门静脉淤血对肝脏缺血再灌注损伤的影响
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摘要
第一部分门静脉淤血对内毒素血症和肝脏缺血再灌注损伤的影响及机制
目的
我们利用家兔肝脏原位冷灌注模型,观察不同门静脉阻断时间恢复灌流时门静脉淤血中内毒素含量的变化,以及去除门静脉淤血对肝脏缺血再灌注损伤的影响,为临床肝移植去除门静脉淤血提供依据。
方法
80只健康成年新西兰大白兔,雌雄不拘,体重2.0～2.5kg,由第二军医大学动物中心提供,随机分为对照组(C组)和实验组。实验组动物按门静脉阻断时间(即冷灌注时间)不同分为20min、30min、40min组,再按去除门静脉淤血去除量不同分为3个亚组:A_0组不去除门静脉淤血;A_5组去除门静脉淤血5ml;A_(10)组去除门静脉淤血10ml。每组8只动物,共9组。另外8只动物为C组仅行手术解剖及门、腔静脉插管,不做门静脉阻断及肝脏灌注。观察恢复灌流时门静脉淤血中内毒素含量的变化,以及去除门静脉淤血对血清内毒素、丙氨酸转氨酶(ALT)、透明质酸(HA)、肿瘤坏死因子-a(TNF-a),肝组织匀浆丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性及肝组织核因子-κB(NF-κB)活性的变化和肝脏组织学改变。
结果
门静脉淤血中内毒素含量随阻断时间延长明显升高,同一阻断时间每去除2.5ml淤血可使血清内毒素含量显著下降,但去除7.5ml后淤血中内毒素含量不再明显下降。在门静脉阻断30min和40min组,去除门静脉淤血能降低血清内毒素、ALT、HA、TNF-α及肝组织匀浆MDA的含量和肝组织NF-κB活性,增加肝组织匀浆SOD活性,改善肝脏病理学变化,与不去除相比较差异有统计学意义。在阻断20min组去除门静脉淤血与不去除相比较,各检测指标差异无统计学意义。
讨论
长时间阻断门静脉,造成胃肠道淤血,肠黏膜缺血、缺氧及通透性升高,导致门静脉血尤其是门静脉淤血中肠源性内毒素明显升高,并且门静脉淤血中的内毒素含量随门静脉阻断时间延长而明显升高。同时发现在最初去除的门静脉淤血中内毒素含量最高,这些高浓度、大剂量的内毒素可能是在恢复灌流时造成肝脏损伤的关键因素。ALT、HA、TNF-α,肝组织匀浆MDA、SOD及肝组织NF-κB的变化和肝脏组织学改变可从不同方面反映肝脏缺血再灌注损伤的程度,去除门静脉淤血能降低复流后血清内毒素、ALT、HA、TNF-α和肝组织匀浆MDA含量及肝组织NF-κB活性,增加SOD活性,改善肝脏病理学变化。
结论
门静脉淤血中内毒素含量随阻断时间延长明显升高,首批放出的5ml门静脉淤血中内毒素含量极高,可能是引起肝脏损伤的主要原因;去除门静脉淤血可以减轻肝脏的缺血再灌注损伤,其机制可能与门静脉淤血去除减少内毒素吸收,进而降低了血清TNF-α产生及肝组织NF-κB活化有关。
第二部分
不同门静脉淤血去除量对内毒素血症及肝脏缺血再灌注损伤的影响
目的
家兔的血容量为人体血容量的1/40,每5ml血液相当于人体血液200ml,我们建立了家兔肝脏原位冷灌注模型,观察恢复灌流时不同去除门静脉淤血去除量对血清内毒素及肝脏再灌注损伤的影响,为临床肝移植提供一种安全有效的方法。
方法
88只健康成年新西兰大白兔随机分为对照组(C组)和实验组,每组8只动物。实验组动物按门静脉阻断时间(即冷灌注时间)不同分为30min、40min组,再按去除门静脉淤血去除量不同分为5个亚组:A_1组去除门静脉淤血2.5ml;A_2组去除门静脉淤血5ml;A_3组去除门静脉淤血10ml;A_4组去除门静脉淤血15ml;B组不去除门静脉淤血。C组仅行手术解剖及门、腔静脉插管,不做肝门阻断及肝脏灌注。观察不同门静脉淤血去除量对恢复灌流后1h、2h、4h血清内毒素、ALT、HA、TNF-α,及4h肝组织匀浆MDA、SOD、肝组织NF-κB的变化和肝脏组织学改变。
结果
去除门静脉淤血能降低复流后血清内毒素、ALT、HA、TNF-α和肝组织匀浆MDA含量及肝组织NF-κB的活性,增加SOD活性,改善肝脏病理学变化。其中,去除门静脉淤血在5ml与10ml时效果最为明显,与不去除相比较差异有统计学意义;去除门静脉淤血2.5ml、15ml时与不去除相比较差异无统计学意义。
讨论
门静脉淤血中内毒素含量随阻断时间延长明显升高,去除门静脉淤血不仅可以从总量上减少内毒素进入肝脏和体循环,也可以减轻峰值内毒素对肝、肺及胃肠道等重要脏器所造成的损伤,减少肠道内毒素进一步吸收。去除门静脉淤血2.5ml与不去除相比未能显示出统计学意义,可能与最初的内毒素含量极高的门静脉淤血未完全去除有关。同时,数据显示随门静脉淤血去除量的继续增加,血清内毒素含量反而有升高趋势,分析主要有一下原因:(1)门静脉淤血最初5ml去除后内毒素含量显著下降,继续去除不能起到同样效果;(2)随去除量增加会出现组织灌注不足,加重器官创伤和内毒素血症。
结论
门静脉淤血适量去除可以减轻内毒素血症及肝脏缺血再灌注损伤,其机制可能与门静脉淤血去除减少内毒素吸收,进而降低了血清TNF-α产生及肝组织NF-κB活化有关。去除不足或过多去除意义不大。
第三部分
门静脉淤血对肝脏缺血再灌注后肺脏和肾脏损伤的影响
目的
去除门静脉淤血可以减轻肝脏的缺血再灌注损伤,能否减轻肝脏缺血再灌注所致肺、肾功能的损伤尚无实验依据。我们利用家兔肝脏原位冷灌注模型,观察恢复灌流时去除门静脉淤血对肺、肾功能的影响,为临床肝移植保护肺、肾等重要脏器,减少术后并发症提供依据。
方法
56只健康成年新西兰大白兔随机分为对照组(C组)和实验组。实验组动物按门静脉阻断时间(即冷灌注时间)不同分为30min、40min组,再按去除门静脉淤血去除量不同分为3个亚组:A_0组不去除门静脉淤血;A_5组去除门静脉淤血5ml;A_(10)组去除门静脉淤血10ml。每组8只动物,共6组。另外8只动物为C组作对照。检测去除门静脉淤血对恢复灌流4h后血清内毒素、TNF-α、尿素氮(BUN)、肌苷(Cr)及肺湿/干重、肺灌洗液蛋白含量的变化;肺、肾组织匀浆MDA、SOD及组织病理学改变。
结果
去除门静脉淤血能降低复流后血清内毒素、TNF-α、BUN、Cr、肺湿/干重、肺灌洗液蛋白含量和肺、肾组织匀浆中MDA含量;增加肺、肾组织匀浆中SOD活性;改善肺、肾组织学变化。
讨论
长时间的门静脉阻断将导致门静脉淤血中毒素含量明显升高,再灌注后激活肝脏枯否细胞,产生以TNF-α为主的大量细胞因子以及活性氧、蛋白水解酶,这些因子一方面造成肝细胞的损伤和肝脏微循环障碍,另一方面活性物质通过体循环到达肺、肾血管床,激活毛细血管内皮细胞、中性粒细胞等,导致肺、肾组织器官结构损伤及功能发生紊乱,表现出体循环压力下降和肝外远端器官的损伤或衰竭。血清内毒素、TNF-α、BUN、Cr、肺湿/干重、肺灌洗液蛋白含量和肺、肾组织匀浆中MDA、SOD及组织病理学该变等指标,客观反映了全身炎症反应综合症及肺、肾组织器官的损伤程度。这些指标的改善提示去除门静脉淤血对肝脏缺血再灌注后肺、肾损伤有保护作用。
结论
去除门静脉淤血可以减轻肝脏缺血再灌注后肺、肾功能的损伤,其机制可能与门静脉淤血去除减少内毒素吸收,进而降低了血清TNF-α产生有关。
第四部分
不同门静脉淤血去除量对临床肝移植术后早期肝功能的影响
目的
放血疗法已为多数临床医生接受,理论上可以减少毒性物质进入肝脏从而减轻对肝脏的再灌注损伤,但临床肝移植门静脉淤血去除量多为经验性,亦未见相关报道。将47例原位肝移植患者按术中门静脉淤血去除量的不同分为50ml和200ml两组,观察各组术后血清内毒素和炎性因子的变化以及肝功能恢复情况,从而为指导临床肝移植去除门静脉淤血提供依据。
方法
1.临床资料:2006年1月至2007年10月我院收治的成年同种异体原位肝移植患者47例,男43例,女4例;年龄33～67岁,平均(49.9±8.5)岁;均为首次肝移植患者。术中按门静脉淤血去除量不同随机分为两组:A组(n=26)去除门静脉淤血50ml;B组(n=21)去除门静脉淤血200ml。
2.观察指标:(1)受者术前及手术情况:性别、年龄、原发疾病类型、Child-pugh分级、供肝冷缺血时间、无肝期时间、手术时间、手术方式、术中出血量及输血量。(2)于麻醉后手术前(T_0)、门静脉阻断开放后60min(T_1)、术毕(T_2)、术后24h(T_3)采集静脉血,测定血清内毒素、D-乳酸、TNF-α、白细胞介素-6(IL-6)的含量。(3)术前、术后1、3、7d生化分析仪检测ALT、天冬氨酸转氨酶(AST)、总胆红素(TBIL)、直接胆红素((DBIL)、白蛋白(Alb)、前白蛋白(PAB)及凝血酶原时间(PT)、部分凝血活酶时间(APTT)、纤维蛋白原(FIB)。
结果
两组在性别、年龄、原发疾病类型、Child-pugh分级、供肝冷缺血时间、手术时间、无肝期时间、手术方式、出血量、输血量及术前各项检测指标无显著差异的条件下,多数检测指标显示B组术后恢复优于A组。其中B组术后血清内毒素、D-乳酸、TNF-α、IL-6、ALT、AST、PT、APTT明显低于A组;PAB明显高于A组,差异均有统计学意义(P＜0.05)。
讨论
血浆内毒素TNF-α、IL-6可以反应肝脏及全身炎症反应程度,血浆D-乳酸水平可以反应肠道的通透性,转氨酶、胆红素、蛋白和凝血功能是评价肝移植术后肝功能恢复的灵敏指标。本研究中,门静脉淤血去除200ml组术后血清内毒素、D-乳酸、TNF-α、IL-6、ALT、AST、PT、APTT明显低于门静脉淤血去除50ml组,术后前白蛋白明显增高,提示200ml门静脉淤血去除较50ml能更加有效地减轻移植肝脏损伤,减轻炎症反应,保护肠黏膜屏障功能,并有助于肝功能的恢复,其机制可能与完全去除最初的内毒素含量极高的门静脉淤血有关。
结论
肝移植术中门静脉淤血去除200ml效果优于50ml,可以更好地减轻术后内毒素血症,并有助于肝功能的恢复。
Part One The effect and mechanism of portal blood stasis on intestinal endotoxemia and hepatic ischemia reperfusion injury in a rabbit model
Objective
A rabbit hepatic ischemia reperfusion injury model was established by in situ hypothermic irrigation for different time to observe the influence of portal blood stasis removal on intestinal endotoxemia and hepatic ischemia reperfusion injury.The purpose was to find an ideal method for portal blood stasis removal and provide the experimental proof for clinical application of liver transplantation.
Methods
Eighty New Zealand white rabbits of both genders,weighing 2.0-2.5 kg,purchased from the Laboratory Animal Center of Second Military Medical University,were randomly divided into control group(group C) and experimental groups.The rabbits of experimental groups were divided into three groups equally by different time of the portal vein occlusion for 20,30,40 minutes and then each group was re-divided into 3 subgroups by different amount of portal blood stasis removal:group A_0 no blood removal,group A_5 5ml blood removal,group A_(10) 10ml blood removal.Each group had eight rabbits,nine groups in all. The other eight rabbits(group C) did not receive hepatic portal occlusion and hypothermic irrigation.Their abdomens were opened and only served as control group.Endotoxin content both in serum and in portal blood stasis,alanine aminotransferase(ALT), hyaluronic acid(HA),tumor necrosis factor-α(TNF-α),hepatic pathology,content of malondialdehyde(MDA) and activity of superoxide dismutase(SOD) and activation of nuclear factor-κB(NF-κB) in liver tissue were examined respectively after reperfusion 4h.
Results
The levels of serum endotoxin were significantly increased by extension of portal vein occlusion.At the same time of portal vein occlusion the level of serum endotoxin in portal blood stasis significantly decreased with each 2.5ml blood removal,subsequently reaching a minima at the 7.5ml blood removal.In groups of portal vein occlusion for 30 and 40 minutes,removing portal blood stasis ameliorated hepatic ischemia reperfusion injury as shown by ALT,HA,TNF-α,MDA,SOD,NF-κB and the pathology.Compared with the non-removal group,the effect was significant,while the effect of removing portal blood stasis in the group of portal vein occlusion for 20 minutes was not significant.
Discussion
Long-time occlusion of the portal vein in the process of liver transplantation results in gastro-intestinal congestion,barrier failure,insufficient blood and oxygen supply,and increasing gut mucosal permeability,which leads to obvious increase of intestinal endotoxin in portal blood,especially portal blood stasis.The levels of serum endotoxin in portal blood stasis were significantly increased by extension of portal vein occlusion.The first 5ml portal blood stasis contains high volume of endotoxin which may be responsible for hepatic reperfusion injury.The alteration of ALT,HA,TNF-α,MDA,SOD,NF-κB and the pathology can reflect hepatic reperfusion injury in all ways.Removing portal blood stasis also ameliorated hepatic ischemia reperfusion injury as shown by those.
Conclusion
The levels of serum endotoxin in portal blood stasis were significantly increased by extension of portal vein occlusion.The first 5ml portal blood stasis contains high volume of endotoxin which may be responsible for hepatic reperfusion injury.Removal of portal blood stasis before the resume of splanchnic circulation may ameliorate hepatic ischemia reperfusion injury.The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption,and this decreases production of serum TNF-αas well as hepatic activation of NF-κB.
Part Two The effect of different dosage of portal blood stasis removal on endotoxemia and hepatic ischemia reperfusion injury
Objective
The blood volume of rabbit is about equal to one fourth that of human body and 5ml blood volume is equivalent to 200ml that of human.A rabbit hepatic ischemia reperfusion injury model was established by in situ hypothermic irrigation for different time to observe the influence of portal blood stasis removal on intestinal endotoxemia and hepatic ischemia reperfusion injury.The purpose was to find an safe and effective method for clnical liver transplantation.
Methods
Eighty-eight healthy New Zealand white rabbits were randomly divided into a control group(group C) and experimental groups.The rabbits of experimental groups were divided into two groups equally by different time of the portal vein occlusion for 30,40 minutes and then each group was re-divided into five subgroups by different amount of portal blood stasis removal:group A_1 2.5ml blood removal,group A_2 5ml blood removal, group A_3 10ml blood removal,group A_4 15ml blood removal,and group B no blood removal.Each group had eight rabbits.The other eight rabbits did not receive hepatic portal occlusion and hypothermic irrigation,whose abdomens were opened and only served as control group.Serum endotoxin content,ALT,HA and TNF-αwere examined respectively after reperfusion 1h,2h,and 4h.Hepatic tissues were sampled to determine the pathology,content of MDA and activity of SOD and activation of NF-κB in liver tissue were examined respectively after reperfusion 4h.
Results
Removing portal blood stasis also ameliorated hepatic ischemia reperfusion injury as shown by ALT,HA,MDA,SOD and the pathology.5ml and 10ml blood removal had the maximal favorable effect,while the effect of 2.5ml or 15ml blood removal was not significant.
Discussion
The levels of serum endotoxin in portal blood stasis were significantly increased by extension of portal vein occlusion.Portal blood stasis removal could not only reduce the total amount of endotoxin absorbed into liver and systemic circulation,but also reduce the damage of some important organs such as liver,lung,gastrointestinal tract.That the effect of 2.5ml or 15ml blood removal was not significant was correlated with that the first portal blood stasis contains high volume of endotoxin were not removed completely.The levels of serum endotoxin tended to rise with more portal blood stasis removal.The main reason was sequence portal blood stasis removal could not improve the protective effect because the first portal blood stasis containing high volume of endotoxin had been removed. Secondly the increase of portal blood stasis removal led to insufficient blood supply which worsened organ injury and endotoxemia.
Conclusion
Appropriate quantity of portal blood stasis removal can protect the liver against ischemia reperfusion injury.The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption,and then decreases production of serum TNF-αas well as hepatic activation of NF-κB.But too much or too little of portal congestion blood released could not improve the protective effect.
Part Three The effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion in a rabbit model
Objective
The portal blood stasis removal can protect the liver against ischemia reperfusion injury,but there was no experimental proof whether it might ameliorate the lung and renal injury induced by hepatic ischemia reperfusion.A rabbit hepatic ischemia reperfusion injury model was established by in situ hypothermic irrigation to observe the effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion.The purpose was to provide the experimental proof for protecting lung and renal and reducing postoperative complications.
Methods
Fifty-six healthy New Zealand white rabbits were randomly divided into control group and experimental groups.
The rabbits of experimental groups were divided into two groups equally by different time of the portal vein occlusion for 30,40 minutes and then each group was re-divided into three subgroups by different amount of portal blood stasis removal:group A_0 no blood removal,group A_5 5ml blood removal,group A_(10) 10ml blood removal.Each group had eight rabbits.The other eight rabbits did not receive hepatic portal occlusion and hypothermic irrigation,whose abdomens were opened and only served as control group. After reperfusion 4h serum endotoxin content,TNF-α,urea nitrogen(BUN),creatinine (Cr),and wet to dry weight ratio,broncho-alveolar lavage fluid protein content in lung tissues were examined respectively.Meantime,lung and kidney tissues were sampled to determine the content of MDA,SOD and the pathology.
Results
Removing portal blood stasis ameliorated lung and renal injury as shown by serum endotoxin,TNF-α,BUN,Cr,wet to dry weight ratio,broncho-alveolar lavage fluid protein content,MDA in lung and kidney tissue being significantly reduced,SOD in lung and kidney tissue being significantly increased and the pathology becoming better.
Discussion
Long-time occlusion of the portal vein resulted in obvious increase of endotoxin in portal blood stasis.At reperfusion the endotoxin in portal blood would activate Kupffer cells,which might contribute to produce a great deal of cytokine,reactive oxygen species, and proteolytic enzyme.Those things not only produced liver injury and microcirculation disturbance,but also,through systemic circulation,resulted in lung and kidney injury by activating capillary endothelium and neutrophil.It showed the pressure of systemic circulation decreased and the injury of extra-hepatic organs,serum endotoxin,TNF-α, BUN,Cr,wet to dry weight ratio,broncho-alveolar lavage fluid protein content,MDA, SOD and the pathology objectively reflect the severity of systemic inflammatory response syndrome and the degree of lung and kidney injury.Those index ameliorated showed that the removal of portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion.
Conclusion
Removal of portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion.The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption,and then decreases production of serum TNF-α.
Part Four Effects of different dosage of portal blood stasis removal on liver function during early stage after liver transplantation
Objective
The pricking blood therapy has been accepted by clinician because it would reduce theoretically endotoxin entering into liver and protect the liver against ischemia reperfusion injury.How much portal blood stasis should be removed in clinic liver transplantation was empirical and there was no related report about it.Forty-seven patients who received liver transplantation in our hospital were divided into 2 groups according to different dosage of portal blood stasis removal during operation:group A 50ml and group B 200ml portal blood stasis removal respectively.The levels of plasma endotoxin, inflammatory factors and the restoring of liver function after liver transplantation was observed in order to provide the experimental proofs for clinical liver transplantation.
Methods
Clinical data:A total of 47 cases undergoing orthotopic liver transplantation were selected from Eastern Hepatobiliary Surgery Hospital,Second Military Medical University from January 2006 to October 2007.In 47 cases,43 males and 4 females,age from 33 to 67(average 49.9±8.5) years,were randomly divided into two groups by different dosage of portal blood stasis removal:group A(n=26) 50ml blood removal and group B(n=21) 200ml blood removal.
Measurements:(1) The patients of sex,age,primary liver diseases and Child-pugh's classification,donor liver of cold ischemic time and total operation and anhepatic time, operation methods,volume of blood loss and transfusion were recorded before and in operation.(2) Samples from venous blood were obtained at beginning of surgery(T_0), 60min after graft reperfusion(T_1),at the end of operation(T_2),and 24h after surgery.The levels of plasma endotoxin,D-lactate,TNF-α,Interleukin-6(IL-6) were measured respectively.(3) The levels of plasma alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),direct bilirubin(DBIL),albumin(Alb), prealbumin(PAB),prothrombin time(PT) activated partial thromboplastin time(APTT) and fibrinogen(FIB) were examined in the day before operation and 1,3,7 d following surgery.
Results
There was no significant difference in sex,age,primary liver diseases and Child-pugh's classification,cold ischemic time,total operation and anhepatic time, operation methods,volume of blood loss and transfusion,plasma endotoxin,D-lactate, TNF-α,IL-6,liver function and blood coagulation parameters before operation.Most of observations showed the restoration in group B was better than that in group A.The plasma levels of endotoxin,D-lactate,TNF-α,IL-6,ALT,AST,PT,APTT in group B were significantly lower than those in group A(P＜0.05).The level of plasma PAB in group B was significantly higher than that in group A(P＜0.05).
Discussion
The plasma levels of endotoxin,TNF-α,IL-6 are very sensitive markers of the degree of hepatic and body injury.The plasma levels of D-lactate response gut mucosal permeability.The plasma levels of aminotransferase,bilirubin,prealbumin,blood coagulation are very sensitive markers of liver functional restoration after liver transplantation.Our study showed that the levels of serum levels of endotoxin,D-lactate, TNF-α,IL-6,ALT,AST,PT,APTT after operation in group of 200ml portal blood stasis removal were significantly lower than those in group of 50ml blood removal.Meantime, the level of serum PAB was significantly higher.This study showed 200ml portal blood stasis removal before resuming of splanchnic circulation may ameliorate hepatic ischemia reperfusion injury,ruduce inflammatory reaction,protect intestinal mucosal barrier and liver functional restoration would be more effective than that of 50ml.The reason was that the first 200ml portal blood stasis containing high volume of endotoxin which might be responsible for hepatic reperfusion injury had been removed completely.
Conclusion
This study showed the effect of 200ml portal congestion blood removal was better than that of 50ml,which contributed to relieving endotoxemia and restoring liver function after liver transplantation.
目的
我们利用家兔肝脏原位冷灌注模型,观察不同门静脉阻断时间恢复灌流时门静脉淤血中内毒素含量的变化,以及去除门静脉淤血对肝脏缺血再灌注损伤的影响,为临床肝移植去除门静脉淤血提供依据。
方法
80只健康成年新西兰大白兔,雌雄不拘,体重2.0～2.5kg,由第二军医大学动物中心提供,随机分为对照组(C组)和实验组。实验组动物按门静脉阻断时间(即冷灌注时间)不同分为20min、30min、40min组,再按去除门静脉淤血去除量不同分为3个亚组:A_0组不去除门静脉淤血;A_5组去除门静脉淤血5ml;A_(10)组去除门静脉淤血10ml。每组8只动物,共9组。另外8只动物为C组仅行手术解剖及门、腔静脉插管,不做门静脉阻断及肝脏灌注。观察恢复灌流时门静脉淤血中内毒素含量的变化,以及去除门静脉淤血对血清内毒素、丙氨酸转氨酶(ALT)、透明质酸(HA)、肿瘤坏死因子-a(TNF-a),肝组织匀浆丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性及肝组织核因子-κB(NF-κB)活性的变化和肝脏组织学改变。
结果
门静脉淤血中内毒素含量随阻断时间延长明显升高,同一阻断时间每去除2.5ml淤血可使血清内毒素含量显著下降,但去除7.5ml后淤血中内毒素含量不再明显下降。在门静脉阻断30min和40min组,去除门静脉淤血能降低血清内毒素、ALT、HA、TNF-α及肝组织匀浆MDA的含量和肝组织NF-κB活性,增加肝组织匀浆SOD活性,改善肝脏病理学变化,与不去除相比较差异有统计学意义。在阻断20min组去除门静脉淤血与不去除相比较,各检测指标差异无统计学意义。
讨论
长时间阻断门静脉,造成胃肠道淤血,肠黏膜缺血、缺氧及通透性升高,导致门静脉血尤其是门静脉淤血中肠源性内毒素明显升高,并且门静脉淤血中的内毒素含量随门静脉阻断时间延长而明显升高。同时发现在最初去除的门静脉淤血中内毒素含量最高,这些高浓度、大剂量的内毒素可能是在恢复灌流时造成肝脏损伤的关键因素。ALT、HA、TNF-α,肝组织匀浆MDA、SOD及肝组织NF-κB的变化和肝脏组织学改变可从不同方面反映肝脏缺血再灌注损伤的程度,去除门静脉淤血能降低复流后血清内毒素、ALT、HA、TNF-α和肝组织匀浆MDA含量及肝组织NF-κB活性,增加SOD活性,改善肝脏病理学变化。
结论
门静脉淤血中内毒素含量随阻断时间延长明显升高,首批放出的5ml门静脉淤血中内毒素含量极高,可能是引起肝脏损伤的主要原因;去除门静脉淤血可以减轻肝脏的缺血再灌注损伤,其机制可能与门静脉淤血去除减少内毒素吸收,进而降低了血清TNF-α产生及肝组织NF-κB活化有关。
第二部分
不同门静脉淤血去除量对内毒素血症及肝脏缺血再灌注损伤的影响
目的
家兔的血容量为人体血容量的1/40,每5ml血液相当于人体血液200ml,我们建立了家兔肝脏原位冷灌注模型,观察恢复灌流时不同去除门静脉淤血去除量对血清内毒素及肝脏再灌注损伤的影响,为临床肝移植提供一种安全有效的方法。
方法
88只健康成年新西兰大白兔随机分为对照组(C组)和实验组,每组8只动物。实验组动物按门静脉阻断时间(即冷灌注时间)不同分为30min、40min组,再按去除门静脉淤血去除量不同分为5个亚组:A_1组去除门静脉淤血2.5ml;A_2组去除门静脉淤血5ml;A_3组去除门静脉淤血10ml;A_4组去除门静脉淤血15ml;B组不去除门静脉淤血。C组仅行手术解剖及门、腔静脉插管,不做肝门阻断及肝脏灌注。观察不同门静脉淤血去除量对恢复灌流后1h、2h、4h血清内毒素、ALT、HA、TNF-α,及4h肝组织匀浆MDA、SOD、肝组织NF-κB的变化和肝脏组织学改变。
结果
去除门静脉淤血能降低复流后血清内毒素、ALT、HA、TNF-α和肝组织匀浆MDA含量及肝组织NF-κB的活性,增加SOD活性,改善肝脏病理学变化。其中,去除门静脉淤血在5ml与10ml时效果最为明显,与不去除相比较差异有统计学意义;去除门静脉淤血2.5ml、15ml时与不去除相比较差异无统计学意义。
讨论
门静脉淤血中内毒素含量随阻断时间延长明显升高,去除门静脉淤血不仅可以从总量上减少内毒素进入肝脏和体循环,也可以减轻峰值内毒素对肝、肺及胃肠道等重要脏器所造成的损伤,减少肠道内毒素进一步吸收。去除门静脉淤血2.5ml与不去除相比未能显示出统计学意义,可能与最初的内毒素含量极高的门静脉淤血未完全去除有关。同时,数据显示随门静脉淤血去除量的继续增加,血清内毒素含量反而有升高趋势,分析主要有一下原因:(1)门静脉淤血最初5ml去除后内毒素含量显著下降,继续去除不能起到同样效果;(2)随去除量增加会出现组织灌注不足,加重器官创伤和内毒素血症。
结论
门静脉淤血适量去除可以减轻内毒素血症及肝脏缺血再灌注损伤,其机制可能与门静脉淤血去除减少内毒素吸收,进而降低了血清TNF-α产生及肝组织NF-κB活化有关。去除不足或过多去除意义不大。
第三部分
门静脉淤血对肝脏缺血再灌注后肺脏和肾脏损伤的影响
目的
去除门静脉淤血可以减轻肝脏的缺血再灌注损伤,能否减轻肝脏缺血再灌注所致肺、肾功能的损伤尚无实验依据。我们利用家兔肝脏原位冷灌注模型,观察恢复灌流时去除门静脉淤血对肺、肾功能的影响,为临床肝移植保护肺、肾等重要脏器,减少术后并发症提供依据。
方法
56只健康成年新西兰大白兔随机分为对照组(C组)和实验组。实验组动物按门静脉阻断时间(即冷灌注时间)不同分为30min、40min组,再按去除门静脉淤血去除量不同分为3个亚组:A_0组不去除门静脉淤血;A_5组去除门静脉淤血5ml;A_(10)组去除门静脉淤血10ml。每组8只动物,共6组。另外8只动物为C组作对照。检测去除门静脉淤血对恢复灌流4h后血清内毒素、TNF-α、尿素氮(BUN)、肌苷(Cr)及肺湿/干重、肺灌洗液蛋白含量的变化;肺、肾组织匀浆MDA、SOD及组织病理学改变。
结果
去除门静脉淤血能降低复流后血清内毒素、TNF-α、BUN、Cr、肺湿/干重、肺灌洗液蛋白含量和肺、肾组织匀浆中MDA含量;增加肺、肾组织匀浆中SOD活性;改善肺、肾组织学变化。
讨论
长时间的门静脉阻断将导致门静脉淤血中毒素含量明显升高,再灌注后激活肝脏枯否细胞,产生以TNF-α为主的大量细胞因子以及活性氧、蛋白水解酶,这些因子一方面造成肝细胞的损伤和肝脏微循环障碍,另一方面活性物质通过体循环到达肺、肾血管床,激活毛细血管内皮细胞、中性粒细胞等,导致肺、肾组织器官结构损伤及功能发生紊乱,表现出体循环压力下降和肝外远端器官的损伤或衰竭。血清内毒素、TNF-α、BUN、Cr、肺湿/干重、肺灌洗液蛋白含量和肺、肾组织匀浆中MDA、SOD及组织病理学该变等指标,客观反映了全身炎症反应综合症及肺、肾组织器官的损伤程度。这些指标的改善提示去除门静脉淤血对肝脏缺血再灌注后肺、肾损伤有保护作用。
结论
去除门静脉淤血可以减轻肝脏缺血再灌注后肺、肾功能的损伤,其机制可能与门静脉淤血去除减少内毒素吸收,进而降低了血清TNF-α产生有关。
第四部分
不同门静脉淤血去除量对临床肝移植术后早期肝功能的影响
目的
放血疗法已为多数临床医生接受,理论上可以减少毒性物质进入肝脏从而减轻对肝脏的再灌注损伤,但临床肝移植门静脉淤血去除量多为经验性,亦未见相关报道。将47例原位肝移植患者按术中门静脉淤血去除量的不同分为50ml和200ml两组,观察各组术后血清内毒素和炎性因子的变化以及肝功能恢复情况,从而为指导临床肝移植去除门静脉淤血提供依据。
方法
1.临床资料:2006年1月至2007年10月我院收治的成年同种异体原位肝移植患者47例,男43例,女4例;年龄33～67岁,平均(49.9±8.5)岁;均为首次肝移植患者。术中按门静脉淤血去除量不同随机分为两组:A组(n=26)去除门静脉淤血50ml;B组(n=21)去除门静脉淤血200ml。
2.观察指标:(1)受者术前及手术情况:性别、年龄、原发疾病类型、Child-pugh分级、供肝冷缺血时间、无肝期时间、手术时间、手术方式、术中出血量及输血量。(2)于麻醉后手术前(T_0)、门静脉阻断开放后60min(T_1)、术毕(T_2)、术后24h(T_3)采集静脉血,测定血清内毒素、D-乳酸、TNF-α、白细胞介素-6(IL-6)的含量。(3)术前、术后1、3、7d生化分析仪检测ALT、天冬氨酸转氨酶(AST)、总胆红素(TBIL)、直接胆红素((DBIL)、白蛋白(Alb)、前白蛋白(PAB)及凝血酶原时间(PT)、部分凝血活酶时间(APTT)、纤维蛋白原(FIB)。
结果
两组在性别、年龄、原发疾病类型、Child-pugh分级、供肝冷缺血时间、手术时间、无肝期时间、手术方式、出血量、输血量及术前各项检测指标无显著差异的条件下,多数检测指标显示B组术后恢复优于A组。其中B组术后血清内毒素、D-乳酸、TNF-α、IL-6、ALT、AST、PT、APTT明显低于A组;PAB明显高于A组,差异均有统计学意义(P＜0.05)。
讨论
血浆内毒素TNF-α、IL-6可以反应肝脏及全身炎症反应程度,血浆D-乳酸水平可以反应肠道的通透性,转氨酶、胆红素、蛋白和凝血功能是评价肝移植术后肝功能恢复的灵敏指标。本研究中,门静脉淤血去除200ml组术后血清内毒素、D-乳酸、TNF-α、IL-6、ALT、AST、PT、APTT明显低于门静脉淤血去除50ml组,术后前白蛋白明显增高,提示200ml门静脉淤血去除较50ml能更加有效地减轻移植肝脏损伤,减轻炎症反应,保护肠黏膜屏障功能,并有助于肝功能的恢复,其机制可能与完全去除最初的内毒素含量极高的门静脉淤血有关。
结论
肝移植术中门静脉淤血去除200ml效果优于50ml,可以更好地减轻术后内毒素血症,并有助于肝功能的恢复。
Part One The effect and mechanism of portal blood stasis on intestinal endotoxemia and hepatic ischemia reperfusion injury in a rabbit model
Objective
A rabbit hepatic ischemia reperfusion injury model was established by in situ hypothermic irrigation for different time to observe the influence of portal blood stasis removal on intestinal endotoxemia and hepatic ischemia reperfusion injury.The purpose was to find an ideal method for portal blood stasis removal and provide the experimental proof for clinical application of liver transplantation.
Methods
Eighty New Zealand white rabbits of both genders,weighing 2.0-2.5 kg,purchased from the Laboratory Animal Center of Second Military Medical University,were randomly divided into control group(group C) and experimental groups.The rabbits of experimental groups were divided into three groups equally by different time of the portal vein occlusion for 20,30,40 minutes and then each group was re-divided into 3 subgroups by different amount of portal blood stasis removal:group A_0 no blood removal,group A_5 5ml blood removal,group A_(10) 10ml blood removal.Each group had eight rabbits,nine groups in all. The other eight rabbits(group C) did not receive hepatic portal occlusion and hypothermic irrigation.Their abdomens were opened and only served as control group.Endotoxin content both in serum and in portal blood stasis,alanine aminotransferase(ALT), hyaluronic acid(HA),tumor necrosis factor-α(TNF-α),hepatic pathology,content of malondialdehyde(MDA) and activity of superoxide dismutase(SOD) and activation of nuclear factor-κB(NF-κB) in liver tissue were examined respectively after reperfusion 4h.
Results
The levels of serum endotoxin were significantly increased by extension of portal vein occlusion.At the same time of portal vein occlusion the level of serum endotoxin in portal blood stasis significantly decreased with each 2.5ml blood removal,subsequently reaching a minima at the 7.5ml blood removal.In groups of portal vein occlusion for 30 and 40 minutes,removing portal blood stasis ameliorated hepatic ischemia reperfusion injury as shown by ALT,HA,TNF-α,MDA,SOD,NF-κB and the pathology.Compared with the non-removal group,the effect was significant,while the effect of removing portal blood stasis in the group of portal vein occlusion for 20 minutes was not significant.
Discussion
Long-time occlusion of the portal vein in the process of liver transplantation results in gastro-intestinal congestion,barrier failure,insufficient blood and oxygen supply,and increasing gut mucosal permeability,which leads to obvious increase of intestinal endotoxin in portal blood,especially portal blood stasis.The levels of serum endotoxin in portal blood stasis were significantly increased by extension of portal vein occlusion.The first 5ml portal blood stasis contains high volume of endotoxin which may be responsible for hepatic reperfusion injury.The alteration of ALT,HA,TNF-α,MDA,SOD,NF-κB and the pathology can reflect hepatic reperfusion injury in all ways.Removing portal blood stasis also ameliorated hepatic ischemia reperfusion injury as shown by those.
Conclusion
The levels of serum endotoxin in portal blood stasis were significantly increased by extension of portal vein occlusion.The first 5ml portal blood stasis contains high volume of endotoxin which may be responsible for hepatic reperfusion injury.Removal of portal blood stasis before the resume of splanchnic circulation may ameliorate hepatic ischemia reperfusion injury.The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption,and this decreases production of serum TNF-αas well as hepatic activation of NF-κB.
Part Two The effect of different dosage of portal blood stasis removal on endotoxemia and hepatic ischemia reperfusion injury
Objective
The blood volume of rabbit is about equal to one fourth that of human body and 5ml blood volume is equivalent to 200ml that of human.A rabbit hepatic ischemia reperfusion injury model was established by in situ hypothermic irrigation for different time to observe the influence of portal blood stasis removal on intestinal endotoxemia and hepatic ischemia reperfusion injury.The purpose was to find an safe and effective method for clnical liver transplantation.
Methods
Eighty-eight healthy New Zealand white rabbits were randomly divided into a control group(group C) and experimental groups.The rabbits of experimental groups were divided into two groups equally by different time of the portal vein occlusion for 30,40 minutes and then each group was re-divided into five subgroups by different amount of portal blood stasis removal:group A_1 2.5ml blood removal,group A_2 5ml blood removal, group A_3 10ml blood removal,group A_4 15ml blood removal,and group B no blood removal.Each group had eight rabbits.The other eight rabbits did not receive hepatic portal occlusion and hypothermic irrigation,whose abdomens were opened and only served as control group.Serum endotoxin content,ALT,HA and TNF-αwere examined respectively after reperfusion 1h,2h,and 4h.Hepatic tissues were sampled to determine the pathology,content of MDA and activity of SOD and activation of NF-κB in liver tissue were examined respectively after reperfusion 4h.
Results
Removing portal blood stasis also ameliorated hepatic ischemia reperfusion injury as shown by ALT,HA,MDA,SOD and the pathology.5ml and 10ml blood removal had the maximal favorable effect,while the effect of 2.5ml or 15ml blood removal was not significant.
Discussion
The levels of serum endotoxin in portal blood stasis were significantly increased by extension of portal vein occlusion.Portal blood stasis removal could not only reduce the total amount of endotoxin absorbed into liver and systemic circulation,but also reduce the damage of some important organs such as liver,lung,gastrointestinal tract.That the effect of 2.5ml or 15ml blood removal was not significant was correlated with that the first portal blood stasis contains high volume of endotoxin were not removed completely.The levels of serum endotoxin tended to rise with more portal blood stasis removal.The main reason was sequence portal blood stasis removal could not improve the protective effect because the first portal blood stasis containing high volume of endotoxin had been removed. Secondly the increase of portal blood stasis removal led to insufficient blood supply which worsened organ injury and endotoxemia.
Conclusion
Appropriate quantity of portal blood stasis removal can protect the liver against ischemia reperfusion injury.The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption,and then decreases production of serum TNF-αas well as hepatic activation of NF-κB.But too much or too little of portal congestion blood released could not improve the protective effect.
Part Three The effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion in a rabbit model
Objective
The portal blood stasis removal can protect the liver against ischemia reperfusion injury,but there was no experimental proof whether it might ameliorate the lung and renal injury induced by hepatic ischemia reperfusion.A rabbit hepatic ischemia reperfusion injury model was established by in situ hypothermic irrigation to observe the effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion.The purpose was to provide the experimental proof for protecting lung and renal and reducing postoperative complications.
Methods
Fifty-six healthy New Zealand white rabbits were randomly divided into control group and experimental groups.
The rabbits of experimental groups were divided into two groups equally by different time of the portal vein occlusion for 30,40 minutes and then each group was re-divided into three subgroups by different amount of portal blood stasis removal:group A_0 no blood removal,group A_5 5ml blood removal,group A_(10) 10ml blood removal.Each group had eight rabbits.The other eight rabbits did not receive hepatic portal occlusion and hypothermic irrigation,whose abdomens were opened and only served as control group. After reperfusion 4h serum endotoxin content,TNF-α,urea nitrogen(BUN),creatinine (Cr),and wet to dry weight ratio,broncho-alveolar lavage fluid protein content in lung tissues were examined respectively.Meantime,lung and kidney tissues were sampled to determine the content of MDA,SOD and the pathology.
Results
Removing portal blood stasis ameliorated lung and renal injury as shown by serum endotoxin,TNF-α,BUN,Cr,wet to dry weight ratio,broncho-alveolar lavage fluid protein content,MDA in lung and kidney tissue being significantly reduced,SOD in lung and kidney tissue being significantly increased and the pathology becoming better.
Discussion
Long-time occlusion of the portal vein resulted in obvious increase of endotoxin in portal blood stasis.At reperfusion the endotoxin in portal blood would activate Kupffer cells,which might contribute to produce a great deal of cytokine,reactive oxygen species, and proteolytic enzyme.Those things not only produced liver injury and microcirculation disturbance,but also,through systemic circulation,resulted in lung and kidney injury by activating capillary endothelium and neutrophil.It showed the pressure of systemic circulation decreased and the injury of extra-hepatic organs,serum endotoxin,TNF-α, BUN,Cr,wet to dry weight ratio,broncho-alveolar lavage fluid protein content,MDA, SOD and the pathology objectively reflect the severity of systemic inflammatory response syndrome and the degree of lung and kidney injury.Those index ameliorated showed that the removal of portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion.
Conclusion
Removal of portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion.The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption,and then decreases production of serum TNF-α.
Part Four Effects of different dosage of portal blood stasis removal on liver function during early stage after liver transplantation
Objective
The pricking blood therapy has been accepted by clinician because it would reduce theoretically endotoxin entering into liver and protect the liver against ischemia reperfusion injury.How much portal blood stasis should be removed in clinic liver transplantation was empirical and there was no related report about it.Forty-seven patients who received liver transplantation in our hospital were divided into 2 groups according to different dosage of portal blood stasis removal during operation:group A 50ml and group B 200ml portal blood stasis removal respectively.The levels of plasma endotoxin, inflammatory factors and the restoring of liver function after liver transplantation was observed in order to provide the experimental proofs for clinical liver transplantation.
Methods
Clinical data:A total of 47 cases undergoing orthotopic liver transplantation were selected from Eastern Hepatobiliary Surgery Hospital,Second Military Medical University from January 2006 to October 2007.In 47 cases,43 males and 4 females,age from 33 to 67(average 49.9±8.5) years,were randomly divided into two groups by different dosage of portal blood stasis removal:group A(n=26) 50ml blood removal and group B(n=21) 200ml blood removal.
Measurements:(1) The patients of sex,age,primary liver diseases and Child-pugh's classification,donor liver of cold ischemic time and total operation and anhepatic time, operation methods,volume of blood loss and transfusion were recorded before and in operation.(2) Samples from venous blood were obtained at beginning of surgery(T_0), 60min after graft reperfusion(T_1),at the end of operation(T_2),and 24h after surgery.The levels of plasma endotoxin,D-lactate,TNF-α,Interleukin-6(IL-6) were measured respectively.(3) The levels of plasma alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),direct bilirubin(DBIL),albumin(Alb), prealbumin(PAB),prothrombin time(PT) activated partial thromboplastin time(APTT) and fibrinogen(FIB) were examined in the day before operation and 1,3,7 d following surgery.
Results
There was no significant difference in sex,age,primary liver diseases and Child-pugh's classification,cold ischemic time,total operation and anhepatic time, operation methods,volume of blood loss and transfusion,plasma endotoxin,D-lactate, TNF-α,IL-6,liver function and blood coagulation parameters before operation.Most of observations showed the restoration in group B was better than that in group A.The plasma levels of endotoxin,D-lactate,TNF-α,IL-6,ALT,AST,PT,APTT in group B were significantly lower than those in group A(P＜0.05).The level of plasma PAB in group B was significantly higher than that in group A(P＜0.05).
Discussion
The plasma levels of endotoxin,TNF-α,IL-6 are very sensitive markers of the degree of hepatic and body injury.The plasma levels of D-lactate response gut mucosal permeability.The plasma levels of aminotransferase,bilirubin,prealbumin,blood coagulation are very sensitive markers of liver functional restoration after liver transplantation.Our study showed that the levels of serum levels of endotoxin,D-lactate, TNF-α,IL-6,ALT,AST,PT,APTT after operation in group of 200ml portal blood stasis removal were significantly lower than those in group of 50ml blood removal.Meantime, the level of serum PAB was significantly higher.This study showed 200ml portal blood stasis removal before resuming of splanchnic circulation may ameliorate hepatic ischemia reperfusion injury,ruduce inflammatory reaction,protect intestinal mucosal barrier and liver functional restoration would be more effective than that of 50ml.The reason was that the first 200ml portal blood stasis containing high volume of endotoxin which might be responsible for hepatic reperfusion injury had been removed completely.
Conclusion
This study showed the effect of 200ml portal congestion blood removal was better than that of 50ml,which contributed to relieving endotoxemia and restoring liver function after liver transplantation.
引文
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