复原胶囊对脓毒症大鼠肾表达HIF的影响
摘要
脓毒症是由感染引起的全身炎症反应综合症(SIRS),严重时可导致多器官功能障碍(MODS),其发病率与死亡率在重症监护病房(ICU)的病人中日益剧增。脓毒症发病的病理生理机制复杂,应激导致神经-免疫-内分泌三大系统激活,炎症级联扩大,随后的免疫抑制、微循环障碍及凝血/抗凝失衡导致的组织缺血缺氧,加重了组织损伤、内环境紊乱、抵抗力降低,使感染进一步扩散。临床上许多高难诊治技术也无法挽救危重症病人的生命,使得脓毒症的治疗效果欠佳。而祖国医学则被证明对严重疾患或疑难杂症有确切的调理作用,早期治疗可明显改善患者的病程进展及预后。因此我们制作脓毒症模型,用中药复原胶囊治疗,观察其对脓毒症大鼠肾组织表达HIF及对炎症反应的影响。
目的
通过复制脓毒症动物模型,予以中药复原胶囊治疗,检测肾组织缺氧诱导因子-1(HIF-1)mRNA含量及血清炎症介质白细胞介素-6(IL-6)水平,观察主要脏器组织学和功能的变化,探讨复原胶囊对脓毒症大鼠器官的保护机制。
方法
1.分组:雄性SD大鼠120只随机分为5个组,假手术组(sham组),模型组,复原胶囊低剂量组,复原胶囊高剂量组,血必净组。每组包括3h,6h,12h,24h四个时相点,各时相点6只大鼠。
2.造模及给药方法:参照文献复制脓毒症CLP模型【13】。复原胶囊高、低剂量组均为连续灌胃(60%复原胶囊混悬液2.5ml/次,2次/天) 4天后行CLP造模;血必净组连续腹腔注射给药(8ml/kg)4天后行CLP造模。
3.观察指标:各组大鼠计数24h死亡率;检测IL-6水平变化;肾功能BUN变化;缺氧诱导因子HIF-1αmRNA的含量;主要脏器(心、肝、肠、肺、肾)的形态学改变。
结果
1、各组大鼠形态学变化:光镜观察(HE染色)发现模型组大鼠肝细胞充血、肿胀、变性;肺间质出现部分扩张、塌陷,肺泡红细胞渗出;心肌出现局灶出血;肾小球出现毛细血管淤血;肠粘膜绒毛坏死、脱落,上皮细胞充血、水肿。以上改变提示脓毒症模型复制成功。
2、各组大鼠24h死亡统计假手术组大鼠24h均无死亡,模型组大鼠24h死亡率为46%(11/24),复原胶囊低剂量组24h死亡率为38%(9/24),复原胶囊高剂量组24h死亡率为25%(6/24),血必净组24h死亡率为21%(5/24)
3、各组大鼠HIFmRNA表达:模型组HIF-1αmRNA表达水平随时间逐渐增高,24h达高峰,与假手术组比较差异有统计学意义(P<0.05或P<0.01);血必净HIF-1αmRNA表达水平升高不明显,与假手术组比较无统计学意义(P>0.05);复原胶囊高剂量组与模型组比较,3hHIF-1amRNA增高,其余各时相点均降低,各时相点差异均有统计学意义(P<0.05或P<0.01);复原胶囊高剂量组与血必净组比较各时相点差异均无统计学意义(P>0.05);复原胶囊低剂量组24h时相点与模型组比较,HIF-1amRNA表达降低,差异有统计学意义(P<0.05)。
4、各组大鼠IL-6表达水平:模型组、复原胶囊高、低剂量组、血必净组IL-6水平随时间逐渐增高,与假手术组比较各组各时相点差异均有统计学意义(P<0.01);与模型组比较,复原胶囊高剂量组各时相点IL-6水平均较低,到6h后IL-6降低水平才有统计学意义(P<0.05);复原胶囊高剂量组与血必净组比较差异无统计学意义(P>0.05);复原胶囊低剂量组与模型组比较差异无统计学意义(P>0.05)。
5、各组大鼠BUN变化:各组大鼠CLP后BUN升高,模型组、复原胶囊低剂量组术后12h、24hBUN升高与假手术组比较,差异有统计学意义(P<0.01)。血必净组各时相点BUN与假手术组比较差异无统计学意义(P>0.05)。复原胶囊高剂量组24h时相点BUN变化与假手术组比较,差异有统计学意义(P<0.05);复原胶囊高剂量组12h、24hBUN变化与模型组比较,差异有统计学意义(P<0.05)。复原胶囊高剂量组与血必净组比较差异无统计学意义(P>0.05);复原胶囊低剂量组各时相点BUN变化与模型组比较,差异无统计学意义;
结论:
1.复原胶囊高、低剂量组均一定程度降低脓毒症大鼠死亡率,高剂量组死亡率更低,提示对脓毒症的防治有一定功效,且与剂量有关。
2.脓毒症时,HIF与炎症介质IL-6均升高,二者趋于一致,说明HIF与炎症反应有关。
3.复原胶囊高剂量组可减轻脓毒症时肾脏损伤,提示复原胶囊对脓毒症各脏器有保护作用。
Systemic inflamatory response syndrome(SIRS) is characteristic of infection with severe sepsis,which can lead to Multiple organ dysfunction(MODS).The morbility and mortality of patient in the Intensive care unit(ICU) is increasd correspondingly. The pathophysiologic mechanism of pathogenesis in sepsis is complicated.Of the three major system Nerve-immune-endocrine is actived by stress,with inflamation cascade expansion followed by immunization paralyzed.Microcirculation dysfunction and coagulation / anticoagulation imbalance intensify tissue ischemia and hypoxia, increased tissue damage, internal environmental disorders, lowered immunity, so that the further spread of infection.The develop of many advance high-technology diagnosis and treatment is also difficult to save the lives of critically ill patients, making the treatment of sepsis ineffective. The Traditional Chinese Medicine has been proved to be good efficacy in mediation of serious incurable condition,early treatment can improve disease progression and prognosis significantly .Therefore, we have produced sepsis model, and should be treated with Traditional Chinese Medicine Fu Yuan capsule,to observe its effect on the inflammatory response.
Objective
Model of sepsis is produced for therapy of Fu Yuan capsule and investigate the difference of hypoxia-inducible factor-1(HIF-1) mRNA levels and serum inflammatory mediators interleukin-6 (IL-6) levels in sepsie rat kidney in contrast to Sham and CLP group. Evaluate organ histology and function change, thus to explore Traditional Chinese Medicine for organ protection mechanisms.
Material and Methods
120 male SD rats were randomly divided into five groups, sham-operation group, model group, low-dose Fu Yuan capsule group and high-dose Fu Yuan capsule groups, xuebijing group,each including 3h, 6h, 12h, 24h four time points,6 per group.Model group marked by cecal ligation and puncture,Sham group was performed as CLP without ligation and puncture of the cecum.The two FuYuan capsule group were also given CLP operation after four days of successive intragastric administration. Rats in each group count of 24h mortality,at each time point. rats blood sample from cardiac extracts serum IL-6 was measured by enzyme linked immunosorbent assay (ELISA),and biochemical changes in renal function Blood urea nitrogen(BUN) were analyzed.Rat kidney tissue HIFmRNA levels were detected by Polymerase chain reaction( PCR) assay at each time point. The major organs (heart, liver, spleen, lung, kidney)histologic and morphological changes were observed by Hematoxylin and rosin(HE) staining method.
Result
1、The 24-hour-mortality of rat was null in Sham group.Rat in CLP group had the mortality of 46%(11/24).Mortality in Low-dose Fu Yuan capsule group and High-dose Fu Yuan capsule group was 38%(9/24) and 26%(6/24) respectively.Mortality of xuebijing group was21%(5/24). Compared with the sham-operated group, other groups at all time points IL-6 were at a higher level, the difference was statistically significant (P <0.01). Model group, IL-6 levels continued to increase over time,The low-dose Fu Yuan capsule group, at each time point IL-6 had no significant change compared with model group(P> 0.05), high-dose Fu Yuan capsule group in 6h、12h、24h time piont Compared with model group, IL-6 levels decreased significantly (P <0.05).
2、Levels of HIF-1mRNA expression in model group、Fu Yuan Low/High dose group were dramaticly higher, the difference was statistically significant compared with sham group (P <0.05 or P <0.01);Levels of HIF-1mRNA expression was higher in High-dose Fu Yuan 3h group,the remaining time point were lower, the difference was statistically significant compared with model group(P <0.05 or P <0.01); low dose Fu Yuan group 24h time points compared with model group, the difference was statistically significant (P < 0.05).
3、Model group、the Fu Yuan capsule high-and low-dose group of IL-6 levels increased gradually over time, compared with the sham operation group at all time points the differences were statistically significant (P <0.01);Each time point IL-6 levels in High-dose Fu Yuan capsule group were lower compared with model group,but until 6h the difference proved significant (P <0.05);The Low-dose Fu Yuan capsule group had no significant change compared with model group (P> 0.05) .
4、Compared with the sham-operated group, HE staining showed severe pathological change in organs of model group.Engorgement,swelling,degeneration and necrosis were found in hepatocytes. Focal atelectasis,erthrocyte exdudation in pulmonary alveoli were observed; myocardium appeared focal hemorrhage, glomerular capillary congestion occurs,Hyperemia,necrosis and detachment were found in ileum mucosa.Renal tissue of Fu Yuan high-dose group had reduced pathological change compared with model group. Model group, low-dose Fu Yuan capsule group 12h, 24h after surgery BUN found increased compared with the sham operation group, the difference was statistically significant (P <0.01);Fu Yuan capsule high dose group 12h, 24h time points BUN lowered ,the difference was statistically significant compared with model group (P <0.05). Fu Yuan capsule high dose group 24h time points BUN changed,the difference was statistically significant compared with sham group(P <0.05).
Conclusion
HIFmRNA and IL-6 elavate consistenly during sepsis,this show HIF has some realationship with IL-6.
Fuyuan capsule high dose group could reduce damage in kindy,with its mechanism to regulate HIF expression.
To some extent the two fuyuan capsule group could decrease death rate.this has some effect for sepsis prevention and cure.and aline with the drug administration.
目的
通过复制脓毒症动物模型,予以中药复原胶囊治疗,检测肾组织缺氧诱导因子-1(HIF-1)mRNA含量及血清炎症介质白细胞介素-6(IL-6)水平,观察主要脏器组织学和功能的变化,探讨复原胶囊对脓毒症大鼠器官的保护机制。
方法
1.分组:雄性SD大鼠120只随机分为5个组,假手术组(sham组),模型组,复原胶囊低剂量组,复原胶囊高剂量组,血必净组。每组包括3h,6h,12h,24h四个时相点,各时相点6只大鼠。
2.造模及给药方法:参照文献复制脓毒症CLP模型【13】。复原胶囊高、低剂量组均为连续灌胃(60%复原胶囊混悬液2.5ml/次,2次/天) 4天后行CLP造模;血必净组连续腹腔注射给药(8ml/kg)4天后行CLP造模。
3.观察指标:各组大鼠计数24h死亡率;检测IL-6水平变化;肾功能BUN变化;缺氧诱导因子HIF-1αmRNA的含量;主要脏器(心、肝、肠、肺、肾)的形态学改变。
结果
1、各组大鼠形态学变化:光镜观察(HE染色)发现模型组大鼠肝细胞充血、肿胀、变性;肺间质出现部分扩张、塌陷,肺泡红细胞渗出;心肌出现局灶出血;肾小球出现毛细血管淤血;肠粘膜绒毛坏死、脱落,上皮细胞充血、水肿。以上改变提示脓毒症模型复制成功。
2、各组大鼠24h死亡统计假手术组大鼠24h均无死亡,模型组大鼠24h死亡率为46%(11/24),复原胶囊低剂量组24h死亡率为38%(9/24),复原胶囊高剂量组24h死亡率为25%(6/24),血必净组24h死亡率为21%(5/24)
3、各组大鼠HIFmRNA表达:模型组HIF-1αmRNA表达水平随时间逐渐增高,24h达高峰,与假手术组比较差异有统计学意义(P<0.05或P<0.01);血必净HIF-1αmRNA表达水平升高不明显,与假手术组比较无统计学意义(P>0.05);复原胶囊高剂量组与模型组比较,3hHIF-1amRNA增高,其余各时相点均降低,各时相点差异均有统计学意义(P<0.05或P<0.01);复原胶囊高剂量组与血必净组比较各时相点差异均无统计学意义(P>0.05);复原胶囊低剂量组24h时相点与模型组比较,HIF-1amRNA表达降低,差异有统计学意义(P<0.05)。
4、各组大鼠IL-6表达水平:模型组、复原胶囊高、低剂量组、血必净组IL-6水平随时间逐渐增高,与假手术组比较各组各时相点差异均有统计学意义(P<0.01);与模型组比较,复原胶囊高剂量组各时相点IL-6水平均较低,到6h后IL-6降低水平才有统计学意义(P<0.05);复原胶囊高剂量组与血必净组比较差异无统计学意义(P>0.05);复原胶囊低剂量组与模型组比较差异无统计学意义(P>0.05)。
5、各组大鼠BUN变化:各组大鼠CLP后BUN升高,模型组、复原胶囊低剂量组术后12h、24hBUN升高与假手术组比较,差异有统计学意义(P<0.01)。血必净组各时相点BUN与假手术组比较差异无统计学意义(P>0.05)。复原胶囊高剂量组24h时相点BUN变化与假手术组比较,差异有统计学意义(P<0.05);复原胶囊高剂量组12h、24hBUN变化与模型组比较,差异有统计学意义(P<0.05)。复原胶囊高剂量组与血必净组比较差异无统计学意义(P>0.05);复原胶囊低剂量组各时相点BUN变化与模型组比较,差异无统计学意义;
结论:
1.复原胶囊高、低剂量组均一定程度降低脓毒症大鼠死亡率,高剂量组死亡率更低,提示对脓毒症的防治有一定功效,且与剂量有关。
2.脓毒症时,HIF与炎症介质IL-6均升高,二者趋于一致,说明HIF与炎症反应有关。
3.复原胶囊高剂量组可减轻脓毒症时肾脏损伤,提示复原胶囊对脓毒症各脏器有保护作用。
Systemic inflamatory response syndrome(SIRS) is characteristic of infection with severe sepsis,which can lead to Multiple organ dysfunction(MODS).The morbility and mortality of patient in the Intensive care unit(ICU) is increasd correspondingly. The pathophysiologic mechanism of pathogenesis in sepsis is complicated.Of the three major system Nerve-immune-endocrine is actived by stress,with inflamation cascade expansion followed by immunization paralyzed.Microcirculation dysfunction and coagulation / anticoagulation imbalance intensify tissue ischemia and hypoxia, increased tissue damage, internal environmental disorders, lowered immunity, so that the further spread of infection.The develop of many advance high-technology diagnosis and treatment is also difficult to save the lives of critically ill patients, making the treatment of sepsis ineffective. The Traditional Chinese Medicine has been proved to be good efficacy in mediation of serious incurable condition,early treatment can improve disease progression and prognosis significantly .Therefore, we have produced sepsis model, and should be treated with Traditional Chinese Medicine Fu Yuan capsule,to observe its effect on the inflammatory response.
Objective
Model of sepsis is produced for therapy of Fu Yuan capsule and investigate the difference of hypoxia-inducible factor-1(HIF-1) mRNA levels and serum inflammatory mediators interleukin-6 (IL-6) levels in sepsie rat kidney in contrast to Sham and CLP group. Evaluate organ histology and function change, thus to explore Traditional Chinese Medicine for organ protection mechanisms.
Material and Methods
120 male SD rats were randomly divided into five groups, sham-operation group, model group, low-dose Fu Yuan capsule group and high-dose Fu Yuan capsule groups, xuebijing group,each including 3h, 6h, 12h, 24h four time points,6 per group.Model group marked by cecal ligation and puncture,Sham group was performed as CLP without ligation and puncture of the cecum.The two FuYuan capsule group were also given CLP operation after four days of successive intragastric administration. Rats in each group count of 24h mortality,at each time point. rats blood sample from cardiac extracts serum IL-6 was measured by enzyme linked immunosorbent assay (ELISA),and biochemical changes in renal function Blood urea nitrogen(BUN) were analyzed.Rat kidney tissue HIFmRNA levels were detected by Polymerase chain reaction( PCR) assay at each time point. The major organs (heart, liver, spleen, lung, kidney)histologic and morphological changes were observed by Hematoxylin and rosin(HE) staining method.
Result
1、The 24-hour-mortality of rat was null in Sham group.Rat in CLP group had the mortality of 46%(11/24).Mortality in Low-dose Fu Yuan capsule group and High-dose Fu Yuan capsule group was 38%(9/24) and 26%(6/24) respectively.Mortality of xuebijing group was21%(5/24). Compared with the sham-operated group, other groups at all time points IL-6 were at a higher level, the difference was statistically significant (P <0.01). Model group, IL-6 levels continued to increase over time,The low-dose Fu Yuan capsule group, at each time point IL-6 had no significant change compared with model group(P> 0.05), high-dose Fu Yuan capsule group in 6h、12h、24h time piont Compared with model group, IL-6 levels decreased significantly (P <0.05).
2、Levels of HIF-1mRNA expression in model group、Fu Yuan Low/High dose group were dramaticly higher, the difference was statistically significant compared with sham group (P <0.05 or P <0.01);Levels of HIF-1mRNA expression was higher in High-dose Fu Yuan 3h group,the remaining time point were lower, the difference was statistically significant compared with model group(P <0.05 or P <0.01); low dose Fu Yuan group 24h time points compared with model group, the difference was statistically significant (P < 0.05).
3、Model group、the Fu Yuan capsule high-and low-dose group of IL-6 levels increased gradually over time, compared with the sham operation group at all time points the differences were statistically significant (P <0.01);Each time point IL-6 levels in High-dose Fu Yuan capsule group were lower compared with model group,but until 6h the difference proved significant (P <0.05);The Low-dose Fu Yuan capsule group had no significant change compared with model group (P> 0.05) .
4、Compared with the sham-operated group, HE staining showed severe pathological change in organs of model group.Engorgement,swelling,degeneration and necrosis were found in hepatocytes. Focal atelectasis,erthrocyte exdudation in pulmonary alveoli were observed; myocardium appeared focal hemorrhage, glomerular capillary congestion occurs,Hyperemia,necrosis and detachment were found in ileum mucosa.Renal tissue of Fu Yuan high-dose group had reduced pathological change compared with model group. Model group, low-dose Fu Yuan capsule group 12h, 24h after surgery BUN found increased compared with the sham operation group, the difference was statistically significant (P <0.01);Fu Yuan capsule high dose group 12h, 24h time points BUN lowered ,the difference was statistically significant compared with model group (P <0.05). Fu Yuan capsule high dose group 24h time points BUN changed,the difference was statistically significant compared with sham group(P <0.05).
Conclusion
HIFmRNA and IL-6 elavate consistenly during sepsis,this show HIF has some realationship with IL-6.
Fuyuan capsule high dose group could reduce damage in kindy,with its mechanism to regulate HIF expression.
To some extent the two fuyuan capsule group could decrease death rate.this has some effect for sepsis prevention and cure.and aline with the drug administration.
引文
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