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Effects of Artesunate on Lung Injury After Cardiac Arrest and Resuscitation in Pigs and Its Mechanism
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摘要:
目的 基于动物实验，探讨青蒿素(artesunate, Art)对心肺复苏(cardiopulmonary resuscitation, CPR)后肺组织是否具有保护作用及可能的机制。 方法 将24头健康雄性大白猪随机分为假手术组(n=6)、CPR组(n=10)和Art组(n=8)。其中CPR组和Art组采用室颤法制备CPR模型，假手术组仅进行外科准备。恢复自主循环后，Art组经股静脉持续泵入Art 4.8 mg/kg，维持2 h；CPR与假手术组同样方法泵入等量溶媒。比较3组动物基线(造模前)及复苏后肺损伤指标与肺损伤病理评分、肺组织炎症及高迁移率族蛋白B1(high mobility group box 1, HMGB1)/Toll样受体4(Toll-like receptor 4, TLR4)/核因子-κB(nuclear factor-κB, NF-κB)炎症通路活性变化。 结果 (1) 肺损伤指标：3组基线血管外肺水指数(extravascular lung water index, ELWI)、肺血管通透性指数(pulmonary vascular permeability index, PVPI)和氧合指数(oxygenation index, OI)差异均无统计学意义(P均＞0.05)。相较于假手术组，CPR组复苏后1 h、2 h和4 h时ELWI和PVPI均升高，复苏后1 h、2 h时OI均降低(P均＜0.05)；相较于CPR组，Art组复苏后不同时间点ELWI、PVPI和OI均所有改善，但仅复苏后2 h、4 h时ELWI、PVPI有显著差异(P均＜0.05)。(2)肺损伤病理评分：相较于假手术组，CPR组、Art组复苏后24 h时肺损伤病理评分均显著升高(P均＜0.05)；相较于CPR组，Art组复苏后24 h时肺损伤病理评分降低(P＜0.05)。(3)肺组织炎症：相较于假手术组，CPR组、Art组复苏后24 h时肺组织肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、白细胞介素(interleukin, IL)-1β和IL-6水平均显著升高(P均＜0.05)；相较于CPR组，Art组复苏后24 h时肺组织TNF-α、IL-1β和IL-6水平均降低(P均＜0.05)。(4)HMGB1/TLR4/NF-κB炎症通路活性：相较于假手术组，CPR组、Art组复苏后24 h时肺组织HMGB1、TLR4和NF-κB p65蛋白水平均显著升高(P均＜0.05)；相较于CPR组，Art组复苏后24 h时肺组织HMGB1、TLR4和NF-κB p65蛋白水平均降低(P均＜0.05)。 结论 Art可减轻心脏骤停复苏后肺组织炎性损伤，其作用机制可能与抑制HMGB1/TLR4/NF-κB炎症信号通路活性有关。 Abstract:Objective To explore whether artesunate (Art) has protective effect on lung tissue after cardiopulmonary resuscitation (CPR) and its potential mechanism based on animal experiment. Methods Twenty-four healthy male white pigs were randomly divided into sham group (n=6), CPR group (n=10), and Art group (n=8). The sham group only underwent the surgical preparation, and the CPR and Art groups established the CPR model by the method of ventricular fibrillation induction. After restoration of spontaneous circulation, the Art group was infused a dose of 4.8 mg/kg of Art via the femoral vein within 2 h. The same volume of vehicle was similarly infused in the sham and CPR groups. The changes of lung injury at baseline and after resuscitation, lung injury score, and lung tissue inflammation and its high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor-κB p65 (NF-κB p65) inflammatory pathway after resuscitation were compared among the three groups. Results (1) Lung injury: the levels of extravascular lung water index (ELWI), pulmonary vascular permeability index (PVPI), and oxygenation index (OI) at baseline were not significantly different among the three groups (all P > 0.05). The values of ELWI and PVPI at 1 h, 2 h, and 4 h after resuscitation were significantly increased while the values of OI at 1 h and 2 h after resuscitation were significantly decreased in the CPR group compared with the sham group (all P < 0.05). The values of ELWI, PVPI, and OI were better at each time point after resuscitation in the Art group than in the CPR group, in which the differences in ELWI and PVPI at 2 h and 4 h after resuscitation were significant between the two groups (all P < 0.05). (2)Lung injury score: the score of lung injury at 24 h after resuscitation was significantly increased in the CPR and Art groups compared with the sham group (all P < 0.05). However, the score of lung injury at 24 h after resuscitation was significantly decreased in the Art group compared with the CPR group (P < 0.05). (3)Lung tissue inflammation: the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the lung at 24 h after resuscitation were significantly increased in the CPR and Art groups compared with the sham group (all P < 0.05). However, the levels of TNF-α, IL-1β, and IL-6 in the lung at 24 h after resuscitation were significantly decreased in the Art group compared to the CPR group (all P < 0.05). (4) HMGB1/TLR4/NF-κB inflammatory pathway: the protein expression levels of HMGB1, TLR4, and NF-κB p65 in the lung at 24 h after resuscitation were significantly increased in the CPR and Art groups compared with the sham group (all P < 0.05). However, the protein expression levels of HMGB1, TLR4, and NF-κB p65 in the lung at 24 h after resuscitation were significantly decreased in the Art group compared with the CPR group (all P < 0.05). Conclusions Art could alleviate lung inflammatory injury after cardiac arrest and resuscitation, possibly through inhibiting the activation of HMGB1/TLR4/NF-κB signaling pathway. -
Key words:
- cardiac arrest /
- cardiopulmonary resuscitation /
- lung injury /
- artesunate /
- inflammatory response
作者贡献：李锋负责数据收集整理、统计分析及论文撰写；吴新杰、陈启江、刘英、徐杰丰、周光居负责实验操作与指标检测；张茂辅助研究设计与论文修订。利益冲突：所有作者均声明不存在利益冲突 -
图 4 3组肺损伤指标比较
ELWI：血管外肺水指数；PVPI：肺血管通透性指数；OI：氧合指数；CPR、Art：同图 1；*与假手术组比较，P＜0.05；#与CPR组比较，P＜0.05
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