不同时程控制性低血压对大鼠海马CA1区及血清中TNF-α和IL-1β表达的影响
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摘要
研究背景
控制性低血压是临床上常用的麻醉技术。目前认为MAP50-55mmHg是控制性低血压的安全低限。在此范围内，脑血流的自身调节能力仍然保持，脑组织能够得到良好的灌注，不会有缺血缺氧的危害。但其研究时间仅仅在1-2小时，然而随着临床上外科学的不断发展，重大而复杂的外科手术（如矫形外科）常常需要5-6个小时的手术时间且术中需要控制性低血压。这就需要麻醉中控制性降压技术的支持。但是较长时间的低血压是否会对脑组织产生缺血缺氧性损伤，目前罕见报道。
脑缺血缺氧性损伤是一个复杂的病理变化过程，大量研究表明，炎症反应时大量白细胞的浸润是对脑组织造成损伤的一个重要诱因，白细胞的浸润又与细胞间粘附分子（ICAM-1）相关，而TNF-α和IL-1β作为促炎症因子则在炎症反应中起到重要作用，两者通过抑制核因子（NF-kB）使单核巨噬细胞和其他细胞使ICAM-1、IL-6、IL-8等细胞因子的分泌增多，ICAM-1表达上调后使得白细胞滚动并聚集在内皮细胞，穿透内皮细胞作用于缺血脑组织，通过兴奋性氨基酸的生产释放，钙离子超载，自由基的形成，血管收缩反应的变化以及微血栓的形成使缺血脑组织的损伤进一步恶化。大量研究表明TNF-α在热休克及缺血再灌注脑缺血损伤大鼠模型中，其表达均有显著升高，从而提示了过多TNF-α参与了脑缺血再灌注损伤的发病过程。同样有研究报道,短暂性脑缺血即可诱导IL-1β的表达上调,若给予注射IL-1β中和抗体或IL-1β受体阻滞剂则可减轻脑组织的缺血缺氧性损伤。
目的本实验通过硝普钠联合艾司洛尔实施控制性降压，观察在安全低限内（MAP50-55mmHg），大鼠对低血压时程的耐受能力以及脑损伤的发生发展情况。
方法SD雄性大鼠随机分为5组，每组6只，①空白组A组②手术对照组C组③控制性降压组H组，又根据时程分为2h,4h,6h,分别对应H1，H2，H3组。术中应用硝普钠联合艾司洛尔进行控制性降压，MAP控制在50-55mmHg。术中监测MAP及HR并做血气分析，术前术后分别留取1ml动脉血离心后留血清标本，术后24小时行大鼠神经行为学评分(NSS)。应用免疫组化和ELISIA技术评估大鼠海马CA1区及血清中TNF-α和IL-1β的表达变化。
结果1.A组、C组、H1组和H2组大鼠在控制性降压后的生存率为100%，而H3组大鼠的生存率为50%，且后者的神经行为学评分高于前者，H3组与前四组相比较，差异有统计学意义（P＜0.05）。
2.手术对照组和各降压组血清中TNF-α和IL-1β浓度的比较：术前血清ELISA检测，各组间的差异无统计学意义（P＞0.05）。术后血清ELISA检测，C组和H2、H3组比较差异有统计学意义（P＜0.05）；H3组和H2、H1组比较，血清中TNF-α和IL-1β浓度随降压时间的延长而升高，差异有统计学意义（P＜0.05）；H2组和H1组比较，差异有统计学意义（P＜0.05）。
3.免疫组化染色检测海马CA1区TNF-α和IL-1β表达情况：A组未见明显阳性表达；C组、H1组大鼠可见散在分布的阳性表达细胞；H3组和H2组大鼠可见不同程度的胞浆棕黄色染色的阳性细胞。
结论1持续控制性低血压（MAP50-55mmHg）6小时，大鼠的神经行为学表现异常，与对照组比较，存活率下降。
2.持续控制性低血压（MAP50-55mmHg）6小时，术后血清中TNF-α和IL-1β浓度均升高，较持续降压4小时大鼠术后血清中TNF-α和IL-1β浓度升高更显著，说明持续控制性低血压6小时对大鼠机体造成一定程度的缺血缺氧性损伤。
3.持续控制性低血压（MAP50-55mmHg）4小时后大鼠海马CA1区TNF-α和IL-1β的表达增强，持续6小时后大鼠海马CA1区TNF-α和IL-1β的表达显著增强，说明持续控制性低血压6小时后大鼠脑组织发生一定程度的缺血缺氧性损伤。
Background： Controlled hypotension is a commonly anesthetictechnique that used in clinical. At present,it is considered that sustainingthe MAP(50-55mmHg) is a safe lower limit of controlled hypotension.Within this range, the autoregulation of cerebral blood flow and perfusionof brain tissue remain action wells,there will be no ischemia-hypoxiainjury. But that process was only limit in1-2hours, with the continuousdevelopment of surgery, however, a major and complex surgery (such asorthopedic surgery) requires5-6hours and controlled hypotension thatalways indispensable in it.Whether continues controlled hypotensionwould lead to irreversible brain injury,is rare reports now.
Cerebral hypoxic-ischemic injury is a complex process of pathologicalchange, a large number of studies indicated that massive white blood cellinfiltration is an important incentive to cause brain tissue damage,and theinfiltration of leukocyte is related to intercellular adhesion molecule (ICAM-1).As the proinflammatory cytokines, TNF-α and IL-1β plays animportant role in the inflammatory response, taken by inhibiting nuclearfactor (NF-kB) to make mononuclear macrophages and other cellssecreting more ICAM-1, IL-6,IL-8.the expression of ICAM-1upregulates that make leukocyte rolling and gathering in the endothelialcells.and make the ischemic injury of brain tissue further deteriorationthrough the release of the excitatory amino acid, calcium overload,formation of free radical, change of vasoconstriction and micro-thrombusformation.Numerous studies indicated that in heat shock andischemia-reperfusion rat model induce cerebral ischemic injury, theexpression of TNF-α were significantly increased, which indicated theover expression of TNF-α involved in the pathogenesis of cerebralischemia and reperfusion injury. There are studies reported that transientcerebral ischemia induce the upregulation of IL-1β, and give injections ofIL-1β antibody or IL-1β receptor blockers reduce the hypoxic-ischemicinjury of brain tissue.
Objective： This study aims to observe the tolerance of sodiumnitroprusside combined with esmolol induced hypotension at differenttimes with the MAP sustain in50-55mmHg in rats,and the mechanism ofbrain injury with continued hypotension in rats.
Methods：Male Sprague-Dawley rats were randomly divided into fivegroups(n=6),①blank group，Group A②operation control group， Group C③controlled hypotension group, Group H, and according toschedule is divided into three groups, H1(2h), H2(4h), and the H3(6h).Hypotension induced by sodium nitroprusside combined with esmolol tosustain the MAP in50-55mmHg for different times. During thestudy,montiored the MAP and HR of the rats and observed the blood gasanalysises, before and after the study, take1ml arterial blood forcentrifugation and save serum samples, after24hours,observedneurological serverity score after study for24hours, Evaluated theexpression ofTNF-α and IL-1βof hippocampal CA1region and serum byimmunohistochemical and ELISIA
Results：1.The survival rate of group A、 C、H1and H2of stydy were100%after24hours,while the survival rate of the group H3was50%,andthe neurological severity scores of group H3compared with the first fourgroups was higher, there were statistic difference (P <0.05).
2.The comparison of the concentration of TNF-α and IL-1β inserum between control group and hypotensive groups: the results ofELISA in preoperative serum,group C and group H were not statisticallysignificant (P>0.05). While the results of ELISA in postoperativeserum,the comparsion of group C and H2、H3,the differences werestatistically significant (P <0.05); the comparsion of group H3and H2、H1, the differences were statistically significant (P <0.05); the differenceof group H2and group H1was statistically significant (P <0.05).
3.The analysis of immunohistochemical staining of theexpression of TNF-α and IL-1β in the hippocampal CA1region: therewas no obviously positive expression in group A;there were positive cellsscattered in the group C and group H1;group H2and group H3showednumerous positive cells with brown-yellow staining particles in thecytoplasm.
Conclusions：1.After hypotension(MAP50-55mmHg)continued for6hours in rats,compared with other groups,the NSS and survival ratedescended.
2. After hypotension(MAP50-55mmHg)continued for6hours,the concentrations of TNF-α and IL-1β in the postoperative serumwere elevated,compared with group H2,the change was moresignificant.This indicated that the rats had a hypoxic-ischemia injury in acertain extent.
3. After hypotension(MAP50-55mmHg)continued for4hours,the expression of TNF-α and IL-1β in the hippocampal CA1regionwere upregulation,while continued for6hours,there were strongerexpression,this indicated the brain showed an ischemia injury in a certainextent.
控制性低血压是临床上常用的麻醉技术。目前认为MAP50-55mmHg是控制性低血压的安全低限。在此范围内，脑血流的自身调节能力仍然保持，脑组织能够得到良好的灌注，不会有缺血缺氧的危害。但其研究时间仅仅在1-2小时，然而随着临床上外科学的不断发展，重大而复杂的外科手术（如矫形外科）常常需要5-6个小时的手术时间且术中需要控制性低血压。这就需要麻醉中控制性降压技术的支持。但是较长时间的低血压是否会对脑组织产生缺血缺氧性损伤，目前罕见报道。
脑缺血缺氧性损伤是一个复杂的病理变化过程，大量研究表明，炎症反应时大量白细胞的浸润是对脑组织造成损伤的一个重要诱因，白细胞的浸润又与细胞间粘附分子（ICAM-1）相关，而TNF-α和IL-1β作为促炎症因子则在炎症反应中起到重要作用，两者通过抑制核因子（NF-kB）使单核巨噬细胞和其他细胞使ICAM-1、IL-6、IL-8等细胞因子的分泌增多，ICAM-1表达上调后使得白细胞滚动并聚集在内皮细胞，穿透内皮细胞作用于缺血脑组织，通过兴奋性氨基酸的生产释放，钙离子超载，自由基的形成，血管收缩反应的变化以及微血栓的形成使缺血脑组织的损伤进一步恶化。大量研究表明TNF-α在热休克及缺血再灌注脑缺血损伤大鼠模型中，其表达均有显著升高，从而提示了过多TNF-α参与了脑缺血再灌注损伤的发病过程。同样有研究报道,短暂性脑缺血即可诱导IL-1β的表达上调,若给予注射IL-1β中和抗体或IL-1β受体阻滞剂则可减轻脑组织的缺血缺氧性损伤。
目的本实验通过硝普钠联合艾司洛尔实施控制性降压，观察在安全低限内（MAP50-55mmHg），大鼠对低血压时程的耐受能力以及脑损伤的发生发展情况。
方法SD雄性大鼠随机分为5组，每组6只，①空白组A组②手术对照组C组③控制性降压组H组，又根据时程分为2h,4h,6h,分别对应H1，H2，H3组。术中应用硝普钠联合艾司洛尔进行控制性降压，MAP控制在50-55mmHg。术中监测MAP及HR并做血气分析，术前术后分别留取1ml动脉血离心后留血清标本，术后24小时行大鼠神经行为学评分(NSS)。应用免疫组化和ELISIA技术评估大鼠海马CA1区及血清中TNF-α和IL-1β的表达变化。
结果1.A组、C组、H1组和H2组大鼠在控制性降压后的生存率为100%，而H3组大鼠的生存率为50%，且后者的神经行为学评分高于前者，H3组与前四组相比较，差异有统计学意义（P＜0.05）。
2.手术对照组和各降压组血清中TNF-α和IL-1β浓度的比较：术前血清ELISA检测，各组间的差异无统计学意义（P＞0.05）。术后血清ELISA检测，C组和H2、H3组比较差异有统计学意义（P＜0.05）；H3组和H2、H1组比较，血清中TNF-α和IL-1β浓度随降压时间的延长而升高，差异有统计学意义（P＜0.05）；H2组和H1组比较，差异有统计学意义（P＜0.05）。
3.免疫组化染色检测海马CA1区TNF-α和IL-1β表达情况：A组未见明显阳性表达；C组、H1组大鼠可见散在分布的阳性表达细胞；H3组和H2组大鼠可见不同程度的胞浆棕黄色染色的阳性细胞。
结论1持续控制性低血压（MAP50-55mmHg）6小时，大鼠的神经行为学表现异常，与对照组比较，存活率下降。
2.持续控制性低血压（MAP50-55mmHg）6小时，术后血清中TNF-α和IL-1β浓度均升高，较持续降压4小时大鼠术后血清中TNF-α和IL-1β浓度升高更显著，说明持续控制性低血压6小时对大鼠机体造成一定程度的缺血缺氧性损伤。
3.持续控制性低血压（MAP50-55mmHg）4小时后大鼠海马CA1区TNF-α和IL-1β的表达增强，持续6小时后大鼠海马CA1区TNF-α和IL-1β的表达显著增强，说明持续控制性低血压6小时后大鼠脑组织发生一定程度的缺血缺氧性损伤。
Background： Controlled hypotension is a commonly anesthetictechnique that used in clinical. At present,it is considered that sustainingthe MAP(50-55mmHg) is a safe lower limit of controlled hypotension.Within this range, the autoregulation of cerebral blood flow and perfusionof brain tissue remain action wells,there will be no ischemia-hypoxiainjury. But that process was only limit in1-2hours, with the continuousdevelopment of surgery, however, a major and complex surgery (such asorthopedic surgery) requires5-6hours and controlled hypotension thatalways indispensable in it.Whether continues controlled hypotensionwould lead to irreversible brain injury,is rare reports now.
Cerebral hypoxic-ischemic injury is a complex process of pathologicalchange, a large number of studies indicated that massive white blood cellinfiltration is an important incentive to cause brain tissue damage,and theinfiltration of leukocyte is related to intercellular adhesion molecule (ICAM-1).As the proinflammatory cytokines, TNF-α and IL-1β plays animportant role in the inflammatory response, taken by inhibiting nuclearfactor (NF-kB) to make mononuclear macrophages and other cellssecreting more ICAM-1, IL-6,IL-8.the expression of ICAM-1upregulates that make leukocyte rolling and gathering in the endothelialcells.and make the ischemic injury of brain tissue further deteriorationthrough the release of the excitatory amino acid, calcium overload,formation of free radical, change of vasoconstriction and micro-thrombusformation.Numerous studies indicated that in heat shock andischemia-reperfusion rat model induce cerebral ischemic injury, theexpression of TNF-α were significantly increased, which indicated theover expression of TNF-α involved in the pathogenesis of cerebralischemia and reperfusion injury. There are studies reported that transientcerebral ischemia induce the upregulation of IL-1β, and give injections ofIL-1β antibody or IL-1β receptor blockers reduce the hypoxic-ischemicinjury of brain tissue.
Objective： This study aims to observe the tolerance of sodiumnitroprusside combined with esmolol induced hypotension at differenttimes with the MAP sustain in50-55mmHg in rats,and the mechanism ofbrain injury with continued hypotension in rats.
Methods：Male Sprague-Dawley rats were randomly divided into fivegroups(n=6),①blank group，Group A②operation control group， Group C③controlled hypotension group, Group H, and according toschedule is divided into three groups, H1(2h), H2(4h), and the H3(6h).Hypotension induced by sodium nitroprusside combined with esmolol tosustain the MAP in50-55mmHg for different times. During thestudy,montiored the MAP and HR of the rats and observed the blood gasanalysises, before and after the study, take1ml arterial blood forcentrifugation and save serum samples, after24hours,observedneurological serverity score after study for24hours, Evaluated theexpression ofTNF-α and IL-1βof hippocampal CA1region and serum byimmunohistochemical and ELISIA
Results：1.The survival rate of group A、 C、H1and H2of stydy were100%after24hours,while the survival rate of the group H3was50%,andthe neurological severity scores of group H3compared with the first fourgroups was higher, there were statistic difference (P <0.05).
2.The comparison of the concentration of TNF-α and IL-1β inserum between control group and hypotensive groups: the results ofELISA in preoperative serum,group C and group H were not statisticallysignificant (P>0.05). While the results of ELISA in postoperativeserum,the comparsion of group C and H2、H3,the differences werestatistically significant (P <0.05); the comparsion of group H3and H2、H1, the differences were statistically significant (P <0.05); the differenceof group H2and group H1was statistically significant (P <0.05).
3.The analysis of immunohistochemical staining of theexpression of TNF-α and IL-1β in the hippocampal CA1region: therewas no obviously positive expression in group A;there were positive cellsscattered in the group C and group H1;group H2and group H3showednumerous positive cells with brown-yellow staining particles in thecytoplasm.
Conclusions：1.After hypotension(MAP50-55mmHg)continued for6hours in rats,compared with other groups,the NSS and survival ratedescended.
2. After hypotension(MAP50-55mmHg)continued for6hours,the concentrations of TNF-α and IL-1β in the postoperative serumwere elevated,compared with group H2,the change was moresignificant.This indicated that the rats had a hypoxic-ischemia injury in acertain extent.
3. After hypotension(MAP50-55mmHg)continued for4hours,the expression of TNF-α and IL-1β in the hippocampal CA1regionwere upregulation,while continued for6hours,there were strongerexpression,this indicated the brain showed an ischemia injury in a certainextent.
引文
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