利巴韦林注射液与参麦注射液单用及联合应用对甲型H1N1流感小鼠重症肺炎的疗效研究

摘要

目的：观察利巴韦林注射液（利巴韦林）与参麦注射液（参麦）单用及联合应用干预甲型H1N1流感重症肺炎小鼠的疗效，探讨两药治疗小鼠甲型H1N1流感重症肺炎的最优方案。方法：C57BL/6小鼠72只随机分为4组，模型组、参麦组、利巴韦林组、利巴韦林联合参麦组，20μL 2×105 TCID50病毒液滴鼻建立流感重症肺炎小鼠模型。利巴韦林于感染前12 h腹腔注射给药，参麦于感染后72 h腹腔注射给药，各药均1次/d，连续给药7 d。通过观察各组小鼠的存活率与体重、肺湿干比、肺组织病理等结果，评价利巴韦林、参麦两药单用及联合应用干预小鼠流感重症肺炎的疗效。结果：模型组小鼠全部死亡，肺组织病理显示，双肺弥漫性炎性反应细胞浸润，肺泡上皮细胞脱落、坏死，支气管上皮细胞变性，伴有水肿、瘀血、出血；利巴韦林组小鼠存活率为100％，肺湿干比明显降低（P＜0.01），但肺组织病理显示肺损伤严重，与模型组无异。参麦组小鼠存活率为10％，肺湿干比低于模型组（P＜0.05），肺部病理损伤严重。利巴韦林联合参麦组小鼠存活率、肺湿干比与利巴韦林组相似，但联合用药组小鼠感染第10 d后体重迅速恢复（P＜0.05），肺组织病理则显示肺脏轻度水肿，支气管、血管周围炎性细胞浸润较少，支气管上皮细胞变性、肺实变范围较小，与模型组小鼠相比肺损伤明显减轻。结论：利巴韦林与参麦联合应用对流感重症肺炎小鼠不仅具有明显的死亡保护作用，而且可减轻肺部病理损伤，促进感染小鼠恢复，缩短病程，二者联合应用疗效优于单独用药。%Objective:To observe the efficacy of Ribavirin combined with Shenmai injection on mice with severe pneumonia induced by influenza A virus and to explore an optimized intervention protocol of applying antivirals and Shenmai on mice with severe pneumonia. Methods:There was a validated mouse model for severe influenza research which could be used to evaluate potential therapeutic drugs in our laboratory.An isolate termed A/Beijing/501/2009(H1N1)(shorten for BJ501)could induce severe respiratory disease in C57 BL/6 mice which displayed a wide range of pathologic phenotypes.All infected mice were randomly divided into model group,Ribavirin group, Shenmai group and Ribavirin combined with Shenmai group.Ribavirin (starting at 12 hours before infection)and Shenmai (starting at 72 hours after infection)were both administered intraperitoneally daily for 7days.Survival rate,weight changes,acute pulmonary edema (lung wet-to-dry ratio)and lung histopathology were measured to evaluate their efficacy.Results:There was no difference in the survival rate between the Shenmai and the model group (10%vs 0%).The acute lung edema calculated by wet-to-dry ratio was eased compared with that in model group(P<0.05)while there was no difference in lung histopathology between them.The Ribavirin group had 100%survival rate and lower wet-to-dry ratio which had statistically significant differences(P<0.01)compared with the model group and SMI group,but there was no difference in lung histopathology.Survival rate in Ribavirin plus SMI group was 100%,and this group had a mini-mum weight loss.Especially after 10 days infection,the mice weight ascended much faster.At the same time,the combination group had very mild lung lesions and edema,exhibiting less inflammatory cell infiltration around bronchi and blood vessels,less bronchial epithelial cell degeneration,less lung tissue consolidation.Conclusion:The efficacy of Ribavirin combined with Shenmai to fight against influenza severe pneumonia on mouse model seems more reliable than simple regimen.The combination of Ribavirin and Shenmai is characterized by shortening the course and reducing lung injury which shows synergistic activity against influenza.Shenmai,a kind of immunomodula-tor,initiates at the time of worsening stage has provided benefit to influenza outcome.