参附黄注射液对脓毒症大鼠的器官保护作用及其分子机制研究
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摘要
脓毒症是具有感染依据的全身炎症反应综合症,是烧创伤、休克、感染等临床危急重症患者的严重并发症之一,也是诱发脓毒性休克、多器官功能障碍综合症的重要原因。脓毒症的发病不仅与炎症失控相关,还涉及到免疫系统、凝血系统、内分泌调节等以及它们之间的相互作用。目前脓毒症发病率居高不下,缺乏行之有效的治疗方法,而且成本高昂,成为严重影响生命健康的重要疾患,中西医结合治疗可能是提高脓毒症防治效果的有效途径之一。
1理论依据
总结临床危急重症救治经验,提出对脓毒症中医病因病机的新认识:外来之毒与内生毒邪互结是主要病因基础;内陷营血是主要病变层次;深入络脉是传变的重要途径;正虚毒损、络脉闭阻是关键病机变化;扶正解毒通络、分层扭转是主要治则。由中药大黄、附子和红参提取有效成分,制备参附黄注射液,作为本治法的代表方剂。
2参附黄注射液对脓毒症动物死亡率和器官功能和形态的影响
采用盲肠结扎穿孔手术(CLP)复制脓毒症大鼠模型,静脉注射参附黄注射液。雄性Wistar大鼠96只,随机分为4组:①正常对照组,n=8;②假手术组,n=8;③盲肠结扎穿孔组,n=40,按时间点分为CLP后2、8、24、48小时组;④参附黄注射液治疗组,n=40,分组同模型组。经腹主动脉采血,无菌留取肝、肺、肾组织,冷冻保存备用。观察脓毒症大鼠死亡率、生存时间和肝、肺脏病理学改变,检测肝功、肾功、心肌酶谱和二胺氧化酶水平变化。结果显示:治疗组术后72小时死亡率明显降低(88.88% vs. 67.57%),术后48小时死亡率也有降低趋势(83.33% vs. 62.16%),治疗组生存时间明显延长,但两组死亡率在术后120小时和1周的终末观察点无差别。可见,参附黄注射液有改善脓毒症动物预后的作用,虽然没有改变死亡的终末结果,但是延长了生存时间,为早期救治赢得宝贵的时机。治疗组动物血清ALT、AST、BUN、Cr水平在CLP术后24小时和48小时均有不同程度的下降,具有统计学差异。治疗组2小时、24小时DAO水平有下降趋势。本药对心肌酶无明显影响。肝、肺组织病理学观察显示:治疗组组织病理改变程度显著减轻。参附黄注射液能够改善脓毒症动物模型的肝、肾器官功能,减轻肝、肺和肠道组织损伤,对脓毒症动物具有一定的器官保护作用。
3参附黄注射液对脓毒症动物炎症介质基因表达和蛋白合成的影响
采用ELISA试剂盒检测脓毒症动物血浆和肝、肺组织匀浆中TNF-α、IL-10的蛋白水平,荧光实时定量PCR技术测定肝、肺组织TNF-αmRNA、IL-10 mRNA表达。TNF-α是目前已知释放最早的细胞因子之一,也是炎症反应的最初触发者。结果显示:正常组织中有少量的TNF-α蛋白合成,其中肝脏含量多,约为肺脏的70倍。术后2小时,肝、肺组织
Sepsis is a systemic inflammatory response syndrome triggered by infection. It is a lethal syndrome that develops with burns, shock and infection, resulting in mortality rates between 30 and 70 percent in the United States. Severe sepsis can be characterized in part by the excessive activation of the host inflammatory response and the inappropriate activation of the coagulation cascade. Despite continuing progress in the development of antibiotics and other supportive care therapies,sepsis remains a leading cause of the high morbidity and mortality in the intensive care unit. The outcome of sepsis has not improved significantly in the past years. Perhaps the treatment combining Modern Medicine and Traditional Chinese Medicine (TCM) is a potential way to solve the problem.
1. Theory hypothesis
The new understanding of sepsis pathogenesis of TCM is built on the basis of clinical experience. The main idea include: exogenous and endogenous toxic substances are main causes of sepsis, internal injury of Ying-blood is location of sepsis, Collateral Vessel is passway of sepsis. The main pathogenesis of sepsis is due to the declined anti-pathogenic Qi, so, the extraneous and endogenetic toxic substances attack collateral vessels which cause heat, blood stasis and phlegm accumulate, leading multiple organ dysfunction. The treatment principle is to strengthen body resistance, relieve toxic materials and activate collateral vessels, such methods should be used step by step.
2. Effect of Shenfuhuang Injection on multiple organ dyafunction and mortality of septic rats
To prepare the septic animal model with cecal ligation and puncture(CLP), 96 male Wistar rats were randomly divided into four groups: normal control group(n= 8), sham operation group(n= 8), CLP group(n= 40, being further divided into 2h, 8h, 24h, 48h subgroups),SFH Injection treatment group (n=40, being further divided into 2h, 8h, 24h, 48h subgroups, drugs were inraveously injected just after operation and per 12h). The mortality of animals and changes in organ function parameters were observed within 7 days after operation. Compared to CLP model, mortality of septic rats in SFH Injection group was significant lower (88.88% vs. 67.57%) and the treatment prolonged survival duration. SFH Injection group showed lower values of ALT, AST, BUN and Cr in serum. HE-stained sections revealed that SFH Injection improved acute lung and liver injury. Conclusion: SFH Injection can obviously reduce the mortality of septic rats and play an important role in attenuating organ disfunction.
1理论依据
总结临床危急重症救治经验,提出对脓毒症中医病因病机的新认识:外来之毒与内生毒邪互结是主要病因基础;内陷营血是主要病变层次;深入络脉是传变的重要途径;正虚毒损、络脉闭阻是关键病机变化;扶正解毒通络、分层扭转是主要治则。由中药大黄、附子和红参提取有效成分,制备参附黄注射液,作为本治法的代表方剂。
2参附黄注射液对脓毒症动物死亡率和器官功能和形态的影响
采用盲肠结扎穿孔手术(CLP)复制脓毒症大鼠模型,静脉注射参附黄注射液。雄性Wistar大鼠96只,随机分为4组:①正常对照组,n=8;②假手术组,n=8;③盲肠结扎穿孔组,n=40,按时间点分为CLP后2、8、24、48小时组;④参附黄注射液治疗组,n=40,分组同模型组。经腹主动脉采血,无菌留取肝、肺、肾组织,冷冻保存备用。观察脓毒症大鼠死亡率、生存时间和肝、肺脏病理学改变,检测肝功、肾功、心肌酶谱和二胺氧化酶水平变化。结果显示:治疗组术后72小时死亡率明显降低(88.88% vs. 67.57%),术后48小时死亡率也有降低趋势(83.33% vs. 62.16%),治疗组生存时间明显延长,但两组死亡率在术后120小时和1周的终末观察点无差别。可见,参附黄注射液有改善脓毒症动物预后的作用,虽然没有改变死亡的终末结果,但是延长了生存时间,为早期救治赢得宝贵的时机。治疗组动物血清ALT、AST、BUN、Cr水平在CLP术后24小时和48小时均有不同程度的下降,具有统计学差异。治疗组2小时、24小时DAO水平有下降趋势。本药对心肌酶无明显影响。肝、肺组织病理学观察显示:治疗组组织病理改变程度显著减轻。参附黄注射液能够改善脓毒症动物模型的肝、肾器官功能,减轻肝、肺和肠道组织损伤,对脓毒症动物具有一定的器官保护作用。
3参附黄注射液对脓毒症动物炎症介质基因表达和蛋白合成的影响
采用ELISA试剂盒检测脓毒症动物血浆和肝、肺组织匀浆中TNF-α、IL-10的蛋白水平,荧光实时定量PCR技术测定肝、肺组织TNF-αmRNA、IL-10 mRNA表达。TNF-α是目前已知释放最早的细胞因子之一,也是炎症反应的最初触发者。结果显示:正常组织中有少量的TNF-α蛋白合成,其中肝脏含量多,约为肺脏的70倍。术后2小时,肝、肺组织
Sepsis is a systemic inflammatory response syndrome triggered by infection. It is a lethal syndrome that develops with burns, shock and infection, resulting in mortality rates between 30 and 70 percent in the United States. Severe sepsis can be characterized in part by the excessive activation of the host inflammatory response and the inappropriate activation of the coagulation cascade. Despite continuing progress in the development of antibiotics and other supportive care therapies,sepsis remains a leading cause of the high morbidity and mortality in the intensive care unit. The outcome of sepsis has not improved significantly in the past years. Perhaps the treatment combining Modern Medicine and Traditional Chinese Medicine (TCM) is a potential way to solve the problem.
1. Theory hypothesis
The new understanding of sepsis pathogenesis of TCM is built on the basis of clinical experience. The main idea include: exogenous and endogenous toxic substances are main causes of sepsis, internal injury of Ying-blood is location of sepsis, Collateral Vessel is passway of sepsis. The main pathogenesis of sepsis is due to the declined anti-pathogenic Qi, so, the extraneous and endogenetic toxic substances attack collateral vessels which cause heat, blood stasis and phlegm accumulate, leading multiple organ dysfunction. The treatment principle is to strengthen body resistance, relieve toxic materials and activate collateral vessels, such methods should be used step by step.
2. Effect of Shenfuhuang Injection on multiple organ dyafunction and mortality of septic rats
To prepare the septic animal model with cecal ligation and puncture(CLP), 96 male Wistar rats were randomly divided into four groups: normal control group(n= 8), sham operation group(n= 8), CLP group(n= 40, being further divided into 2h, 8h, 24h, 48h subgroups),SFH Injection treatment group (n=40, being further divided into 2h, 8h, 24h, 48h subgroups, drugs were inraveously injected just after operation and per 12h). The mortality of animals and changes in organ function parameters were observed within 7 days after operation. Compared to CLP model, mortality of septic rats in SFH Injection group was significant lower (88.88% vs. 67.57%) and the treatment prolonged survival duration. SFH Injection group showed lower values of ALT, AST, BUN and Cr in serum. HE-stained sections revealed that SFH Injection improved acute lung and liver injury. Conclusion: SFH Injection can obviously reduce the mortality of septic rats and play an important role in attenuating organ disfunction.
引文
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