HMGB1在老龄大鼠术后认知受损中的作用及机制研究
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摘要
目的：1.探讨麻醉和手术对老龄大鼠认知功能的影响。
2.初步探讨晚期炎症因子HMGB1在老龄大鼠发生术后认知受损中的作用。
方法：第一部分：①.22-23月龄雌性老龄SD大鼠随机分为对照组(n=15)、麻醉组(A1、A3、A7麻醉后第1、3、7天,n=15/组)和手术组(S1、S3、S7手术后1、3、7天,n=15/组)。麻醉组大鼠3%异氟烷诱导后气管插管,2%异氟烷维持2小时,麻醉过程监测大鼠生命体征及气体浓度。手术组与麻醉组相同的麻醉条件下行脾脏切除手术,对照组单纯吸入空氧混合气体2小时.②.造模前Morris水迷宫定向航行试验训练6天,第7天造模,造模后1、3、7天Morris水迷宫记忆测试试验测试大鼠空间学习记忆能力,smart junior软件跟踪记录大鼠游泳的距离、潜伏期及速度。
第二部分：各项指标检测每组随机5个样本,①.行为学测试后取血,提取血清,ELISA检测血清中HMGB1、TNF-α、IL-1β的表达。②.灌注后取脑组织IgG免疫组化法检测海马区血脑屏障通透性,荧光染色法检测海马区HMGB1表达,尼氏染色观察海马区神经元形态及数目。③.取海马组织透射电镜法检测血脑屏障微观结构。④.取双侧海马组织液氮冻存,冻存的右侧海马组织RT-PCR检测HMGB1、 TNF-α、IL-1β及受体RAGE的mRNA表达。⑤.冻存的左侧海马组织进行western blot检测HMGB1、TNF-α、IL-1β及受体RAGE的蛋白表达。SPSS17.0软件进行统计学分析。
结果：第一部分：手术创伤导致大鼠认知受损,在手术后1、3天游泳距离(1天732.97±157.38cm,3天613.17±175.63cm,P<0.001)及潜伏期(1天44.54±6.63s,3天38.3±6.25s,P<0.001)与对照组(距离：322.36±116.88cm,潜伏期：24.7±8.63s)相比延长,在单独麻醉后1天上述指标也具有统计学意义(距离557.93±187.42sP=0.003,潜伏期35.99±7.70s P=0.001)。
第二部分：①.手术创伤导致外周血中HMGB1在手术后1天表达上调(0.204±0.023ug/L,P=0.003),术后3天及7天组无统计学差异,TNF-α、IL-1β在各组之间无显著差异。②.免疫组化结果显示术后1天血脑屏障通透性增加,电镜结果显示术后1天血脑屏障的微观结构受损,而麻醉组损伤相对较轻。③.手术创伤导致海马组织中HMGB1、TNF-α、IL-1β及受体RAGE在术后1天及3天表达上调(P<0.001),上述指标麻醉后1天也具有统计学意义(P<0.001)。④.手术创伤未导致海马CA1区神经元丢失,与对照组相比无统计学差异。
结论：第一部分：①.麻醉、手术引起老龄大鼠术后认知功能短期且可逆性受损。②.手术创伤引起老龄大鼠认知功能受损程度相对麻醉而言更为严重,且持续时间更长。
第二部分：①手术创伤诱导老龄大鼠外周血HMGB1表达上调与POCD密切相关。②.外周血HMGB1增加可能是引起海马区血脑屏障受损及进一步神经炎症的机制之一。③HMGB1-RAGE通路激活可能是手术刺激引起术后认知功能障碍的机制之一。
Aim:1.To explore the impact of anesthesia and surgery on cognitive function in aged rats.
2. We sought to determine the relationship between cognitive decline and inflammation, namely high mobility group box-1(HMGB1), after surgery in aged rats.
Methods:(1) The first part of the experiment:①Female Sprague Dawley (SD) aged rats (22-23months) were randomly divided into seven groups:control (C,n=15)、anesthesia only (A1、A3、A7anesthesia at days1、3and7, n=15/group), anesthesia plus surgery (S1、S3、S7surgery at days1、3and7, n=15/group). Rats were exposed to isoflurane anesthesia (3%isoflurane for induction followed by2%for maintenance) for2h with endotracheal intubation in anesthesia group, monitoring of vital signs and gas concentration. Animals in the anesthesia plus surgery groups underwent splenectomy. Rats in the control group were exposed to oxygen for2h in a gas chamber.②Spatial learning and memory were evaluated in the MWM, rats were trained for6days with three trials per day, On day7, animals underwent surgery and/or general anesthesia; on posttreatment days1,3and7, rats were subjected to a reversal test. The time to reach the platform (latency)、 distance and speed was recorded by smart junior system.
(2) The second part of the experiment:5rats in each group were randomly used for one indicator.①.After MWM test, blood samples were collected, the Levels of HMGB1、TNF-a and IL-1β in the serum were measured by ELISA.②. After perfused, the brain was removed. BBB permeability was measured by IgG immuno-histochemistry, expression of HMGB1in the hippocampus was measured using immunofluorescenc, the morphology and number of the neurons were measured by nissl staining③. BBB ultrastructure was measured by transmission electron microscope (TEM).④. The hippocampi were quickly dissected and frozen in liquid nitrogen, the mRNA levels of HMGB1、TNF-α IL-1β and RAGE were measured by PT-PCR.⑤.The protein levels of HMGB1. TNF-α、IL-1β and RAGE were measured by western blot. All statistical data were analyzed using SPSS17.0.
Results:The first part of the experiment:surgical trauma resulted in impairments in distance (732.97±157.38cm at day1,613.17±175.63cm at day3,P<0.001respectively) and latency(44.54±6.63s at day1,38.3±6.25s at dya3,P<0.001respectively) on postoperative day1and3in aged rats compared with control group (distance:322±116.88cm latency:24.7±8.63s). Distance (557.93±187.42cm P=0.003) and latency(35.99±7.70s P=0.001) were impaired at day1after anesthesia.
The second part of the experiment:①HMGB1was significantly upregulated after surgery on postoperative day1(0.204±0.023ug/L,P=0.003), before returning to baseline,No changes from baseline were observed in TNF-α and IL-1β at all time points.②Immunohistochemistry and TEM showed BBB disruption induced by surgery and anesthesia.③Levels of HMGB1、TNF-α、IL-1β and the RAGE were significantly upregulated in the hippocampus of operated animals (P<0.001), and significantly increased after exposure to anesthesia at day1(P<0.001).④The number of neurons in the hippocampal CA1region was not decreased by surgery, and no statistically significant difference compared with the control group.
Conclusions:The first part of the experiment:Anesthesia and surgical trauma, appears to contribute to the cognitive dysfunction in aged rats, and more severely in surgery group.
The second part of the experiment:①The proinflammatory cytokines HMGB1was upregulated by surgical trauma contribute to the cognitive dysfunction in aged rats.②HMGB1in the peripheral may contribute to the BBB dysfunction and neuroinflammation.③HMGB1and RAGE signaling appear pivotal mediators of surgery-induced cognitive decline after peripheral surgical trauma.
2.初步探讨晚期炎症因子HMGB1在老龄大鼠发生术后认知受损中的作用。
方法：第一部分：①.22-23月龄雌性老龄SD大鼠随机分为对照组(n=15)、麻醉组(A1、A3、A7麻醉后第1、3、7天,n=15/组)和手术组(S1、S3、S7手术后1、3、7天,n=15/组)。麻醉组大鼠3%异氟烷诱导后气管插管,2%异氟烷维持2小时,麻醉过程监测大鼠生命体征及气体浓度。手术组与麻醉组相同的麻醉条件下行脾脏切除手术,对照组单纯吸入空氧混合气体2小时.②.造模前Morris水迷宫定向航行试验训练6天,第7天造模,造模后1、3、7天Morris水迷宫记忆测试试验测试大鼠空间学习记忆能力,smart junior软件跟踪记录大鼠游泳的距离、潜伏期及速度。
第二部分：各项指标检测每组随机5个样本,①.行为学测试后取血,提取血清,ELISA检测血清中HMGB1、TNF-α、IL-1β的表达。②.灌注后取脑组织IgG免疫组化法检测海马区血脑屏障通透性,荧光染色法检测海马区HMGB1表达,尼氏染色观察海马区神经元形态及数目。③.取海马组织透射电镜法检测血脑屏障微观结构。④.取双侧海马组织液氮冻存,冻存的右侧海马组织RT-PCR检测HMGB1、 TNF-α、IL-1β及受体RAGE的mRNA表达。⑤.冻存的左侧海马组织进行western blot检测HMGB1、TNF-α、IL-1β及受体RAGE的蛋白表达。SPSS17.0软件进行统计学分析。
结果：第一部分：手术创伤导致大鼠认知受损,在手术后1、3天游泳距离(1天732.97±157.38cm,3天613.17±175.63cm,P<0.001)及潜伏期(1天44.54±6.63s,3天38.3±6.25s,P<0.001)与对照组(距离：322.36±116.88cm,潜伏期：24.7±8.63s)相比延长,在单独麻醉后1天上述指标也具有统计学意义(距离557.93±187.42sP=0.003,潜伏期35.99±7.70s P=0.001)。
第二部分：①.手术创伤导致外周血中HMGB1在手术后1天表达上调(0.204±0.023ug/L,P=0.003),术后3天及7天组无统计学差异,TNF-α、IL-1β在各组之间无显著差异。②.免疫组化结果显示术后1天血脑屏障通透性增加,电镜结果显示术后1天血脑屏障的微观结构受损,而麻醉组损伤相对较轻。③.手术创伤导致海马组织中HMGB1、TNF-α、IL-1β及受体RAGE在术后1天及3天表达上调(P<0.001),上述指标麻醉后1天也具有统计学意义(P<0.001)。④.手术创伤未导致海马CA1区神经元丢失,与对照组相比无统计学差异。
结论：第一部分：①.麻醉、手术引起老龄大鼠术后认知功能短期且可逆性受损。②.手术创伤引起老龄大鼠认知功能受损程度相对麻醉而言更为严重,且持续时间更长。
第二部分：①手术创伤诱导老龄大鼠外周血HMGB1表达上调与POCD密切相关。②.外周血HMGB1增加可能是引起海马区血脑屏障受损及进一步神经炎症的机制之一。③HMGB1-RAGE通路激活可能是手术刺激引起术后认知功能障碍的机制之一。
Aim:1.To explore the impact of anesthesia and surgery on cognitive function in aged rats.
2. We sought to determine the relationship between cognitive decline and inflammation, namely high mobility group box-1(HMGB1), after surgery in aged rats.
Methods:(1) The first part of the experiment:①Female Sprague Dawley (SD) aged rats (22-23months) were randomly divided into seven groups:control (C,n=15)、anesthesia only (A1、A3、A7anesthesia at days1、3and7, n=15/group), anesthesia plus surgery (S1、S3、S7surgery at days1、3and7, n=15/group). Rats were exposed to isoflurane anesthesia (3%isoflurane for induction followed by2%for maintenance) for2h with endotracheal intubation in anesthesia group, monitoring of vital signs and gas concentration. Animals in the anesthesia plus surgery groups underwent splenectomy. Rats in the control group were exposed to oxygen for2h in a gas chamber.②Spatial learning and memory were evaluated in the MWM, rats were trained for6days with three trials per day, On day7, animals underwent surgery and/or general anesthesia; on posttreatment days1,3and7, rats were subjected to a reversal test. The time to reach the platform (latency)、 distance and speed was recorded by smart junior system.
(2) The second part of the experiment:5rats in each group were randomly used for one indicator.①.After MWM test, blood samples were collected, the Levels of HMGB1、TNF-a and IL-1β in the serum were measured by ELISA.②. After perfused, the brain was removed. BBB permeability was measured by IgG immuno-histochemistry, expression of HMGB1in the hippocampus was measured using immunofluorescenc, the morphology and number of the neurons were measured by nissl staining③. BBB ultrastructure was measured by transmission electron microscope (TEM).④. The hippocampi were quickly dissected and frozen in liquid nitrogen, the mRNA levels of HMGB1、TNF-α IL-1β and RAGE were measured by PT-PCR.⑤.The protein levels of HMGB1. TNF-α、IL-1β and RAGE were measured by western blot. All statistical data were analyzed using SPSS17.0.
Results:The first part of the experiment:surgical trauma resulted in impairments in distance (732.97±157.38cm at day1,613.17±175.63cm at day3,P<0.001respectively) and latency(44.54±6.63s at day1,38.3±6.25s at dya3,P<0.001respectively) on postoperative day1and3in aged rats compared with control group (distance:322±116.88cm latency:24.7±8.63s). Distance (557.93±187.42cm P=0.003) and latency(35.99±7.70s P=0.001) were impaired at day1after anesthesia.
The second part of the experiment:①HMGB1was significantly upregulated after surgery on postoperative day1(0.204±0.023ug/L,P=0.003), before returning to baseline,No changes from baseline were observed in TNF-α and IL-1β at all time points.②Immunohistochemistry and TEM showed BBB disruption induced by surgery and anesthesia.③Levels of HMGB1、TNF-α、IL-1β and the RAGE were significantly upregulated in the hippocampus of operated animals (P<0.001), and significantly increased after exposure to anesthesia at day1(P<0.001).④The number of neurons in the hippocampal CA1region was not decreased by surgery, and no statistically significant difference compared with the control group.
Conclusions:The first part of the experiment:Anesthesia and surgical trauma, appears to contribute to the cognitive dysfunction in aged rats, and more severely in surgery group.
The second part of the experiment:①The proinflammatory cytokines HMGB1was upregulated by surgical trauma contribute to the cognitive dysfunction in aged rats.②HMGB1in the peripheral may contribute to the BBB dysfunction and neuroinflammation.③HMGB1and RAGE signaling appear pivotal mediators of surgery-induced cognitive decline after peripheral surgical trauma.
引文
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