由国防部W81XWH-15-2-0038（TLC）和BA180078（TLC）以及BK和Betty Stevens Endowment（TLC）资助。JMA得到了沙特阿拉伯王国的财政援助。米歇尔·金（Michelle King）在进行这项研究时在佛罗里达大学工作。她目前受雇于佳得乐体育科学研究所，这是百事可乐研发的一个部门。
Materials
| 1080P HD 4 Security Cameras 4CH Home Video Security Camera System w/ 1TB HDD 2MP Night View Cameras CCTV Surveillance Kit | LaView | ||
| 5-0 Coated Vicryl Violet Braided | Ethicon | ||
| 5-0 Ethilon Nylon suture Black Monofilament | Ethicon | ||
| Adhesive Surgical Drape with Povidone 12×18 | Jorgensen Labset al. | ||
| BK Precision Multi-Range Programmable DC Power Supplies Model 9201 | BK Precision | ||
| DR Instruments Medical Student Comprehensive Anatomy Dissection Kit | DR Instruments | ||
| Energizer Power Supply | Starr Life Sciences | ||
| G2 Emitteret al. | Starr Life Sciences | ||
| Layfayette Motorized Wheel Model #80840B | Layfayette | ||
| Patterson Veterinary Isoflurane | Patterson Veterinary | ||
| Platform receiveret al. | Starr Life Sciences | ||
| Scientific Environmental Chamber Model 3911 | ThermoForma | ||
| Training Wheels | Columbus Inst. |
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