体外循环对脑血管功能影响及相关脑保护策略的实验研究
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摘要
概述:随着心脏外科手术和体外循环技术的不断进步,体外循环造成术后多脏器功能损害日益受到重视。早期和晚期的神经系统并发症发生率仍然很高。脑血流中断或局部血流分配不充分是脑损伤的重要机制,而脑血流灌注完全取决于脑血管的功能状态。目前国内外对于体外循环引起脑血管功能变化的研究很少,尤其是国内对于脑血管功能变化的文献基本是空白。因此迫切需要深入的实验研究来揭示体外循环对脑血管功能变化及其发生机制,并在此基础上提出相关的脑保护策略。
第一部分S.D.大鼠闭胸体外循环模型的研究
目的:建立S.D.大鼠体外循环(CPB)模型,为体外循环脑、肺、肝、肾等重要脏器损伤的基础研究提供经济实用的动物模型。
方法:30只S.D.大鼠平均体重(467.9±44.5)g,随机平均分为5组,每组6只。A组:体外循环60分钟组、B组:体外循环120分钟组、C组:深低温低流量60分钟组、D组:深低温停循环60分钟组和E组:空白对照组。体外循环采用右颈内动脉插管灌注、右颈外静脉插管至右房引流方法建立闭胸体外循环转流,低温诱发室颤心脏停跳。术中进行体温、有创血压、心电图监测,并在在麻醉成功后(T1)、CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)和体外循环结束后(T7)七个时间点记录生命体征和进行股动脉血气分析。血气管理采用α稳态策略。
结果:24只大鼠均顺利建立体外循环模型,生命体征和血气指标均在合理范围内,脱离体外循环时平均血压维持60mmHg以上,脱离体外循环后心功能均顺利恢复。
结论:本实验建立大鼠闭胸不同体外循环模型是切实可行的,该模型是研究体外循环生理的一个可信赖的平台,有利于研究体外循环后多脏器损伤的病理生理变化。
第二部分体外循环对大鼠脑血管功能的影响及其机制研究
目的:研究体外循环转流期间脑血管舒缩变化和不同体外循环时间和体外循环模式对脑血管反应性的影响,并探讨脑血管功能的改变的机制。通过蛋白水平和细胞水平实验指标测定体外循环对脑细胞损伤程度及脑代谢改变,明确脑损伤的程度与脑血管功能变化之间的相关性。
方法:
一、大鼠脑血管在不同体外循环模式下功能的变化:
实验分组同实验第一部分。在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点观察内皮素-1(ET-1)和一氧化氮(NO)血浆浓度变化,并通过计算ET-1/NO比值研究体外循环中脑血管舒缩变化规律。取右大脑中动脉(MCA),进行血管反应性测定,包括乙酰胆碱(Ach)浓度相关的血管内皮细胞介导的血管舒张反应、血管平滑肌对不同压力的肌源性反应、硝普钠(SNP)和血管紧张素诱发的血管平滑肌舒缩反应。取海马区脑组织进行微血管的内皮细胞超微结构观察。
二、体外循环对大鼠脑血管功能失调的机制研究:
在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点测定肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)的动态血浆浓度变化,并分析其与脑血管舒缩变化规律的关系。采用免疫组织化学ICAM-1染色半定量观察脑血管壁的炎性反应强度。采用Western Blotting技术进行海马内皮型一氧化氮合酶蛋白的定量测定,并分析其与颈内静脉NO含量的关系。
三、大鼠体外循环脑血管功能变化与脑损伤的关系研究:
在CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)4个时间点测定血浆S100β蛋白含量,并评价其变化与脑血管舒缩状态指标ET-1/NO比值相关性。磷脂结合蛋白V法测定海马细胞凋亡比例,并评价脑细胞凋亡比例与脑血管舒缩状态相关性;脑组织病理切片H.E.染色评价神经元损伤情况。采用电泳法测定额顶叶皮质脑组织ATP含量,并评价脑组织ATP含量与脑血管舒缩状态相关性。在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点测定乳酸含量和颈内静脉氧饱和度,并评价颈内静脉乳酸含量和氧饱和度与脑血管舒缩状态相关性。
结果:
一、大鼠脑血管在不同体外循环模式下功能的变化:
4组S.D.大鼠均成功建立和脱离体外循环。体外循环60分钟后ET-1随转流时间延长而升高,在DHLF和DHCA组复温再灌注时ET-1含量也明显升高。NO含量在转流30分钟达到峰值,此后逐渐下降。ET-1/NO比值在转流30分钟低于术前水平,而此后逐渐升高,各组均在转流末达峰值。
在不同压力负荷下,MCA肌源性活动功能检测各组间无明显差异。血管紧张素诱导的血管平滑肌收缩功能和硝普钠诱导的血管平滑肌舒张功能均正常。而在不同乙酰胆碱浓度下,A组MCA内皮细胞依赖的血管舒张功能即明显受损。B组与A组相比在各个Ach浓度血管舒张率无差异,而C组和D组在Ach浓度依赖的血管舒张率均明显较B组差,而C、D二组间比较无明显差异。
海马微血管和内皮细胞超微结构观察发现A、B二组内皮细胞结构与正常组相仿,未见异常改变。而C组毛细血管形态结构基本正常,V-R间隙增宽,D组毛细血管内皮细胞损伤明显,V-R间隙严重增宽伴周围组织脑水肿。
二、体外循环对大鼠脑血管功能失调的机制研究
TNF-α和IL-6的浓度在体外循环各组随转流时间延长而显著升高。TNF-α与ET-1/NO比值间相关系数为r=0.637(P＜0.001)。IL-6与ET-1/NO比值间相关系数为r=0.521(P＜0.001)。海马病理切片ICAM免疫组织化学染色提示在体外循环各组均呈阳性。各组间比较按A、B、C、D组顺序炎症反应强度依次递增,且该强度与ET-1/NO比值间相关系数为r=0.872(P＜0.001)。
Western Blotting法检测eNOS蛋白含量发现各体外循环组含量均明显低于空白对照。B组eNOS蛋白含量亦低于A组(P=0.002)。D组亦显著低于C组(P=0.002)。eNOS蛋白含量与颈内静脉NO含量相关系数r=0.866(P＜0.001)。
三、大鼠体外循环脑血管功能变化与脑损伤的关系研究
S100β蛋白水平在各体外循环组随转流时间延长而不断升高。而各组间比较,S100β蛋白水平在T5、T6高低依次为D组、C组和B组。S100β蛋白含量与ET-1/NO比值之间相关系数为0.753(P＜0.001)。
体外循环可引起海马神经细胞凋亡明显增加,Annexin v法测定凋亡比例大小依次为D组、C组、B组和A组。细胞凋亡比例与ET-1/NO比值之间相关系数为0.793(P＜0.001)。病理学检测在各组切片均未观察到明显的神经元受损的表现,仅可见血管周围炎症,各组病理学评分均为0分。
常温转流组ATP含量与E组间无明显差异,而C组和D组明显下降,其中D组ATP含量最低,组间差异具有统计学意义(P=0.002)。脑组织ATP含量与T6时间点ET-1/NO比值之间相关系数为-0.808(P＜0.001)。乳酸含量测定发现C组和D组在T4、T5、T6明显高于其他各组,与ET-1/NO比值相关性较弱。
结论:
一、大鼠脑血管在不同体外循环模式下功能的变化:
1.脑血管在体外循环期间的缩血管效应明显大于舒血管效应,整体脑组织处于低灌注状态。
2.大脑中动脉内皮细胞依赖的血管舒张功能受损,在体外循环60分钟即可出现,并且在DHLF和DHCA组损伤明显加重,表明脑血管舒缩紧张度的不稳定性;而体外循环对平滑肌细胞功能无明显影响。
3.通过大脑微血管和内皮细胞的超微结构观察,发现在DHCA组内皮细胞损伤表现及周围脑组织水肿。
二、体外循环对大鼠脑血管功能失调的机制研究
1.体外循环可引起TNF-α和IL-6为代表的炎性因子显著升高,炎性因子水平与脑血管舒缩状态存在明显相关性,说明脑血管舒缩功能受损可能或部分为全身炎症反应引起。
2.体外循环可引起脑组织eNOS蛋白表达水平明显降低,且在DHLF和DHCA组降低尤为明显,提示炎症反应和缺血-再灌注损伤是影响eNOS蛋白水平的重要因素。
3.脑组织eNOS蛋白水平与颈内静脉血NO含量呈明显相关,提示脑血管eNOS功能状态是脑血管舒缩状态的重要因素。
三、大鼠体外循环脑血管功能变化与脑损伤的关系研究
1.体外循环,特别是DHLF和DHCA转流可引起血浆S100β蛋白为标志的神经细胞明显损伤,其损伤程度与脑血管灌注水平一致。
2.体外循环可引起神经细胞凋亡比例升高,说明凋亡是神经系统损伤的重要原因之一。细胞凋亡比例与脑血管舒缩状态之间存在相关性。
3.体外循环后早期2小时之内,未能在H.E.染色的病理切片上发现明显的神经细胞受损证据。
4.DHLF和DHCA可引起细胞ATP含量明显下降和颈内静脉乳酸水平明显升高,其程度与脑血管舒缩状态一致。
第三部分应用一氧化氮供体对大鼠体外循环脑损伤的保护策略研究
目的:观察通过给予NO供体以提高血浆NO浓度,能否通过减轻体外循环引起的炎症反应强度,提高脑组织灌注状态,从而减轻大鼠体外循环后急性脑损伤。
方法:36只大鼠随机平均分为6组,每组6只。B组:常温体外循环120min组、C组:深低温低流量60min组、D组:深低温停循环60min组、F组:常温体外循环120min+保护组、G组:深低温低流量60min+保护组和H组:深低温停循环60min+保护组。保护方法为静脉输注硝普钠3mg/kg/h至CPB结束,加用去氧肾上腺素维持平均动脉血压在60mmHg以上。
各组CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)4个时间点测定血浆S100β蛋白、Annexin V法测定海马细胞凋亡比例、右额顶叶皮质脑组织ATP含量测定、在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点测定颈内静脉乳酸含量和氧饱和度等脑代谢指标及大脑海马区神经元和胶质细胞超微结构观察分别进行保护组与非保护组比较,观察NO供体的保护效应。
在CPB体外循环开始(T2)和体外循环120分钟(T6)二个时间点抽取颈内静脉血,组间进行TNF-α和IL-6浓度比较,确定NO供体是否通过降低炎性因子水平起到神经保护作用。定量测定各组海马eNOS蛋白并进行组间比较,了解给予NO供体后对eNOS蛋白含量的影响。
结果:各组36只S.D.大鼠均顺利建立体外循环。B组和F组、C组和G组、D组和H组比较,在T5、T6时间点各保护组颈内静脉血S100β蛋白含量均低于对照组;各保护组凋亡比例均明显低于对照组;各保护组额顶叶皮质脑组织ATP含量均高于对照组;在DHLF和DHCA保护组转流末乳酸含量明显低于对照组。T6时间点IL-6浓度F、G、H组均明显低于B、C、D组,F组eNOS蛋白含量低于B组(P=0.037),而C组与G组、D组与H组间eNOS蛋白含量相仿。
结论:
1.SNP作为一种外源性NO的供体,可以明显减轻体外循环引起的神经细胞损伤和减少细胞的凋亡。
2.扩张脑血管增加血流灌注和氧供、抑制体外循环炎症反应可能是NO供体脑保护的机制。
Introduction With the improvement of techniques of cardiac surgery and cardiopulmonary bypass(CPB),attention is increasingly focused on the multi-organ dysfunction caused by the CPB.The early and late neurologic morbidities are still high.The interruption of cerebral blood flow and the regional low-flow cerebral perfusion are the vast mechanisms of the brain injury,and the cerebral perfusion is totally based on the functional status of the cerebral vessels.There are few studies on effect of the CPB on cerebral vascular changes nowadays;especially the field is almost empty in domestic.This research was assigned to experimentally study on the effect of the CPB on cerebral vascular changes and mechanisms,and raised associated cerebral protective strategy.
PartⅠThe Study of the Animal Model of Closed Chest Cardiopulmonary Bypass in Sprague-Dawley Rats
Objectives To establish the animal model of closed chest cardiopulmonary bypass in the Sprague-Dawley rats and provide a economical animal model for the basic research of multi-organ dysfunction induced by CPB.
Methods The S.D.rats were assigned to undergo CPB via right carotid and jugular cannulation,and self-designed and improved the elements of CPB circuit.The cardiac arrest was induced by the hypothermal ventricular fibrillation.Mean body weight of the 30 rats was(467.9±44.5)g.The 30 rats were equally divided into five groups which were underwent CPB for 60 minutes(Group A),CPB for 120 minutes(Group B), deep hypothermic low flow(DHLF) bypass 60 minutes(Group C),deep hypothermic circulatory arrest(DHCA) 60 minutes(Group D) and sham(Group E) individually. During the bypass,temperature,invasive arterial blood pressure,electrocardiograph and arterial blood gas analysis were monitored and recorded at the following time point:after the anesthesia(T1),before CPB(T2),30min(T3),60min(T4),90min(T5), 120min(T6) during CPB and end of CPB(T7).Theα-stat strategy was used as blood gas analysis management.
Results The CPB were performed successfully in all the rats.The blood gas analysis results were all maintained in acceptable range and the mean arterial pressure were over 60 mmHg when off-pump.The cardiac function recovered after the rat weaned from the CPB.
Conclusions The animal model of closed chest CPB can be established successfully in rats with excellent survive.This model is a stable platform for the study of the pathophysiology of CPB and post-CPB multiple organ dysfunctions.
PartⅡThe Study on Effect of the Cardiopulmonary Bypass on Cerebral Vascular Changes in Rats and Associated Mechanisms
Objectives 1.To study on the cerebral vasomotor changes during the CPB and cerebral vascular reactivity changes after different bypass time and modes and to investigate the associated mechanisms.2.To test the cerebral injuries and metabolism in protein and cell levels to correlate the cerebral injuries and cerebral vasomotor changes.
Methods
1.The Study on the Cerebral Vasomotor Changes During the CPB and Cerebral Vascular Reactivity Changes after Different Bypass Time and Modes in Rats. The 30 rats were divided into 5 groups as PartⅠ.The internal jugular vein blood samples were taken before CPB(T2),30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB to test the serologic endothelin-1(ET-1) and nitric oxide(NO) changes.The ET-1/NO ratio was calculated to investigate the cerebral vasomotor changes.The right middle cerebral artery(MCA) was harvested and prepared for assessment of the myogenic tone with different transmural pressure,the endothelial cell response induced by different concentration of acetylcholine and the vascular smooth muscle cell response induced by the sodium nitroprusside and serotonin.The hippocampus tissue was harvested to observe the ultramicrostructure of endothelial cell in capillary with electron microscope.
2.The Mechanism of Cerebral Vascular Dysfunction Induced by the Cardiopulmonary Bypass in Rats.
The internal jugular vein blood samples were taken before CPB(T2),30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB to test the tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) in serum.The statistical analysis was used to test correlation between the cytokines and the cerebral vasomotor changes.The eNOS protein expression in hippocampus was determined by the Western immunoblotting and the correlation between the eNOS expression and NO content was accessed.
3.The Study on the Correlation Between the Cerebral Vascular Changes and Cerebral Injuries Induced by CPB in Rats.
The internal jugular vein blood samples were taken 30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB to test the S100βprotein levels and assess the correlation between S100βlevels and ET-1/NO ratio.The apoptosis cell percentage in hippocampus was determined by Annexin V/PI exam and the correlation between the apoptosis cell ratio and ET-1/NO ratio on T6 was accessed.The neuron injury was scored by the histopathology.The ATP content in frontal and apical lobe of the brain was tested by the electrophoresis and correlated with the ET-1/NO ratio on T6.The lactic acid content and internal jugular vein saturation were tested before CPB(T2),30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB.The correlation were analyzed between the lactic acid content/ internal jugular vein saturation and the ET-1/NO ratio.
Results
1.The Study on the Cerebral Vasomotor Changes During the CPB and Cerebral Vascular Reactivity Changes after Different Bypass Time and Modes in Rats. All the rats were successfully established and weaned from the bypass.The ET-1 content increased with the bypass time and in DHLF and DHCA group,the ET-1 content increased in rewarming period.The NO content reached summit at T3 but decreased gradually after that.The ET-1/NO ratio was lower than T2 in T3 but increased to summit at the end of bypass.
The bypass did not alter the results of myogenic tone test with different transmural pressure.Furthermore,the vascular smooth muscle cell response induced by the sodium nitroprusside and serotonin were also intact in all the rats.Acetylcholine caused a dose-dependent vasodilation in the sham group that was absent in animals undergoing CPB.Significantly,this was apparent after only 60 minutes of CPB and the endothelial cell vasodilation responses were lower in DHLF and DHCA groups compared with group B.
The ultramicrostructure of endothelial cell and capillary in hippocampus observed by electron microscope found normal structure in group A and B,but the V-R space widened in group C and structural injury in endothelial cell and cerebral edema in group D.
2.The Mechanism of Cerebral Vascular Dysfunction Induced by the Cardiopulmonary Bypass in Rats.
CPB led to an early and marked increase in TNF-αand IL-6.The correlation coefficient between TNF-αand ET-1/NO ratio was 0.637(P＜0.001).The correlation coefficient between IL-6 and ET-1/NO ratio was 0.521(P＜0.001).The ICAM-1 were overexpressed in all the CPB groups and the intensity of ICAM-1 expression increased by turns in group A,B,C and D.The correlation coefficient between ICAM-1 and ET-1/NO ratio was 0.872(P＜0.001).
The CPB was correlated with the significantly reduction in eNOS expression.The ranks comparison based on Wilcoxson tests indicated that the eNOS protein level was lower in group B than group A(P=0.002) and group D than group C(P=0.002).The correlation coefficient between eNOS protein expression and NO content in internal jugular vein was 0.866(P＜0.001),and the regression equation was NO content= 1.91+1.73×eNOS expression.
3.The Study on the Relationship Between the Cerebral Vascular Changes and Cerebral Injuries Induced by CPB in Rats.
The CPB was correlated with the significantly increased in S100βprotein.DHCA caused highest S100βprotein levels compared with group B and C.The ranks comparison indicated that the S100βprotein level was higher in DHLF group compared with group B.The correlation coefficient between S100βprotein and ET-1/NO ratio was 0.753(P＜0.001).
The CPB was correlated with the significantly increased in apoptosis cell percentage in hippocampus.DHCA caused highest percentage of apoptosis cells compared with group B and C.The correlation coefficient between percentage of apoptosis cells and ET-1/NO ratio was 0.793(P＜0.001).No neuron injury was found pathologically and scored 0 in all the groups.
CPB did not alter the level of ATP compared with sham group,but the level reduced significantly in group C and D.The ranks comparison based on Wilcoxson tests indicated that the ATP level was lower in group D than group C(P=0.002).The correlation coefficient between ATP level and ET-1/NO ratio in T6 was -0.808 (P＜0.001).The lactic acid were higher in group C and D compared with group A and B in T4,T5,T6,but weak correlation was found with ET-1/NO ratio.
Conclusions
1.The Study on the Cerebral Vasomotor Changes During the CPB and Cerebral Vascular Reactivity Changes after Different Bypass Time and Modes in Rats.
a.The cerebral vasoconstriction effect is greater than vasodilatation effect during the CPB,which lead to poor cerebral perfusion.
b.The specific loss of acetylcholine- induced vasodilation suggests endothelial cell dysfunction,which appeares 60 min after the onset of CPB and are worsen in DHLF and DHCA group.Adversely,the vascular smooth muscle functions are not impaired after CPB.
c.The observation of ultramicrostructure of endothelial cell and capillary in hippocampus finds structural injury in endothelial cell and cerebral edema in DHCA group.
2.The Mechanism of Cerebral Vascular Dysfunction Induced by the Cardiopulmonary Bypass in Rats.
a.The increase of TNF-αand IL-6 induced by CPB is correlated with the cerebral vasomotor changes,which demonstrates that the impair cerebrovascular function is caused by the systemic inflammatory response.
b.The eNOS protein expression is reduced by CPB,especially in DHLF and DHCA group,which suggests the systemic inflammatory response and ischemia-reperfusion injury are the vast factors that affect the expression of eNOS protein.
c.The cerebrovascular eNOS protein expression is correlated with the NO content in internal jugular vein,which suggests the expression level of eNOS is a main factor of cerebral vasomotor changes.
3.The Study on the Relationship Between the Cerebral Vascular Changes and Cerebral Injuries Induced by CPB in Rats.
a.CPB,especially DHCA and DHLF leads to the increase of serum S100βprotein, which is a marker of the cerebral damage.And the serum S100βprotein level is correlated with the cerebral vasomotor changes.
b.Apoptosis is induced by CPB in cells of hippocampus,which suggests that apoptosis is a vast mechanism of cerebral damage.The apoptosis cell percentage is correlated with the cerebral vasomotor changes.
c.No evidence of neuron damage can be found pathologically in 2 hours after CPB.
d.DHLF and DHCA can lead to the reduction of ATP level in brain and increase of the lactic acid level in internal jugular vein.The ATP level is correlated with the cerebral vasomotor changes.
PartⅢThe Study of Protective Effect of NO Donor on Cerebral Damage Induced by CPB in Rats
Objectivs To investigate the cerebral protective effect and mechanism of NO donor reducing the cerebral damage induced by CPB.
Methods 36 rats were equally divided into six groups which were underwent CPB for 120 minutes(Group B),DHLF 60 minutes(Group C),DHCA 60 min(Group D),CPB for 120 minutes with SNP(Group F),DHLF 60 minutes with SNP(Group G),DHCA 60 min with SNP(Group H).The protective strategy was to infuse SNP 3mg/kg/h intravenously with deoxyepinephrine to maintain the MAP over 60mmHg till end of CPB.The serum S100βprotein level,the apoptosis cell percentage,the ATP levels, the lactic acid and internal jugular vein saturation and the microstructure were compared between the corresponding groups with and without SNP.
The blood samples were taken at T2 and T6 to evaluate the TNF-αand IL-6 levels. The levels were compared between the corresponding groups with and without SNP. The eNOS protein expression were determined to assess the changes affected by the NO donor.
Results 36 rats were successfully established the bypass.The serum S100βprotein levels and apoptosis cell percentages were lower at T5 and T6 in groups with SNP compared with the control groups.The ATP levels were higher in groups with SNP compared with the control groups while the lactic acid levels were lower in DHCA/DHLF groups with SNP compared with corresponding control groups.The IL-6 levels were lower in groups with SNP compared with corresponding control groups at T6.The SNP altered the eNOS protein expression in group F(P=0.037) compared with group B,while the expression levels were similar in DHLF/DHCA groups with or without SNP.
Conclusions
1.As an exogenous NO donor,SNP can significantly reduce the cerebral damage and cellular apoptosis induced by CPB.
2.The mechanism of cerebral protection of SNP is contributed to the vasodilatation to increase the blood flow and oxygen and inhibition of systemic inflammatory response induced by CPB.
第一部分S.D.大鼠闭胸体外循环模型的研究
目的:建立S.D.大鼠体外循环(CPB)模型,为体外循环脑、肺、肝、肾等重要脏器损伤的基础研究提供经济实用的动物模型。
方法:30只S.D.大鼠平均体重(467.9±44.5)g,随机平均分为5组,每组6只。A组:体外循环60分钟组、B组:体外循环120分钟组、C组:深低温低流量60分钟组、D组:深低温停循环60分钟组和E组:空白对照组。体外循环采用右颈内动脉插管灌注、右颈外静脉插管至右房引流方法建立闭胸体外循环转流,低温诱发室颤心脏停跳。术中进行体温、有创血压、心电图监测,并在在麻醉成功后(T1)、CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)和体外循环结束后(T7)七个时间点记录生命体征和进行股动脉血气分析。血气管理采用α稳态策略。
结果:24只大鼠均顺利建立体外循环模型,生命体征和血气指标均在合理范围内,脱离体外循环时平均血压维持60mmHg以上,脱离体外循环后心功能均顺利恢复。
结论:本实验建立大鼠闭胸不同体外循环模型是切实可行的,该模型是研究体外循环生理的一个可信赖的平台,有利于研究体外循环后多脏器损伤的病理生理变化。
第二部分体外循环对大鼠脑血管功能的影响及其机制研究
目的:研究体外循环转流期间脑血管舒缩变化和不同体外循环时间和体外循环模式对脑血管反应性的影响,并探讨脑血管功能的改变的机制。通过蛋白水平和细胞水平实验指标测定体外循环对脑细胞损伤程度及脑代谢改变,明确脑损伤的程度与脑血管功能变化之间的相关性。
方法:
一、大鼠脑血管在不同体外循环模式下功能的变化:
实验分组同实验第一部分。在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点观察内皮素-1(ET-1)和一氧化氮(NO)血浆浓度变化,并通过计算ET-1/NO比值研究体外循环中脑血管舒缩变化规律。取右大脑中动脉(MCA),进行血管反应性测定,包括乙酰胆碱(Ach)浓度相关的血管内皮细胞介导的血管舒张反应、血管平滑肌对不同压力的肌源性反应、硝普钠(SNP)和血管紧张素诱发的血管平滑肌舒缩反应。取海马区脑组织进行微血管的内皮细胞超微结构观察。
二、体外循环对大鼠脑血管功能失调的机制研究:
在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点测定肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)的动态血浆浓度变化,并分析其与脑血管舒缩变化规律的关系。采用免疫组织化学ICAM-1染色半定量观察脑血管壁的炎性反应强度。采用Western Blotting技术进行海马内皮型一氧化氮合酶蛋白的定量测定,并分析其与颈内静脉NO含量的关系。
三、大鼠体外循环脑血管功能变化与脑损伤的关系研究:
在CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)4个时间点测定血浆S100β蛋白含量,并评价其变化与脑血管舒缩状态指标ET-1/NO比值相关性。磷脂结合蛋白V法测定海马细胞凋亡比例,并评价脑细胞凋亡比例与脑血管舒缩状态相关性;脑组织病理切片H.E.染色评价神经元损伤情况。采用电泳法测定额顶叶皮质脑组织ATP含量,并评价脑组织ATP含量与脑血管舒缩状态相关性。在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点测定乳酸含量和颈内静脉氧饱和度,并评价颈内静脉乳酸含量和氧饱和度与脑血管舒缩状态相关性。
结果:
一、大鼠脑血管在不同体外循环模式下功能的变化:
4组S.D.大鼠均成功建立和脱离体外循环。体外循环60分钟后ET-1随转流时间延长而升高,在DHLF和DHCA组复温再灌注时ET-1含量也明显升高。NO含量在转流30分钟达到峰值,此后逐渐下降。ET-1/NO比值在转流30分钟低于术前水平,而此后逐渐升高,各组均在转流末达峰值。
在不同压力负荷下,MCA肌源性活动功能检测各组间无明显差异。血管紧张素诱导的血管平滑肌收缩功能和硝普钠诱导的血管平滑肌舒张功能均正常。而在不同乙酰胆碱浓度下,A组MCA内皮细胞依赖的血管舒张功能即明显受损。B组与A组相比在各个Ach浓度血管舒张率无差异,而C组和D组在Ach浓度依赖的血管舒张率均明显较B组差,而C、D二组间比较无明显差异。
海马微血管和内皮细胞超微结构观察发现A、B二组内皮细胞结构与正常组相仿,未见异常改变。而C组毛细血管形态结构基本正常,V-R间隙增宽,D组毛细血管内皮细胞损伤明显,V-R间隙严重增宽伴周围组织脑水肿。
二、体外循环对大鼠脑血管功能失调的机制研究
TNF-α和IL-6的浓度在体外循环各组随转流时间延长而显著升高。TNF-α与ET-1/NO比值间相关系数为r=0.637(P＜0.001)。IL-6与ET-1/NO比值间相关系数为r=0.521(P＜0.001)。海马病理切片ICAM免疫组织化学染色提示在体外循环各组均呈阳性。各组间比较按A、B、C、D组顺序炎症反应强度依次递增,且该强度与ET-1/NO比值间相关系数为r=0.872(P＜0.001)。
Western Blotting法检测eNOS蛋白含量发现各体外循环组含量均明显低于空白对照。B组eNOS蛋白含量亦低于A组(P=0.002)。D组亦显著低于C组(P=0.002)。eNOS蛋白含量与颈内静脉NO含量相关系数r=0.866(P＜0.001)。
三、大鼠体外循环脑血管功能变化与脑损伤的关系研究
S100β蛋白水平在各体外循环组随转流时间延长而不断升高。而各组间比较,S100β蛋白水平在T5、T6高低依次为D组、C组和B组。S100β蛋白含量与ET-1/NO比值之间相关系数为0.753(P＜0.001)。
体外循环可引起海马神经细胞凋亡明显增加,Annexin v法测定凋亡比例大小依次为D组、C组、B组和A组。细胞凋亡比例与ET-1/NO比值之间相关系数为0.793(P＜0.001)。病理学检测在各组切片均未观察到明显的神经元受损的表现,仅可见血管周围炎症,各组病理学评分均为0分。
常温转流组ATP含量与E组间无明显差异,而C组和D组明显下降,其中D组ATP含量最低,组间差异具有统计学意义(P=0.002)。脑组织ATP含量与T6时间点ET-1/NO比值之间相关系数为-0.808(P＜0.001)。乳酸含量测定发现C组和D组在T4、T5、T6明显高于其他各组,与ET-1/NO比值相关性较弱。
结论:
一、大鼠脑血管在不同体外循环模式下功能的变化:
1.脑血管在体外循环期间的缩血管效应明显大于舒血管效应,整体脑组织处于低灌注状态。
2.大脑中动脉内皮细胞依赖的血管舒张功能受损,在体外循环60分钟即可出现,并且在DHLF和DHCA组损伤明显加重,表明脑血管舒缩紧张度的不稳定性;而体外循环对平滑肌细胞功能无明显影响。
3.通过大脑微血管和内皮细胞的超微结构观察,发现在DHCA组内皮细胞损伤表现及周围脑组织水肿。
二、体外循环对大鼠脑血管功能失调的机制研究
1.体外循环可引起TNF-α和IL-6为代表的炎性因子显著升高,炎性因子水平与脑血管舒缩状态存在明显相关性,说明脑血管舒缩功能受损可能或部分为全身炎症反应引起。
2.体外循环可引起脑组织eNOS蛋白表达水平明显降低,且在DHLF和DHCA组降低尤为明显,提示炎症反应和缺血-再灌注损伤是影响eNOS蛋白水平的重要因素。
3.脑组织eNOS蛋白水平与颈内静脉血NO含量呈明显相关,提示脑血管eNOS功能状态是脑血管舒缩状态的重要因素。
三、大鼠体外循环脑血管功能变化与脑损伤的关系研究
1.体外循环,特别是DHLF和DHCA转流可引起血浆S100β蛋白为标志的神经细胞明显损伤,其损伤程度与脑血管灌注水平一致。
2.体外循环可引起神经细胞凋亡比例升高,说明凋亡是神经系统损伤的重要原因之一。细胞凋亡比例与脑血管舒缩状态之间存在相关性。
3.体外循环后早期2小时之内,未能在H.E.染色的病理切片上发现明显的神经细胞受损证据。
4.DHLF和DHCA可引起细胞ATP含量明显下降和颈内静脉乳酸水平明显升高,其程度与脑血管舒缩状态一致。
第三部分应用一氧化氮供体对大鼠体外循环脑损伤的保护策略研究
目的:观察通过给予NO供体以提高血浆NO浓度,能否通过减轻体外循环引起的炎症反应强度,提高脑组织灌注状态,从而减轻大鼠体外循环后急性脑损伤。
方法:36只大鼠随机平均分为6组,每组6只。B组:常温体外循环120min组、C组:深低温低流量60min组、D组:深低温停循环60min组、F组:常温体外循环120min+保护组、G组:深低温低流量60min+保护组和H组:深低温停循环60min+保护组。保护方法为静脉输注硝普钠3mg/kg/h至CPB结束,加用去氧肾上腺素维持平均动脉血压在60mmHg以上。
各组CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)4个时间点测定血浆S100β蛋白、Annexin V法测定海马细胞凋亡比例、右额顶叶皮质脑组织ATP含量测定、在CPB开始前(T2)、CPB30min(T3)、CPB60min(T4)、CPB90min(T5)、CPB120min(T6)5个时间点测定颈内静脉乳酸含量和氧饱和度等脑代谢指标及大脑海马区神经元和胶质细胞超微结构观察分别进行保护组与非保护组比较,观察NO供体的保护效应。
在CPB体外循环开始(T2)和体外循环120分钟(T6)二个时间点抽取颈内静脉血,组间进行TNF-α和IL-6浓度比较,确定NO供体是否通过降低炎性因子水平起到神经保护作用。定量测定各组海马eNOS蛋白并进行组间比较,了解给予NO供体后对eNOS蛋白含量的影响。
结果:各组36只S.D.大鼠均顺利建立体外循环。B组和F组、C组和G组、D组和H组比较,在T5、T6时间点各保护组颈内静脉血S100β蛋白含量均低于对照组;各保护组凋亡比例均明显低于对照组;各保护组额顶叶皮质脑组织ATP含量均高于对照组;在DHLF和DHCA保护组转流末乳酸含量明显低于对照组。T6时间点IL-6浓度F、G、H组均明显低于B、C、D组,F组eNOS蛋白含量低于B组(P=0.037),而C组与G组、D组与H组间eNOS蛋白含量相仿。
结论:
1.SNP作为一种外源性NO的供体,可以明显减轻体外循环引起的神经细胞损伤和减少细胞的凋亡。
2.扩张脑血管增加血流灌注和氧供、抑制体外循环炎症反应可能是NO供体脑保护的机制。
Introduction With the improvement of techniques of cardiac surgery and cardiopulmonary bypass(CPB),attention is increasingly focused on the multi-organ dysfunction caused by the CPB.The early and late neurologic morbidities are still high.The interruption of cerebral blood flow and the regional low-flow cerebral perfusion are the vast mechanisms of the brain injury,and the cerebral perfusion is totally based on the functional status of the cerebral vessels.There are few studies on effect of the CPB on cerebral vascular changes nowadays;especially the field is almost empty in domestic.This research was assigned to experimentally study on the effect of the CPB on cerebral vascular changes and mechanisms,and raised associated cerebral protective strategy.
PartⅠThe Study of the Animal Model of Closed Chest Cardiopulmonary Bypass in Sprague-Dawley Rats
Objectives To establish the animal model of closed chest cardiopulmonary bypass in the Sprague-Dawley rats and provide a economical animal model for the basic research of multi-organ dysfunction induced by CPB.
Methods The S.D.rats were assigned to undergo CPB via right carotid and jugular cannulation,and self-designed and improved the elements of CPB circuit.The cardiac arrest was induced by the hypothermal ventricular fibrillation.Mean body weight of the 30 rats was(467.9±44.5)g.The 30 rats were equally divided into five groups which were underwent CPB for 60 minutes(Group A),CPB for 120 minutes(Group B), deep hypothermic low flow(DHLF) bypass 60 minutes(Group C),deep hypothermic circulatory arrest(DHCA) 60 minutes(Group D) and sham(Group E) individually. During the bypass,temperature,invasive arterial blood pressure,electrocardiograph and arterial blood gas analysis were monitored and recorded at the following time point:after the anesthesia(T1),before CPB(T2),30min(T3),60min(T4),90min(T5), 120min(T6) during CPB and end of CPB(T7).Theα-stat strategy was used as blood gas analysis management.
Results The CPB were performed successfully in all the rats.The blood gas analysis results were all maintained in acceptable range and the mean arterial pressure were over 60 mmHg when off-pump.The cardiac function recovered after the rat weaned from the CPB.
Conclusions The animal model of closed chest CPB can be established successfully in rats with excellent survive.This model is a stable platform for the study of the pathophysiology of CPB and post-CPB multiple organ dysfunctions.
PartⅡThe Study on Effect of the Cardiopulmonary Bypass on Cerebral Vascular Changes in Rats and Associated Mechanisms
Objectives 1.To study on the cerebral vasomotor changes during the CPB and cerebral vascular reactivity changes after different bypass time and modes and to investigate the associated mechanisms.2.To test the cerebral injuries and metabolism in protein and cell levels to correlate the cerebral injuries and cerebral vasomotor changes.
Methods
1.The Study on the Cerebral Vasomotor Changes During the CPB and Cerebral Vascular Reactivity Changes after Different Bypass Time and Modes in Rats. The 30 rats were divided into 5 groups as PartⅠ.The internal jugular vein blood samples were taken before CPB(T2),30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB to test the serologic endothelin-1(ET-1) and nitric oxide(NO) changes.The ET-1/NO ratio was calculated to investigate the cerebral vasomotor changes.The right middle cerebral artery(MCA) was harvested and prepared for assessment of the myogenic tone with different transmural pressure,the endothelial cell response induced by different concentration of acetylcholine and the vascular smooth muscle cell response induced by the sodium nitroprusside and serotonin.The hippocampus tissue was harvested to observe the ultramicrostructure of endothelial cell in capillary with electron microscope.
2.The Mechanism of Cerebral Vascular Dysfunction Induced by the Cardiopulmonary Bypass in Rats.
The internal jugular vein blood samples were taken before CPB(T2),30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB to test the tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) in serum.The statistical analysis was used to test correlation between the cytokines and the cerebral vasomotor changes.The eNOS protein expression in hippocampus was determined by the Western immunoblotting and the correlation between the eNOS expression and NO content was accessed.
3.The Study on the Correlation Between the Cerebral Vascular Changes and Cerebral Injuries Induced by CPB in Rats.
The internal jugular vein blood samples were taken 30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB to test the S100βprotein levels and assess the correlation between S100βlevels and ET-1/NO ratio.The apoptosis cell percentage in hippocampus was determined by Annexin V/PI exam and the correlation between the apoptosis cell ratio and ET-1/NO ratio on T6 was accessed.The neuron injury was scored by the histopathology.The ATP content in frontal and apical lobe of the brain was tested by the electrophoresis and correlated with the ET-1/NO ratio on T6.The lactic acid content and internal jugular vein saturation were tested before CPB(T2),30 min(T3),60 min(T4),90 min(T5) and 120 min(T6) during CPB.The correlation were analyzed between the lactic acid content/ internal jugular vein saturation and the ET-1/NO ratio.
Results
1.The Study on the Cerebral Vasomotor Changes During the CPB and Cerebral Vascular Reactivity Changes after Different Bypass Time and Modes in Rats. All the rats were successfully established and weaned from the bypass.The ET-1 content increased with the bypass time and in DHLF and DHCA group,the ET-1 content increased in rewarming period.The NO content reached summit at T3 but decreased gradually after that.The ET-1/NO ratio was lower than T2 in T3 but increased to summit at the end of bypass.
The bypass did not alter the results of myogenic tone test with different transmural pressure.Furthermore,the vascular smooth muscle cell response induced by the sodium nitroprusside and serotonin were also intact in all the rats.Acetylcholine caused a dose-dependent vasodilation in the sham group that was absent in animals undergoing CPB.Significantly,this was apparent after only 60 minutes of CPB and the endothelial cell vasodilation responses were lower in DHLF and DHCA groups compared with group B.
The ultramicrostructure of endothelial cell and capillary in hippocampus observed by electron microscope found normal structure in group A and B,but the V-R space widened in group C and structural injury in endothelial cell and cerebral edema in group D.
2.The Mechanism of Cerebral Vascular Dysfunction Induced by the Cardiopulmonary Bypass in Rats.
CPB led to an early and marked increase in TNF-αand IL-6.The correlation coefficient between TNF-αand ET-1/NO ratio was 0.637(P＜0.001).The correlation coefficient between IL-6 and ET-1/NO ratio was 0.521(P＜0.001).The ICAM-1 were overexpressed in all the CPB groups and the intensity of ICAM-1 expression increased by turns in group A,B,C and D.The correlation coefficient between ICAM-1 and ET-1/NO ratio was 0.872(P＜0.001).
The CPB was correlated with the significantly reduction in eNOS expression.The ranks comparison based on Wilcoxson tests indicated that the eNOS protein level was lower in group B than group A(P=0.002) and group D than group C(P=0.002).The correlation coefficient between eNOS protein expression and NO content in internal jugular vein was 0.866(P＜0.001),and the regression equation was NO content= 1.91+1.73×eNOS expression.
3.The Study on the Relationship Between the Cerebral Vascular Changes and Cerebral Injuries Induced by CPB in Rats.
The CPB was correlated with the significantly increased in S100βprotein.DHCA caused highest S100βprotein levels compared with group B and C.The ranks comparison indicated that the S100βprotein level was higher in DHLF group compared with group B.The correlation coefficient between S100βprotein and ET-1/NO ratio was 0.753(P＜0.001).
The CPB was correlated with the significantly increased in apoptosis cell percentage in hippocampus.DHCA caused highest percentage of apoptosis cells compared with group B and C.The correlation coefficient between percentage of apoptosis cells and ET-1/NO ratio was 0.793(P＜0.001).No neuron injury was found pathologically and scored 0 in all the groups.
CPB did not alter the level of ATP compared with sham group,but the level reduced significantly in group C and D.The ranks comparison based on Wilcoxson tests indicated that the ATP level was lower in group D than group C(P=0.002).The correlation coefficient between ATP level and ET-1/NO ratio in T6 was -0.808 (P＜0.001).The lactic acid were higher in group C and D compared with group A and B in T4,T5,T6,but weak correlation was found with ET-1/NO ratio.
Conclusions
1.The Study on the Cerebral Vasomotor Changes During the CPB and Cerebral Vascular Reactivity Changes after Different Bypass Time and Modes in Rats.
a.The cerebral vasoconstriction effect is greater than vasodilatation effect during the CPB,which lead to poor cerebral perfusion.
b.The specific loss of acetylcholine- induced vasodilation suggests endothelial cell dysfunction,which appeares 60 min after the onset of CPB and are worsen in DHLF and DHCA group.Adversely,the vascular smooth muscle functions are not impaired after CPB.
c.The observation of ultramicrostructure of endothelial cell and capillary in hippocampus finds structural injury in endothelial cell and cerebral edema in DHCA group.
2.The Mechanism of Cerebral Vascular Dysfunction Induced by the Cardiopulmonary Bypass in Rats.
a.The increase of TNF-αand IL-6 induced by CPB is correlated with the cerebral vasomotor changes,which demonstrates that the impair cerebrovascular function is caused by the systemic inflammatory response.
b.The eNOS protein expression is reduced by CPB,especially in DHLF and DHCA group,which suggests the systemic inflammatory response and ischemia-reperfusion injury are the vast factors that affect the expression of eNOS protein.
c.The cerebrovascular eNOS protein expression is correlated with the NO content in internal jugular vein,which suggests the expression level of eNOS is a main factor of cerebral vasomotor changes.
3.The Study on the Relationship Between the Cerebral Vascular Changes and Cerebral Injuries Induced by CPB in Rats.
a.CPB,especially DHCA and DHLF leads to the increase of serum S100βprotein, which is a marker of the cerebral damage.And the serum S100βprotein level is correlated with the cerebral vasomotor changes.
b.Apoptosis is induced by CPB in cells of hippocampus,which suggests that apoptosis is a vast mechanism of cerebral damage.The apoptosis cell percentage is correlated with the cerebral vasomotor changes.
c.No evidence of neuron damage can be found pathologically in 2 hours after CPB.
d.DHLF and DHCA can lead to the reduction of ATP level in brain and increase of the lactic acid level in internal jugular vein.The ATP level is correlated with the cerebral vasomotor changes.
PartⅢThe Study of Protective Effect of NO Donor on Cerebral Damage Induced by CPB in Rats
Objectivs To investigate the cerebral protective effect and mechanism of NO donor reducing the cerebral damage induced by CPB.
Methods 36 rats were equally divided into six groups which were underwent CPB for 120 minutes(Group B),DHLF 60 minutes(Group C),DHCA 60 min(Group D),CPB for 120 minutes with SNP(Group F),DHLF 60 minutes with SNP(Group G),DHCA 60 min with SNP(Group H).The protective strategy was to infuse SNP 3mg/kg/h intravenously with deoxyepinephrine to maintain the MAP over 60mmHg till end of CPB.The serum S100βprotein level,the apoptosis cell percentage,the ATP levels, the lactic acid and internal jugular vein saturation and the microstructure were compared between the corresponding groups with and without SNP.
The blood samples were taken at T2 and T6 to evaluate the TNF-αand IL-6 levels. The levels were compared between the corresponding groups with and without SNP. The eNOS protein expression were determined to assess the changes affected by the NO donor.
Results 36 rats were successfully established the bypass.The serum S100βprotein levels and apoptosis cell percentages were lower at T5 and T6 in groups with SNP compared with the control groups.The ATP levels were higher in groups with SNP compared with the control groups while the lactic acid levels were lower in DHCA/DHLF groups with SNP compared with corresponding control groups.The IL-6 levels were lower in groups with SNP compared with corresponding control groups at T6.The SNP altered the eNOS protein expression in group F(P=0.037) compared with group B,while the expression levels were similar in DHLF/DHCA groups with or without SNP.
Conclusions
1.As an exogenous NO donor,SNP can significantly reduce the cerebral damage and cellular apoptosis induced by CPB.
2.The mechanism of cerebral protection of SNP is contributed to the vasodilatation to increase the blood flow and oxygen and inhibition of systemic inflammatory response induced by CPB.
引文
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