药学学报, 2019, 54(3): 540-546
唐开城, 程立婷, 汪小又, 李翀. 一种简便的一氧化碳递送策略及抗脓毒症肺损伤的研究[J]. 药学学报, 2019, 54(3): 540-546.
TANG Kai-cheng, CHENG Li-ting, WANG Xiao-you, LI Chong. A simple strategy for delivery of carbon monoxide against septic lung injury[J]. Acta Pharmaceutica Sinica, 2019, 54(3): 540-546.

唐开城, 程立婷, 汪小又, 李翀
西南大学药学院, 重庆 400716
一氧化碳(carbon monoxide,CO)是机体内一种重要的化学气体信使分子,具有明确的抗炎活性,但作为一种气态的活性物质,如何安全、有效地递送至病灶发挥疗效有待研究。基于一氧化碳与红细胞(red blood cell,RBC)主要成分血红蛋白的天然亲和性,本文拟构建一种一氧化碳-红细胞(CO-RBC)复合体系,以脓毒症肺损伤为模型,一氧化碳释放分子(carbon monoxide releasing molecule-2,CORM-2)为对照,研究其对模型小鼠肺损伤的治疗作用。以CO-RBC中CO的释放、稳定性、安全性及体内肺靶向性对CO-RBC复合体系进行表征;以细胞间黏附分子(ICAM-1)、肺表面活性蛋白-A(SP-A)的表达评价动物模型;以肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)炎症因子的分泌、小鼠存活时间及肺组织病理变化评价CO-RBC复合体系对脓毒症肺损伤的治疗作用。实验设计获得西南大学实验动物伦理审查委员会批准,符合动物实验福利伦理准则。结果表明:CO-RBC复合体系在氮气保护下储存,稳定性强,48 h内基本无释放,而在近生理条件下时,12 h内释放约70%,解决了CORM-2中CO突释的问题,同时对小鼠无毒性;体内荧光成像显示CO-RBC复合体系能在肺部有效聚集,具有一定的肺靶向作用;给药治疗后,CO-RBC组相较于其他组,TNF-α和IL-6的分泌明显降低,肺间质水肿程度减轻,白细胞浸润减少,存活率显著提高。因此,本研究制备的CO-RBC复合体系相比CORM-2对脓毒症小鼠肺部炎症反应有显著的抑制作用,有望为脓毒症的治疗提供新思路。
A simple strategy for delivery of carbon monoxide against septic lung injury
TANG Kai-cheng, CHENG Li-ting, WANG Xiao-you, LI Chong
College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
Carbon monoxide (CO) is an important chemical gas messenger molecule in the body with anti-inflammatory activity. As an active substance in gaseous state, the method for its safe and effective delivery towards the lesion sites remains to be established. Based on the natural affinity of carbon monoxide to hemoglobin, a main component of red blood cells (RBCs), this study proposes a carbon monoxide-red blood cell (CO-RBC) composite system, and tested its therapeutic effect against lung injury in an animal model. The mouse model of septic lung injury was adopted, and the carbon monoxide release molecule (CORM-2) was used as a positive control. CO-RBC system was characterized by CO release, stability, toxicity and in vivo lung targeting. The expression of intercellular adhesion molecule (ICAM-1) and pulmonary surfactant protein-A (SP-A) were evaluated in the animal model and the therapeutic effect of CO-RBC system for sepsis was measured by inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), as well as survival time of mice and pathological changes of the lung. Our results show that CO-RBC system exhibited satisfactory stability with negligible CO release during 48 h storage under nitrogen protection, while the CO release was about 70% within 12 h under physiological condition, in contrast to CO burst release from CORM-2. The CO-RBC system showed no significant toxicity in the animal model, and in vivo fluorescence imaging results showed effective accumulation in the lungs, supporting its lung targeting effects. The secretion of TNF-α and IL-6 in the CO-RBC group was significantly lower than that in other groups, the degree of pulmonary interstitial edema was relieved, the white blood cell infiltration was decreased, and the survival rate was significantly improved. Therefore, the CO-RBC system has a significant inhibitory effect on the pulmonary inflammatory response in septic mice compared with CORM-2. This system provides a new hope for therapeutic treatment of sepsis.
Key words:   
收稿日期: 2018-12-12
DOI: 10.16438/j.0513-4870.2018-1105
基金项目: 中央高校基本科研业务费专项资金项目资助(XDJK2018AC003).
通讯作者: 李翀
Email: chongli2009@gmail.com
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