血红蛋白类携一氧化碳载体CO-PolyPHb对重度烫伤延迟复苏大鼠心肌保护及功能重建的机制研究

Protection of severe burn patient’s heart is clinically important, because of the cardiac damage, myocardial contractility inhibition, cardiac output decrease happened 1 hour after suffering severe burns. This situation will not only induce or aggravate shock, but also cause damages or dysfunction in important organs, such as liver, kidneys, lungs, thus increase the mortality of the patient. However, the exact mechanisms for this cardiac damage after severe burns are not completely understood. Also, it lack promising treatment. Based on our previous findings, this study, by use of functional magnetic resonance imaging (fMRI) and molecular biological methods, we will investigate the cardioprotective effect of carbon monoxide saturated hemoglobin based oxygen carrier (CO-PolyPHb) on rat suffering from severe burns with delayed fluid resuscitation. In addition, this study will reveal that CO-PolyPHb will activate mitochondrial biosynthesis-related CO/Nrf2 signaling pathway, in addition to its excellent perfusion capacity in microcirculation, which will promote cardiac structural and functional reconstruction. Based on this study, we will provide a more reasonable and effective strategy in treatment of severe burn patient, and will provide theoretical foundation and practical basis to further explore the mechanism underlying organ dysfunction in severe burns with delayed fluid resuscitation.

重度烧伤延迟复苏患者早期心脏的保护至关重要。烧伤后1小时即可发生心肌损害，不仅会诱发或加重休克，还将序贯性导致肝、肾、肺等重要脏器结构和功能损伤的多器官功能障碍或衰竭，死亡率极高。但目前对重度烧伤早期心肌损伤的机制不清，也缺乏有效的保护措施。基于前期研究基础，本申请将通过大鼠重度烫伤模型，结合功能性核磁共振（fMRI）以及分子生物学手段，系统研究血红蛋白类携一氧化碳载体CO-PolyPHb在延迟复苏状态下对大鼠心脏的保护作用及剂量相关性，揭示CO-PolyPHb可通过激活与线粒体合成密切相关的CO/Nrf2信号通路，以及自身高效的微循环灌注能力，发挥双重保护作用，促进烧伤后延迟复苏大鼠心脏心肌结构恢复及功能重塑。本课题的顺利实施，不仅可以为重度烧伤病人的诊疗提供一种更合理，更高效的心脏保护方案和策略，还将为进一步探明重度烧伤延迟复苏患者严重并发症的发生机制及治疗靶点奠定理论依据和技术支持。

重度烧伤延迟复苏患者早期心脏的保护至关重要。烧伤后1小时即可发生心肌损害，不仅会诱发或加重休克，还将序贯性导致肝、肾、肺等重要脏器结构和功能损伤的多器官功能障碍或衰竭，死亡率极高。但目前对重度烧伤早期心肌损伤的机制不清，也缺乏有效的保护措施。基于前期研究基础，本课题制备了血红蛋白类一氧化碳载体（CO-PolyPHb），建立了稳定的重度烫伤大鼠复苏模型，并通过离体与在体实验，（1）发现CO-PolyPHb溶液置换可逆转重度烫伤大鼠的心脏功能损害；（2）证实CO-PolyPHb可防止重度烫伤导致的血管内皮细胞脱离；（3）证实CO-PolyPHb对于改善重度烫伤大鼠心肌线粒体氧化应激有显著作用；（4）证实CO-PolyPHb是通过胰岛素信号相关通路介导重度烫伤后心肌线粒体修复。综上，该课题揭示重度烧伤早期心肌损伤涉及线粒体氧化应激、主动脉内皮细胞受损、糖代谢受损等多个环节，并证实CO-PolyPHb可通过胰岛素通路改善烧伤后心肌线粒体氧化应激，从而促进烧伤后心肌结构的恢复及功能重塑。该结果为重度烧伤病人提供了更合理、更高效的心脏保护方案和策略。受该基金资助，共发表论著5篇，其中SCI 4 篇。培养博士研究生1人，硕士研究生2人。