Kupffer细胞在血红素氧合酶-1保护大鼠移植肝缺血再灌注损伤中的作用研究
|
摘要
自1963年Starzl施行首例临床肝移植手术以来,肝移植已成为当今治疗终末期肝病的唯一有效方法。然而,同其它大器官移植一样,供肝离体后的缺血再灌注损伤乃是面临的重大难题之一,常导致手术后供肝原发性无功能,被认为是肝移植失败的主要原因。移植肝脏经历冷缺血再灌注损伤后,会产生大量的氧自由基,促炎性细胞因子等加重肝脏的损伤,导致肝细胞坏死和器官功能衰竭。氧自由基是器官经历缺血再灌注后加重组织损伤的最早和最重要的成分之一,它们主要来源于细胞内黄嘌呤氧化酶的氧化作用,Kupffer细胞和多形核白细胞的缺氧刺激。多形核白细胞和Kupffer细胞产生的大量氧自由基导致内皮细胞损伤,最后使微血管完整性丧失和血流减少(无复流现象)。然而,到目前为止仍然没有一种有效的处理方法来预防肝脏缺血再灌注损伤。
研究发现,血红素氧合酶-1(HO-1)对肝脏缺血再灌注损伤具有保护作用,但其具体的作用机制仍不十分清楚。已发现的血红素氧合酶系统有三种同工酶,HO-1为诱导型,又称为热休克蛋白32;HO-2为非诱导型,又称为结构型;HO-3与HO-2相关但含量较少。HO-1是一种血红素降解的催化酶和限速酶,可将血红素分解成一氧化碳(CO)、胆绿素(BV)和游离铁(Fe~(2+))。胆绿素被胆红素还原酶进一步还原为胆红素,游离铁参与细胞内代谢或结合为铁蛋白储存于体内,研究还发现CO能保护肝脏移植物缺血再灌注损伤并延长其冷保存时间。器官在多种应激情况下能诱导HO-1表达对组织器官起到保护作用,因此,HO-1对器官的缺血再灌注损伤有重要的抗炎性作用和临床应用潜能。
Kupffer细胞是位于肝血窦内的巨噬细胞,寄居于肝血窦内皮细胞之间或之上,是体内固定型巨噬细胞中最大的群体,约占肝细胞总数的10—15%、全身定居巨噬细胞总数的80%左右。在缺血再灌注早期,Kupffer细胞被激活,产生形态学改变并突向窦状隙内导致血流减少。激活的Kupffer细胞释放多种活性介质,如:炎性细胞因子,活性氧类物质等。Kupffer细胞在肝脏缺血再灌注损伤早期发挥着重要的作用,有研究表明,抑制Kupffer细胞的激活能改善肝脏缺血再灌注损伤,因为激活的Kupffer细胞会导致一系列的炎性介质、生长因子和活性氧类物质的释放。通过单克隆抗体免疫组化结果发现HO-1主要分布在Kupffer细胞上,然而,HO-1在发挥保护肝脏冷缺血再灌注损伤时Kupffer细胞的发挥作用研究却很少。
因此,本研究采用大鼠肝移植冷缺血再灌注模型,探讨HO-1保护肝脏缺血再灌注损伤与Kupffer细胞的作用,从而为HO-1保护缺血再灌注损伤作用的基础研究提供一定的理论基础和实验依据。
方法:
1.采用大鼠肝脏离体Ⅳ型胶原酶灌注,剪碎肝脏,37℃消化30分钟,低速离心去除肝细胞,Percoll不连续密度梯度离心和选择性贴壁的方法分离Kupffer细胞,细胞按2×10~6/ml的密度用RPMI 1640培养液接种于培养板内,通过墨汁吞噬实验和ED2免疫细胞化学来鉴定Kupffer细胞。
2.SPF级健康成年雄性SD大鼠,体重220～250g,被随机分为三组:①对照组:供肝不用任何药物处理;②锌原卟啉处理组:获取供肝24小时前腹腔注射HO-1抑制剂锌原卟啉;③钴原卟啉处理组:获取供肝24小时前腹腔注射HO-1诱导剂钴原卟啉。供肝使用4℃生理盐水灌注并冷保存90min后移植给同基因SD大鼠,门静脉开放6小时后获取标本。分离并培养Kupffer细胞,培养48小时后收集上清,提取Kupffer细胞总mRNA或蛋白质。观察移植前肝脏HO-1的表达水平,检测血清ALT和AST评价肝功能,组织病理观察肝细胞损伤程度,检测血浆和培养上清促炎性细胞因子IL-6和TNF-α的含量,通过RT-PCR和Western blot法测定Kupffer细胞CD14的表达水平。
结果:
1.分离的KCs的得率在细胞贴壁前2.1±0.3×10~6/g肝脏、贴壁后1.5±0.1×10~6/g肝脏,用0.4%台盼蓝染色,活率大于92%,ED2染色阳性的细胞达90%以上,分离的细胞培养后功能完整并延伸呈不规则型。
2.获取大鼠供肝前使用锌原卟啉预处理后肝脏HO-1表达降低,钴原卟啉预处理后HO-1表达增加。钴原卟啉处理组大鼠血清转氨酶(ALT/AST)明显降低,而锌原卟啉处理组与对照组和钴原卟啉组相比增高。通过组织病理学观察发现锌原卟啉处理组肝细胞坏死严重、窦状隙充血肿胀,钴原卟啉处理组可见完整的肝小叶结构。检测血浆和细胞培养上清细胞因子(IL-6/TNF-α)的含量,锌原卟啉组细胞因子的含量明显增高,而钴原卟啉组明显降低。锌原卟啉处理后培养的Kupffer细胞HO-1表达明显降低,CD14mRNA和蛋白质水平表达上调,钴原卟啉处理后Kupffer细胞HO-1表达增高,CD14mRNA和蛋白质水平表达下调。
结论:
1.本实验建立的大鼠肝脏Kupffer细胞的分离培养方法简便、高效、稳定,培养的细胞具有良好的生物学性状,为进一步研究提供基础。
2.HO-1具有保护大鼠移植肝冷缺血再灌注损伤的作用,能减轻肝脏损伤,抑制IL-6和TNF-α的产生,改善肝功能,抑制Kupffer细胞的激活可能是其作用机制之一。
From the first report of Starzl,who performed clinical liver transplantation in 1963,orthotopic liver transplantation(OLT) is an effective treatment for end-stage liver diseases.Today,liver ischemia/reperfusion(I/R) injury is one of the confronted important problems and considered a major cause of graft injury,causing liver dysfunction and even failure post transplantation.The damage to the liver caused by I/R represents a continuum of processes that culminate in hepatocellular injury.These processes are triggered when liver is transiently deprived of oxygen and subsequent to reoxygenation,which inflicts direct tissue damage and initiates a cascade of deleterious cellular responses with concomitant release of oxygen-free radicals(OFR) and cytokines leading to cellular injury that culminates in the ultimate cell death and graft failure.OFR is one of the earliest and most important components of tissue injury after reperfusion of ischemic organs.The prime sources of OFR production in ischemic livers include cytosolic xanthine oxidase(XO),Kupffer cells(KCs) and adherent polymorphonuclear leukocytes(PMN).Endothelial cell(EC) damage results from free radicals produced from KCs and adherent PMN.Ultimately,this results in loss of microvascular integrity and reduction of blood flow('no-reflow phenomenon'). However,at present there is no treatment available to prevent liver I/R injury.
Studies have shown that heme oxygenase-1(HO-1) exerts a cytoprotective function in a number of liver I/R injury.However,exact mechanisms by which HO-1 induction may lead to cytoprotection during I/R injury in organ transplantation have not been fully clarified.Three HO isoforms have been identified:inducible HO-1, also known as heat shock protein 32;constitutively expressed HO-2;and a related but less well-characterized HO-3.HO-1 is the rate-limiting step in the oxidative degradation of heme into biliverdin,carbon monoxide(CO) and free iron.Biliverdin is reduced to bilirubin(BR) by bilirubin reductase,and the free iron used in intracellular metabolism or sequestered in ferritin.Studies have also reported that CO protects graft livers against cold I/R injury associate with prolonged cold preservation. HO-1 is induced in a variety of organs during diverse stress-related conditions and is thought to provide cytoprotection.Thus,HO-1 is attractive target for anti-inflammatory therapies and potential candidate responsible for organs I/R injury.
Kupffer cells,the resident macrophages of the liver,are the largest population of tissue macrophages and predominantly distributed in the lumen of hepatic sinusoids. KCs account for approximately 10～15%of all liver cells in number and for 80%of resident macrophages in the whole body.During the initial stages of reperfusion KCs are activated,producing morphologic changes that cause them to protrude into the sinusoids,contributing to the reduction of blood flow within the sinusoidal lumen. Activated KCs release a large amount of biologically active mediators such as proinflammatory and reactive oxygen species(ROS).Multiple lines of evidence have suggested that Kupffer cells are critical to the onset of liver I/R injury.Studies have shown that liver I/R injury can be attenuated by the suppression of KCs.Because activation of KCs results in the release of an array of inflammatory mediators,growth factors and ROS.Immunochemical studies with specific monoclonal antibodies have revealed that HO-1 express principally in Kupffer cells.However,little is known about the roles of KCs in HO-1 protecting liver cold I/R injury.
In the present study,we investigated the roles of KCs and protective effect of HO-1 in liver cold I/R injury model.We'll provide rationally experimental evidence accordance with this study for further research.
Methods:
1.Ex vivo rat liver tissue was perfused with collagenaseⅣand diced into pieces. The diced tissue was digested for 30 min at 37℃and following centrifuged to remove hepatocytes.Percoll density gradient centrifugation and selective adherence were combined.The cells were seeded onto tissue culture plates at a density of 2×10~6/ml and cultured in RPMI 1640 medium.Phagocytosis of ink and ED2 immunocytochemistry were used for cell identification.
2.Male Sprague-Dawley(S-D) Rats weighing 220-250g were used and divided randomly into three groups:①Control group:no drugs were applied;②ZnPP treatment group:donors received ZnPP,an HO-1 inhibitor(i.p.) 24h prior to harvest;③CoPP treatment group:donors received CoPP,an HO-1 inducer(i.p.) 24h prior to harvest.All liver grafts were harvested and stored with saline solution for 90min at 4℃,and orthotopically transplanted into syngeneic S-D recipients.Separate groups of rats were killed at 6h after their vessels were unclamped,and liver samples were collected for further analysis.Kupffer cells were isolated from integral left liver tissue obtained from fresh specimens and were incubated for 48h.The supematant from Kupffer cells culture was collected,and total RNA or proteins were extracted from Kupffer cells.HO-1 expression in livers pretransplant was assessed,and the hepatocellular function(ALT,AST) was analyzed.The hepatocellular damage was evaluated by liver histology.The IL-6/TNF-αlevels of plasma and supematant were detected.CD14 mRNA expression levels of KCs were examined by RT-PCR and Western blot.
Results:
1.The average cell yield per gram of liver before plastic adherence was 2.1±0.3×10~6,and 1.5±0.1×10~6 following plastic adherence.The viability of the KCs after isolation was＞92%as determined by trypan blue exclusion.The purity of KCs identified by ED2 was＞90%.Cultures of isolated KCs were functionally intact and expanded irregularly.
2.Livers harvested from donors that were pretreated with CoPP significantly up-regulated HO-1 mRNA expression levels as compared with Control or the ZnPP group.ZnPP treatment decreased HO-1 mRNA as compared with Control.Group pretreatment with CoPP significantly decreased Serum ALT/AST levels.Serum AST/AST levels were also significantly increased in the ZnPP treatment group as compared with both the Control and the CoPP group.The hepatocellular damage was evaluated by liver histology.Livers in ZnPP group showed a more severe hepatocyte necrosis,sinusoidal congestion and ballooning.In contrast,livers in CoPP group revealed almost complete preservation of lobular architecture.Plasma and supernatant cytokines(IL-6/TNF-α) concentrations were detected.ZnPP treatment significantly increased after reperfusion.However,the IL-6/TNF-αlevels in CoPP pretreated group were significantly lower,when compared to the Control group and ZnPP group.HO-1 mRNA expression levels of Kupffer cells with ZnPP pretreated were significantly down-regulated,and those with CoPP pretreated were up-regulated.A prominent increase of CD 14 mRNA and protein levels in Kupffer cells was detected in the ZnPP group as compared with the Control group or the CoPP group.
Conclusions:
1.The method of isolating and culturing Kupffer cells in this study is convenient, efficient and stable.The biological characters of the cultured Kupffer cells were retained,and the cells can be used to further study.
2.HO-1 protects liver against I/R injury in rat liver transplantation,ameliorating hepatic damage,suppressing cytokines IL-6 and TNF-αrelease and improving liver function.It is possible that HO-1 inhibiting Kupffer cells activation is one of the mechanisms.
研究发现,血红素氧合酶-1(HO-1)对肝脏缺血再灌注损伤具有保护作用,但其具体的作用机制仍不十分清楚。已发现的血红素氧合酶系统有三种同工酶,HO-1为诱导型,又称为热休克蛋白32;HO-2为非诱导型,又称为结构型;HO-3与HO-2相关但含量较少。HO-1是一种血红素降解的催化酶和限速酶,可将血红素分解成一氧化碳(CO)、胆绿素(BV)和游离铁(Fe~(2+))。胆绿素被胆红素还原酶进一步还原为胆红素,游离铁参与细胞内代谢或结合为铁蛋白储存于体内,研究还发现CO能保护肝脏移植物缺血再灌注损伤并延长其冷保存时间。器官在多种应激情况下能诱导HO-1表达对组织器官起到保护作用,因此,HO-1对器官的缺血再灌注损伤有重要的抗炎性作用和临床应用潜能。
Kupffer细胞是位于肝血窦内的巨噬细胞,寄居于肝血窦内皮细胞之间或之上,是体内固定型巨噬细胞中最大的群体,约占肝细胞总数的10—15%、全身定居巨噬细胞总数的80%左右。在缺血再灌注早期,Kupffer细胞被激活,产生形态学改变并突向窦状隙内导致血流减少。激活的Kupffer细胞释放多种活性介质,如:炎性细胞因子,活性氧类物质等。Kupffer细胞在肝脏缺血再灌注损伤早期发挥着重要的作用,有研究表明,抑制Kupffer细胞的激活能改善肝脏缺血再灌注损伤,因为激活的Kupffer细胞会导致一系列的炎性介质、生长因子和活性氧类物质的释放。通过单克隆抗体免疫组化结果发现HO-1主要分布在Kupffer细胞上,然而,HO-1在发挥保护肝脏冷缺血再灌注损伤时Kupffer细胞的发挥作用研究却很少。
因此,本研究采用大鼠肝移植冷缺血再灌注模型,探讨HO-1保护肝脏缺血再灌注损伤与Kupffer细胞的作用,从而为HO-1保护缺血再灌注损伤作用的基础研究提供一定的理论基础和实验依据。
方法:
1.采用大鼠肝脏离体Ⅳ型胶原酶灌注,剪碎肝脏,37℃消化30分钟,低速离心去除肝细胞,Percoll不连续密度梯度离心和选择性贴壁的方法分离Kupffer细胞,细胞按2×10~6/ml的密度用RPMI 1640培养液接种于培养板内,通过墨汁吞噬实验和ED2免疫细胞化学来鉴定Kupffer细胞。
2.SPF级健康成年雄性SD大鼠,体重220～250g,被随机分为三组:①对照组:供肝不用任何药物处理;②锌原卟啉处理组:获取供肝24小时前腹腔注射HO-1抑制剂锌原卟啉;③钴原卟啉处理组:获取供肝24小时前腹腔注射HO-1诱导剂钴原卟啉。供肝使用4℃生理盐水灌注并冷保存90min后移植给同基因SD大鼠,门静脉开放6小时后获取标本。分离并培养Kupffer细胞,培养48小时后收集上清,提取Kupffer细胞总mRNA或蛋白质。观察移植前肝脏HO-1的表达水平,检测血清ALT和AST评价肝功能,组织病理观察肝细胞损伤程度,检测血浆和培养上清促炎性细胞因子IL-6和TNF-α的含量,通过RT-PCR和Western blot法测定Kupffer细胞CD14的表达水平。
结果:
1.分离的KCs的得率在细胞贴壁前2.1±0.3×10~6/g肝脏、贴壁后1.5±0.1×10~6/g肝脏,用0.4%台盼蓝染色,活率大于92%,ED2染色阳性的细胞达90%以上,分离的细胞培养后功能完整并延伸呈不规则型。
2.获取大鼠供肝前使用锌原卟啉预处理后肝脏HO-1表达降低,钴原卟啉预处理后HO-1表达增加。钴原卟啉处理组大鼠血清转氨酶(ALT/AST)明显降低,而锌原卟啉处理组与对照组和钴原卟啉组相比增高。通过组织病理学观察发现锌原卟啉处理组肝细胞坏死严重、窦状隙充血肿胀,钴原卟啉处理组可见完整的肝小叶结构。检测血浆和细胞培养上清细胞因子(IL-6/TNF-α)的含量,锌原卟啉组细胞因子的含量明显增高,而钴原卟啉组明显降低。锌原卟啉处理后培养的Kupffer细胞HO-1表达明显降低,CD14mRNA和蛋白质水平表达上调,钴原卟啉处理后Kupffer细胞HO-1表达增高,CD14mRNA和蛋白质水平表达下调。
结论:
1.本实验建立的大鼠肝脏Kupffer细胞的分离培养方法简便、高效、稳定,培养的细胞具有良好的生物学性状,为进一步研究提供基础。
2.HO-1具有保护大鼠移植肝冷缺血再灌注损伤的作用,能减轻肝脏损伤,抑制IL-6和TNF-α的产生,改善肝功能,抑制Kupffer细胞的激活可能是其作用机制之一。
From the first report of Starzl,who performed clinical liver transplantation in 1963,orthotopic liver transplantation(OLT) is an effective treatment for end-stage liver diseases.Today,liver ischemia/reperfusion(I/R) injury is one of the confronted important problems and considered a major cause of graft injury,causing liver dysfunction and even failure post transplantation.The damage to the liver caused by I/R represents a continuum of processes that culminate in hepatocellular injury.These processes are triggered when liver is transiently deprived of oxygen and subsequent to reoxygenation,which inflicts direct tissue damage and initiates a cascade of deleterious cellular responses with concomitant release of oxygen-free radicals(OFR) and cytokines leading to cellular injury that culminates in the ultimate cell death and graft failure.OFR is one of the earliest and most important components of tissue injury after reperfusion of ischemic organs.The prime sources of OFR production in ischemic livers include cytosolic xanthine oxidase(XO),Kupffer cells(KCs) and adherent polymorphonuclear leukocytes(PMN).Endothelial cell(EC) damage results from free radicals produced from KCs and adherent PMN.Ultimately,this results in loss of microvascular integrity and reduction of blood flow('no-reflow phenomenon'). However,at present there is no treatment available to prevent liver I/R injury.
Studies have shown that heme oxygenase-1(HO-1) exerts a cytoprotective function in a number of liver I/R injury.However,exact mechanisms by which HO-1 induction may lead to cytoprotection during I/R injury in organ transplantation have not been fully clarified.Three HO isoforms have been identified:inducible HO-1, also known as heat shock protein 32;constitutively expressed HO-2;and a related but less well-characterized HO-3.HO-1 is the rate-limiting step in the oxidative degradation of heme into biliverdin,carbon monoxide(CO) and free iron.Biliverdin is reduced to bilirubin(BR) by bilirubin reductase,and the free iron used in intracellular metabolism or sequestered in ferritin.Studies have also reported that CO protects graft livers against cold I/R injury associate with prolonged cold preservation. HO-1 is induced in a variety of organs during diverse stress-related conditions and is thought to provide cytoprotection.Thus,HO-1 is attractive target for anti-inflammatory therapies and potential candidate responsible for organs I/R injury.
Kupffer cells,the resident macrophages of the liver,are the largest population of tissue macrophages and predominantly distributed in the lumen of hepatic sinusoids. KCs account for approximately 10～15%of all liver cells in number and for 80%of resident macrophages in the whole body.During the initial stages of reperfusion KCs are activated,producing morphologic changes that cause them to protrude into the sinusoids,contributing to the reduction of blood flow within the sinusoidal lumen. Activated KCs release a large amount of biologically active mediators such as proinflammatory and reactive oxygen species(ROS).Multiple lines of evidence have suggested that Kupffer cells are critical to the onset of liver I/R injury.Studies have shown that liver I/R injury can be attenuated by the suppression of KCs.Because activation of KCs results in the release of an array of inflammatory mediators,growth factors and ROS.Immunochemical studies with specific monoclonal antibodies have revealed that HO-1 express principally in Kupffer cells.However,little is known about the roles of KCs in HO-1 protecting liver cold I/R injury.
In the present study,we investigated the roles of KCs and protective effect of HO-1 in liver cold I/R injury model.We'll provide rationally experimental evidence accordance with this study for further research.
Methods:
1.Ex vivo rat liver tissue was perfused with collagenaseⅣand diced into pieces. The diced tissue was digested for 30 min at 37℃and following centrifuged to remove hepatocytes.Percoll density gradient centrifugation and selective adherence were combined.The cells were seeded onto tissue culture plates at a density of 2×10~6/ml and cultured in RPMI 1640 medium.Phagocytosis of ink and ED2 immunocytochemistry were used for cell identification.
2.Male Sprague-Dawley(S-D) Rats weighing 220-250g were used and divided randomly into three groups:①Control group:no drugs were applied;②ZnPP treatment group:donors received ZnPP,an HO-1 inhibitor(i.p.) 24h prior to harvest;③CoPP treatment group:donors received CoPP,an HO-1 inducer(i.p.) 24h prior to harvest.All liver grafts were harvested and stored with saline solution for 90min at 4℃,and orthotopically transplanted into syngeneic S-D recipients.Separate groups of rats were killed at 6h after their vessels were unclamped,and liver samples were collected for further analysis.Kupffer cells were isolated from integral left liver tissue obtained from fresh specimens and were incubated for 48h.The supematant from Kupffer cells culture was collected,and total RNA or proteins were extracted from Kupffer cells.HO-1 expression in livers pretransplant was assessed,and the hepatocellular function(ALT,AST) was analyzed.The hepatocellular damage was evaluated by liver histology.The IL-6/TNF-αlevels of plasma and supematant were detected.CD14 mRNA expression levels of KCs were examined by RT-PCR and Western blot.
Results:
1.The average cell yield per gram of liver before plastic adherence was 2.1±0.3×10~6,and 1.5±0.1×10~6 following plastic adherence.The viability of the KCs after isolation was＞92%as determined by trypan blue exclusion.The purity of KCs identified by ED2 was＞90%.Cultures of isolated KCs were functionally intact and expanded irregularly.
2.Livers harvested from donors that were pretreated with CoPP significantly up-regulated HO-1 mRNA expression levels as compared with Control or the ZnPP group.ZnPP treatment decreased HO-1 mRNA as compared with Control.Group pretreatment with CoPP significantly decreased Serum ALT/AST levels.Serum AST/AST levels were also significantly increased in the ZnPP treatment group as compared with both the Control and the CoPP group.The hepatocellular damage was evaluated by liver histology.Livers in ZnPP group showed a more severe hepatocyte necrosis,sinusoidal congestion and ballooning.In contrast,livers in CoPP group revealed almost complete preservation of lobular architecture.Plasma and supernatant cytokines(IL-6/TNF-α) concentrations were detected.ZnPP treatment significantly increased after reperfusion.However,the IL-6/TNF-αlevels in CoPP pretreated group were significantly lower,when compared to the Control group and ZnPP group.HO-1 mRNA expression levels of Kupffer cells with ZnPP pretreated were significantly down-regulated,and those with CoPP pretreated were up-regulated.A prominent increase of CD 14 mRNA and protein levels in Kupffer cells was detected in the ZnPP group as compared with the Control group or the CoPP group.
Conclusions:
1.The method of isolating and culturing Kupffer cells in this study is convenient, efficient and stable.The biological characters of the cultured Kupffer cells were retained,and the cells can be used to further study.
2.HO-1 protects liver against I/R injury in rat liver transplantation,ameliorating hepatic damage,suppressing cytokines IL-6 and TNF-αrelease and improving liver function.It is possible that HO-1 inhibiting Kupffer cells activation is one of the mechanisms.
引文
[1]Knook DL,Sleyster EC.Separation of Kupffer and endothelial cells of the rat liver by centrifugal elutriation.Exp Cell Res.1976;99:444-449.
[2]V.Valatas,C.Xidakis,H.Roumpaki,et al.Isolation of rat Kupffer cells:a combined methodology for highly purified primary cultures.Cell Biol Int.2003;27:67-73.
[3]Edward B.Alabraba,Stuart M.Curbishley,Wai K.Lai,et al.A new approach to isolation and culture of human Kupffer cells.J Immunol Methods.2007;326:139-144.
[4]Mawet E,Shiratori Y,Hikiba Y,et al.Cytokine-induced neutrophil chemoattractant release from hepatocytes is modulated by Kupffer cells.Hepatology.1996;23:353-358.
[5]Marangoni A,Aldini R,Sambri V,et al.Production of tumor necrosis factor alpha by Treponema pallidum,Borrelia burgdorferi s.l.,and Leptospira interrogans in isolated rat Kupffer cells.FEMS Immunol Med Microbiol.2004;40:187-191.
[6]Luckey SW,Taylor M,Sampey BP,et al.4-hydroxynonenal decreases interleukin-6 expression and protein production in primary rat Kupffer cells by inhibiting nuclear factor-kappaB activation.J Pharmacol Exp Ther.2002;302:296-303.
[7]张长习,高绪照,谢文彪.大鼠及人肝库否细胞的分离纯化和培养.肝胆外科杂志,2007;15:308-310.
[8]施鑫,李保仝,黎介寿.大鼠肝Kupffer细胞分离培养及鉴定.医学研究生学报,2000;13:242-246.
[9]蔡伟,李非.大鼠肝脏Kupffer细胞的分离,纯化.中国普外基础与临床杂志,2007;14:292-295.
[10]Neaud V,Dubuisson L,Balabaud C,et al.Ultrastructure of human Kupffer cells maintained in culture.J Submicrosc Cytol Pathol.1995;27:161-170.
[11]Dory D,Echchannaoui H,Letiembre M,et al.Generation and functional characterization of a clonal murine periportal Kupffer cell line from H-2Kb -tsA58 mice.J Leukoc Biol.2003;74:49-59.
[12]You Q,Cheng L,Kedl RM,et al.Mechanism of T cell tolerance induction by murine hepatic Kupffer cells.Hepatology.2008;48:978-990.
[13]柳枫,朱继业,李涛等.大鼠库普弗细胞分离培养方法的改良.中华肝脏病杂志,2006;14:532-535.
[14]Ikejima K,Enomoto N,Seabra V,et al.Pronase destroys the lipopolysaccharide receptor CD14 on Kupffer cells.AM J Phsysiol.1999;276:G591-598.
[15]刘亮,张宗明,张驰等.适于膜片钳技术的大鼠肝Kupffer细胞急性分离和鉴定.世界华人消化杂志,2005;13:202-206.
[16]Catala M,Anton A,Portoles MT.Characterization of the simultaneous binding of Escherichia coli endotoxin to Kupffer and endothelial liver cells by flow cytometry.Cytometry.1999;36:123-130.
[17]Perez R,Johnson J,Winkler JD,et al.Kupffer cell-mediated lymphocyte apoptosis:a PGE2-dependent mechanism of portal venous transfusion-induced immunosuppression? J Surg Res.1998;78:37-41.
[17]李涛,朱继业,柳枫等.RNA干扰供体大鼠库普弗细胞B7分子表达对受体大鼠淋巴细胞激活的影响.世界华人消化杂志,2008;16:39-44.
[18]Xidakis C,Ljumovic D,Manousou P,et al.Production of pro- and anti-fibrotic agents by rat Kupffer cells;the effect of octreotide.Dig Dis Sci.2005;50:935-941.
[19]Xidskis C,Mastrodimou N,Notas G,et al.RT-PCR and immunocytochemistry studies support the presence of somatostatin,cortistatin and somatostatin receptor subtypes in rat Kupffer cells.Regul Pept.2007;143:76-82.
[20]Mawet E,Shiratori Y,Hikiba Y,et al.Cytokine-induced neutrophil chemoattractant release from hepatocytes is modulated by Kupffer cells.Hepatology.1996;23:353-358.
[1]Starzl TE,Demetris Aj.Liver transplantation:a 31-year perspective,Pert Ⅲ.Curr Probl Surg.1990;27:181-240.
[2]Clavien PA,Harvey PR,Strasberg SM.Preservation and reperfusion injuries in liver allografts.An overview and synthesis of current studies.Transplantation.1992;53:957-958.
[3]Fondevila C,Busuttil RW,Kupiec-Weglinski JW,et al.Hepatic ischemia/reperfusion injury-a flesh look.Exp Mol Pathol.2003;74:86-93.
[4]Fan C,Zwacka RM.Therapeutic approaches for ischemia/reperfusion injury in the liver.J Mol Med.1999;77:577-596.
[5]Lemasters JJ,Thurman RG.Hypoxia and reperfusion injury to the liver.Prog Liver Dis.1994; 11:85-114.
[6]Lemasters JJ,Bunzendahl H,Thurman RG Reperfusion injury to donor livers stored for transplantation.Liver Transpl Surg.1995;1:124-138.
[7]Jaeschke H,Gores GJ,Cederbaum AI,et al.Mechanisms of hepatotoxicity.Toxicol Sci.2002;65:166-176.
[8]Wanner GA,Ertel W,Muller P,et al.Liver ischemia and reperfusion induces a systemic inflammatory response through Kupffer cell activation.Shock.1996;5:34-40.
[9]Grace L.SU.Lipopolysaccharides in liver injury:molecular mechanisms of Kupffer cell activation.Am J Physiol Gastrointest Liver Physiol.2002;283:G256-G265.
[10]Nobuyuki Enomoto,Yoshiyuki Takei,Miyoko Hirose,et al.Thalidomide prevents alcoholic liver injury in rats through inhibition of Kupffer cell sensitization.Comp Hepatol.2004;3:S37.
[11]Wang YY,Dahle Mk,Agren J,et al.Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation.Shock.2006;25:141-146.
[12]Choi A,Alam J.Heme oxygenase-1:function,regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury.Am J Respir Cell Mol Biol.1996;15:9-19.
[13]Fujita T,Toda K,Karimova A et al.Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis.Nat Med.2001;7:598-604.
[14]Coito Aj,Buelow R,Shen XD et al.Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury.Transplantation.2002;74:96-102.
[15]Maines MD.The heme oxygenase system:a regulator of second messenger gases.Annu Rev Pharmacol Toxicol.1997;37:517-554.
[16]Kobayashi T,Hirano K,Yamamoto T,et al.Protective role of Kupffer cells in ischemia-reperfused rat liver.Arch Histol Cytol.2002;65:251-261.
[17]Takashi Kobayashi,Yoshinobu Sato,Satoshi Yamamoto,et al.Augmentation of heme oxygenase-1 expression in the graft immediately after implantation in adult living-donor liver transplantation.Transplantation.2005;79:977-980.
[18]Hirohisa Kato,Farin Amersi,Roland Buelow,et al.Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation.Am J Transplant.2001;1:121-128.
[19]Goda,N.,Suzuki,K.,Naito,M.,et al.Distribution of heme oxygenase isoforms in rat liver.Topographic basis for carbon monoxide-mediated microvascular relaxation.J.Clin.Invest.1998;101:604-612.
[20]Bauer,I.,Wanner,.G.A.,et al.Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver.Hepatology.1998;27;829-838.
[21]Kobayashi T,Hirano K,Yamamoto T,et al.The protective role of Kupffer cells in the ischemia-reperfusion rat liver.Arch Histol Cytol.2002;65:251-261.
[22]Erwin Geuken,Carlijn I.Buis,Dorien S.Visser,et al.Expression of heme oxygenase-1 in human livers before transplantation correlates with graft injury and function after transplantation.Am J Transplant.2005;5:1875-1885.
[23]Alexandra K.Kiemer,Tobias Gerwig,Alexander L.Gerbes,et al.Kupffer-cell specific induction of heme oxygenase 1(hsp32) by the atrial natriuretic peptide—role of cGMP.J Hepatol.2003;38:490-498.
[24]Kamada N,Calne RY.A surgical experience with five hundred thirty liver transplants in the rat.Surgery.1983;93:64-69.
[25]Montalvo Jave EE,Escalante Tattersfield T,Ortega Salgado JA,et al.Factors in the pathophysiology of the liver ischemia-reperfusion injury.J Surg Res.2008;147:153-159.
[26]Malhi H,Gores GJ,Lemasters JJ.Apoptosis and necrosis in the liver:a tale of two deaths?Hepatology.2006;43:S31-S44.
[27]Jaeschke H.Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning.Am J Physiol Gastrointest Liver Physiol.2003;284:G15-G26.
[28]Farmer DG,Amersi F,Kupiec-Weglinski JW,et al.Current status of ischemia and reperfusion injury in the liver.Transplant Rev.2000;14:106-126.
[29]Huang Y,Shan J,Wang C,et al.Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation.Transpl Immunol.2009;20:127-131.
[30]Burton JR,Rosen HR.Diagnosis and management of allograft failure.Clin Liver Dis.2006;10:407-35.
[31]Kupiec Weglinski JW,Busuttil RW.Ischemia and reperfusion injury in liver transplantation.Transplant Proc.2005;37:1653-1656.
[32]Selzner N,Rudiger H,Graf R,et al.Protective strategies against ischemic injury of the liver.Gastroenterology 2003;125:917-936.
[33]Suematsu M,Kashiwagi S,Sano T,et al.Carbon monoxide as an endogenous modulator of hepatic vascular perfusion.Biochem Biophys Res Commun.1994;205:1333-1337.
[34]Redaelli CA,Tian YH,Schaffner T,et al.Extended preservation of rat liver graft by induction of heme oxygenase-1.Hepatology.2002;35:1082-1092.
[35]Katori M,Buelow R,Ke B,et al.Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway.Transplantation 2002;73:287-292.
[36]Tullius,S.G.;Nieminen-Kelha,M.;Buelow,R.;et al.Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1.Transplantation.2002;74:591-598.
[37]Bilban M,Haschemi A,Wegiel B,et al.Heme oxygenase and carbon monoxide initiate homeostatic signaling.J Mol Med.2008;86:267-279.
[38]D'Amico G,Lam F,Hagen T,et al.Inhibition of cellular respiration by endogenously produced carbon monoxide.J Cell Sci.2006;119:2291-2298.
[39]Verma A,Hirsch D,Glatt C,et al.Carbon monoxide:a putative neural messenger.Science.1993;259:381-384.
[40]Motterlini R,Mann BE,Johnson T,et al.Bioactivity and pharmacological actions of carbon monoxide-releasing molecules.Curr Pharm Des.2003;9:2525-2539.
[41]Otterbein LE,Zuckerbraun B,Haga M,et al.Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury.Nat Med.2003;9:183-190.
[42]Song R,Kubo M,Morse D,et al.Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via antiinflammatory and anti-apoptotic effects.Am J Pathol.2003;163:231-242.
[43]Zuckerbraun B,Billiar T,Otterbein S,et al.Carbon monoxide protects against liver failure through nitric oxide-induced heme oxygenase 1.J Exp Med.2003;198:1707-1716.
[44]Zuckerbraun S,Chin B,Wegiel B,et al.Carbon monoxide reverses established pulmonary hypertension.J Exp Med.2006;203:2109-2119.
[45]Wagener F,Volk H,Willis D,et al.Different faces of the home-home oxygenase system in inflammation.Pharmacol Rcv.2003;55:551-571.
[46]Caban A,Oczkowicz G,Abdcl Samad O,ct al.Influence of Kupffer cells on the early phase of liver reperfusion.Transplant Proc.2002;34:694-697.
[47]Lcntsch AB,Yoshidome H,Chcadle WG,et al.Chemokine involvement in hepatic ischemia/repcrfusion injury in mice:roles for macrophage inflammatory protein-2 and Kupffer cells.Hepatology.1998;27:507-512.
[48]Takashi Kaizu,Atsunori Nakao,AllanTsung,et al.Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.Surgery 2005;138:229-235.
[49]Tomiyama K,Ikeda A,Ueki S,et al.Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats.Hepatology.2008;48:1608-1620.
[50]Sei-ichiro Tsuchihashi,Yuan Zhai,Qiao Bo,et al.Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury:inhibition of type-1 interferon signaling.Transplantation 2007;83:1628-1634.
[51]Stephen J.McNally,Ewen M.Harrison,James A.Ross,et al.Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury.Transplantation 2006;81:623-626.
[52]Lai IR,Chang KJ,Tsai HW,et al.Pharmacological preconditioning with simvastatin protects liver from ischemia-reperfusion injury by heme oxygenase-1 induction.Transplantation 2008;85:732-738.
[53]Sei-ichiro Tsuchihashi,Masha Livhits,Yuan Zhai,et al.Basal rather than induced heme oxygenase-1 levels are in the antioxidant cytoprotection.J Immunol 2006;177:4749-57.
[54]Cutrn JC,Perrelli MG,Cavalieri B,et al.Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning.Free Radic Biol Med 2002;33:1200-1208.
[55]Tsukamoto H.Redox regulation of cytokine expression in Kupffer cells.Antioxid Redox Signal 2002;4:741-748.
[56]Hanschen M,Zahler S,Krombach F,et al.Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion.Transplantation.2008;86:710-718.
[57]Thomas P,Hayashi H,Lazure D,et al.Inhibition of lipopolysaccharide activation of Kupffer cells by transition metals.J Surg Res.2008;148:116-120.
[58]Kaur H,Hughes MN,Green CJ,et al.Interaction of bilirubin and biliverdin with reactive nitrogen species.FEBS Lett.2003;543:113-119.
[59]Monbaliu D,Van Pelt J,De Vos R,et al.Primary graft nonfunction and Kupffer cell activation after liver transplantation from non-heart-beating donors in pigs.Liver Transpl.2007;13:239-247.
[60]Antal-Szalmas P.Evaluation of CD14 in host defence.Eur J Clin Invest 2000;30:167-179.
[61]Li XH,Gong JP,Shi YJ,et al.In vitro expression of CD14 protein and its gene in Kupffer cells induced by lipopolysaccharide.Hepatobiliary Pancreat Dis Int.2003;2:571-575.
[62]Qiu DK,Hua J,Li JQ,et al.CD14 expression on Kupffer cells during the course of carbon tetrachloride-mediated liver injury.Chin J Dig Dis.2005;6:137-141.
[63]Miyaso H,Morimoto Y,Ozaki M,et al.Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats:possible involvement of CD14 and TLR-4 downregulation on Kupffer cells.Dig Dis Sci.2006;51:2007-2012.
[64]Devey L,Ferenbach D,Mohr E,et al.Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism.Mol Ther.2009;17:65-72.
[1]Makoto Naito,Go Hasegawa,Yusuke Ebe,et al.Differentiation and function of Kupffer cells.Meal Electron Microsc.2004,37:16-28.
[2]Giakoustidis DE,Iliadis S,Tsantilas D,et al.Blockade of Kupffer cells by gadolinium chloride reduces lipid peroxidation and protects liver from ischemia / reperfusion injury.Hcpatogastroenterology.2003,50:1587-1592.
[3]Luis A.Videla,Virginia Fernandez,Gladys Tapia,et al.Oxidative stress-mediated hepatotoxicity of iron and copper:Role of Kupffer cells.Bio Metals.2003,16:103-111.
[4]Ohkochi N,Shibuya H,Tsukamoto M,et al.Kupffer's cells modulate neutrophile activity by superoxide anion and tumor necrosis factor-α in reperfusion injury of liver transplantation mechanisms of radical generation and reperfusion injury after cold ischemia.Transplant Proc.1999,31:1055-1058.
[5]Hidekazu Tsukamoto.Redox regulation of cytokine expression in Kupffer cells.Antioxid.Redox Signal.2002,4:741-748.
[6]Atsushi Kato,Cem Gabay,Tomohisa Okaya,et al.Specific role of intedeukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion.American Journal of Pathology.2002,161:1797-1803.
[7]Ferdinand Serracino-inglott,Nagy A.Habib,Robert T.Mathie,et al.Hepatic ischemiareperfusion injury.The American Journal of Surgery.2001,181:160-166.
[8]Kox W J,Volk T,Kox SN,et al.Immunomodulatory therapies in sepsis.Intensive Care Med.2000,26:S124-S128.
[9]Sun Z,Klein AS,Radaeva S,et al.In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats.Gastroenterology.2003,125:202-215.
[10]Tadashi Matsumoto,Kerri O'Malley,Philip A.Efron,et al.Interleukin-6 and STAT3 protect the liver from hepatic ischemia and reperfusion injury during ischemic preconditioning.Surgery. 2006,140:793-802.
[11]Danielle GSouza,Vanessa Pinho,Adriana C.Soares,et al.Role of PAF receptors during intestinal ischemia and reperfusion injury.A comparative study between PAF receptor-deficient mice and PAF receptor antagonist treatment.British Journal of Pharmacology.2003,139:733-740.
[12]Hulya Ozturk,Hayrettin Ozturk,Yusuf Yagmur.PAF antagonist BN-52021 reduces intercellular adhesion molecule-1 expression and oxidative stress in rats with reperfusion damage due to unilateral testicular torsion.Pediatr Surg Int.2006,22:191-196.
[13]N.Ohkohchi.Suppression of Kupffer cell function is a key for liver transplantation from the non-heart-beating donor.Transplant Proc.2001,33:3728-3731.
[14]Isozaki H,Okajima K,Hara H,et al.The protective effect of thromboxane A2 synthetase inhibitor against ischemic liver injury.Surgery Today.1994,24:435-440.
[15]N.Ohkohchi.Mechanisms of preservation and ischemic/reperfusion injury in liver transplantation.Transplant Proc.2002,34:2670-2673.
[16]Hirano K-I,Kobayashi T,Watanabe T,et al.Role of heme oxygenase-1 and Kupffer cells in the production of bilirubin in the rat liver.Arch Histol Cytol.2001,64:111-120.
[17]Yachie A,Niida Y,Wada T,et al.Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.J Clin Invest.1999,103:129-135.
[18]Yakashi Kobayashi,Ken-ichiro Hirano,Takashi Yamamoto,et al.The protective role of Kupffer cells in the ischemia-reperfused rat liver.Arch Histol Cytol.2002,65:251-261.
[19]Kyokane T,Norimizu S,Taniai H,et al.Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver.Gastroenterology.2001,120:1227-1240.
[20]Robert B Dorman,Mary Lynn Bajt,Anwar Farhood,et al.Heme oxygenase-1 induction in hepatocytes and non-parenchymal cells protects against liver injury during endotoxemia.Comp Hepatol.2004,3:S42.
[21]Wunder C,Brock RW,McCarter SD,et al.Inhibition of heam oxygenase activity increases leukocyte accumulation in the liver following limb ischaemia-reperfusion in mice.J Physiol.2002,540:1013-1021.
[22]Takashi Kobayashi,Yoshinobu Sato,Satoshi Yamamoto,et al.Augmentation of gene oxygenase-1 expression in the graft immediately after implantation in adult living-donor liver transplantation.Transplantation.2005,79:977-980.
[23]Tuzuner E,Liu L,Shimada M,et al.Heme oxygenase-1 protects human hepatocytes in vitro against warm and cold hypoxia.J Hepatol.2004,41:764-772.
[24]McNally SJ,Harrison EM,Ross JA,et al.Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury.Transplantation.2006,81:623-626.
[25]Ebenezer Olatunde Farombi,Young-Joon Surh,et al.Heme oxygenase-1 as a potential therapeutic target for hepatoprotection.Journal of Biochemistry and Molecular Biology.2006,39:479-491.
[26]Gill RG,Coulombe M,Lafferty KJ:Pancreatic islet allograft immunity and tolerance:the two-signal hepothesis revisited.Immuno Rev.1996,149:75-96.
[27]Yorihiro Akamatsu,Nobuhiro Ohkohchi,Hideyuki Doi,et al.Effect of elimination of donor Kupffer cells and / or recipient macrophages on acute rejection in liver transplantation.Hepato Gastroenterology.2003,50:1105-1110.
[28]Y.Akamatsu,N.Ohkohchi,H.Doi,et al.Does elimination of Kupffer cells prolong survival time in liver transplantation? Transplant Proc.1999,31:545-547.
[29]Andrew D.Clouston,Julie R.Jonsson,Glenda A.Balderson,et al.Lymphocyte apoptosis and cell replacement in humen liver allografts.Transplantation.2002,73:1828-1834.
[30]Ulrich T(o｜¨)x,Marcus A Burkhardt,Christine Benz,et al.Expression of apoptosis and apoptosis-related peptides in various stages of rejection in the human transplanted liver.Hepato-Gastroenterology.2001,48:1697-1700.
[31]Yamaguchi Y,Okabe K,Matsumara F,et al.Peroxynitrite formation during rat hepatic allograft rejection.Hepatology.1999,29:777-784.
[32]Svensson G,Friman S,Jacobsson L,et al.Hepatocyte and Kupffer cell function after liver transplantation in the rat in vivo evaluation with dynamic scintigraphy.Liver.1995,15:189-195.
[33]Hua Liu,Hui Cao,Zhi-Yong WU.Isolation of Kupffer cells and their suppressive effects on T lymphocyte growth in rat orthotopic liver transplantation.World J Gastroenterol.2007,13:3133-3136.
[34]Sharland A,Yan Y,Wang C,et al.Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.Transplantation.1999,68:1736-1745.
[35]Zhaoli Sun,Tatehiko Wada,Kosei Maemura,et al.Hepatic allograft-derived Kupffer cells regulate T cell response in rats.Liver Transplantation.2003,9:489-497.
[36]Aya Miyagawa-Hayashino,Tatsuaki Tsuruyama,Hiroto Egawa.FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL~+ Kupffer cells are indicators of rejection activity in human liver allografts.The American Journal of Pathology.2007,171:1499-1508.
[37]Yuichi Nagakawa,Shuji Nomoto,Yukihiko Kato,et al.Over-expression of AIF-1 in liver allografts and peripheral blood correlates with acute rejection after transplantation in rats.American Journal of Transplantation.2004,4:1949-1957.
[38]Nagakawa Y,Williams GM,Zheng Q,et al.Oxidative mitochondrial DNA damage and deletion in hepatocytes of rejecting liver allografts in rats:Role of TNF-alpha.Hepatology.2005,42:208-215.
[39]Guangwei Liu,Haixia Ma,Lingling Jiang,et al.Allograft inflammatory factor-1 and its immune regulation.Autoimmunity.2007,40:95-102.
[40]Aya Miyagawa-Hayashino,Tatsuaki Tsuruyama,Hironori Haga,et al.Arteriopathy in chronic allograft rejection in liver transplantation.Liver Transplantation.2004,10:513-519.
[41]A.S.Gaweco,R.H.Wiesner,S.Yong,et al.Kupffer cell expression of CD40L(CD154) in human chronic liver allograft rejection.Transplantation Proceedings.1999,31:560-561.
[42]Adam S.R.Bartlett,John L.McCall,Rohan Ameratunga,et al.Analysis of intragraft gene and protein expression of the costimulatory molecules,CD80,CD86 and CD154.in orthotopic liver transplant recipients.American Journal of Transplantation.2003,3:1363-1368.
[43]Sun H,Subbotin V,Chen C,et al.Prevention of chronic rejection in mouse aortic allograft by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody.Transplantation.1997,64:1838-1843.
[44]Allan D.Kirk,David M.Harlan,Nicholas N.Armstrong,et al.CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates.Proc.Natl.Acad.Sci.USA.1997,94:8789-8794.
[45]Paola Pontrelli,Michele Ursi,Elena Ranieri,et al.CD40L proinflammatory and profibrotic effects on proximal tubular epithelial cells:Role of NF-κB and Lyn.Journal of the American Society of Nephrology.2006,17:627-636.
[46]Koishi Sato,Kiyotaka Yabuki,Takanori Haba,et al.Role of Kupffer cells in the induction of tolerance after liver transplantation.Journal of Surgical Research.1996,63:433-438.
[47]Savier E,Lemasters JJ,Thurman RG.Kupffer cells participate in rejection following liver transplantation in the rat.Transplant International.1994,7:S183-S186.
[48]Roland CR,Mangino MJ,Duffy BF,et al.Lymphocyte suppression by Kupffer cells prevents portal venous tolerance induction:a study of macrophage function after intravenous gadolinium.Transplantation.1993,55:1151-1158.
[49]Diaz-Peromingo JA,Gonzalez-Quintela A.Influence of gadolinium-induced Kupffer cell blockade on portal venous tolerance in rat skin allograft transplantation.European Surgical Research.2005,37:45-49.
[50]Yong Chen,Zuojin Liu,Shaoyong Liang,et al.Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats.Liver Transplantation.2008,14:823-836.
[51]S.Yamamoto,Y.Sato,T.Suda,et al.Can donor-specific transfusion via the portal vein unfer activated Kupffer cells enhance the beneficial effect of portal venous tolerance for rat small intestinal transplantation? Transplantation Proceedings.2000,32:2485.
[52]Akiko Iwasaki,Ruslan Medzhitov.Toll-like receptor control of the adaptive immune responses.Nature immunology.2004,5:987-995.
[53]Ian N.Crispe,Matthew Giannandrea,Ingo Klein,et al.Cellular and molecular mechanisms of liver tolerance.Immunological Reviews.2006,213:101-118.
[54]Knolle P,Sehlaak J,Uhrig A,et al.Human Kupffer cells secrete IL-10 in response to lipopolysaceharide(LPS) challenge.Journal of Hepatology.1995,22:226-229.
[55]Annette Erhardt,Markus Biburger,Thomas Papadopoulos,et al.IL-10,regulatory T cells,and Kupffer cells mediate tolerance in concanavalon A-induced liver injury in mice.Hepatology.2007,45:475-485.
[56]Sun D,Chen D,Du B,et al.Heat shock response inhibits NF-kappaB activation and cytokine production in murine Kupffer cells.The Journal of surgical research.2005,129:114-121.
[57]Ojaniemi M,Liljeroos M,Harju K,et al.TLR-2 is upregulated and mobilized to the hepatocyte plasma membrane in the space of Disse and to the Kupffer cells TLR-4 dependently during acute endotoxemia in mice.Immunology Letters.2006,102:158-168.
[58]Jahnke C,Mehrabi A,Golling M,et al.Evaluation of microperfusion disturbances in the transplanted liver after Kupffer cell destruction using GdC13:an experimental porcine study.Transplantation Proceedings.2006,38:1588-1595.
[59]Jung JY,Lee SM.The roles of Kupffer cells in hepatic dysfunction induced by ischemia/reperfusion in rats.Archives of Pharmacal Research.2005,28:1386-1391.
[60]Matsue H,Matsue K,Walters M,et al.Induction of antigen-specific immunosuppression by CD95L cDNA-reansfected 'killer' dendritic cells.Nature Medicine.1999,5:930-937.
[61]Zhang HG,SU X,Liu D,et al.Induction of specific T cell tolerance by Fas ligand-expressing antigen-presenting cells.Journal of immunology.1999,162:1423-1430.
[62]Z.-L.Sun,T.Wada,K.Uchikura,et al.Role of Fas/Fasl in Kupffer cell-dependent deletion of alloantigen activated T cells following liver transplantation.Transplantation Proceedings.2001,33:279-282.
[63]Keiichiro Uchikura,Tatehiko Eada,Sumito Hoshino,et al.Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species.Am J Physiol Gastrointest Liver Physiol.2004,287:G620-G626.
[64]Varsha Thakur,Michele T.Pritchard,Megan R.McMullen.Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells:role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-α Production.Journal of Leukocyte Biology.2006,79:1348-1356.
[65]Kosei Maemura,Qizhi Zheng,Tatehiko Wada,et al.Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells.Immunology and Cell Biology.2005,83:336-343.
[66]Mocellin S,Panelli MC,Wang E,et al.The dual role of IL-10.Trands in Immunology.2003,24:36-43.
[67]Maloy K J,Salaun L,Cahill R,et al.CD4~+ CD25~+ T_R cells suppress innate immune pathology through cytokine-dependent mechanisms.J Exp Med.2003,197:111-119.
[68]Zhang X,Koldzic DN,Izikson L,et al.IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25~+CD4~+ regulatory T cells.Int Immunol.2004,16:249-256.
[69]Masaki Ham,Cherry I.Kingsley,Masanori Niimi,et al.IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo.The Journal of Immunology.2001,166:3789-3796.
[70]Li Wei-min,Liu Wei,Gao Cheng,et al.Antigen-specific tolerance induced by IL-10 gene modified immature dendritic cells in experimental autoimmune myocarditis in rats.Chin Med J.2006,119:1646-1652.
[71]Shusen Yang,Weimin Li,Wei Liu,et al.IL-10 gene modified dendritic cells induced antigen-specific tolerance in experimental autoimmune myoearditis.Clinical Immunology.2006,121:63-73.
[72]Yukihiro Yokoyama,William C.Kitehens,Balazs Toth,et al.Role of IL-10 in regulating proinflammatory cytokine release by Kupffer cells following trauma-hemorrhage.Am J Physiol Gastrointest Liver Physiol.2004,286:G942-G946.
[2]V.Valatas,C.Xidakis,H.Roumpaki,et al.Isolation of rat Kupffer cells:a combined methodology for highly purified primary cultures.Cell Biol Int.2003;27:67-73.
[3]Edward B.Alabraba,Stuart M.Curbishley,Wai K.Lai,et al.A new approach to isolation and culture of human Kupffer cells.J Immunol Methods.2007;326:139-144.
[4]Mawet E,Shiratori Y,Hikiba Y,et al.Cytokine-induced neutrophil chemoattractant release from hepatocytes is modulated by Kupffer cells.Hepatology.1996;23:353-358.
[5]Marangoni A,Aldini R,Sambri V,et al.Production of tumor necrosis factor alpha by Treponema pallidum,Borrelia burgdorferi s.l.,and Leptospira interrogans in isolated rat Kupffer cells.FEMS Immunol Med Microbiol.2004;40:187-191.
[6]Luckey SW,Taylor M,Sampey BP,et al.4-hydroxynonenal decreases interleukin-6 expression and protein production in primary rat Kupffer cells by inhibiting nuclear factor-kappaB activation.J Pharmacol Exp Ther.2002;302:296-303.
[7]张长习,高绪照,谢文彪.大鼠及人肝库否细胞的分离纯化和培养.肝胆外科杂志,2007;15:308-310.
[8]施鑫,李保仝,黎介寿.大鼠肝Kupffer细胞分离培养及鉴定.医学研究生学报,2000;13:242-246.
[9]蔡伟,李非.大鼠肝脏Kupffer细胞的分离,纯化.中国普外基础与临床杂志,2007;14:292-295.
[10]Neaud V,Dubuisson L,Balabaud C,et al.Ultrastructure of human Kupffer cells maintained in culture.J Submicrosc Cytol Pathol.1995;27:161-170.
[11]Dory D,Echchannaoui H,Letiembre M,et al.Generation and functional characterization of a clonal murine periportal Kupffer cell line from H-2Kb -tsA58 mice.J Leukoc Biol.2003;74:49-59.
[12]You Q,Cheng L,Kedl RM,et al.Mechanism of T cell tolerance induction by murine hepatic Kupffer cells.Hepatology.2008;48:978-990.
[13]柳枫,朱继业,李涛等.大鼠库普弗细胞分离培养方法的改良.中华肝脏病杂志,2006;14:532-535.
[14]Ikejima K,Enomoto N,Seabra V,et al.Pronase destroys the lipopolysaccharide receptor CD14 on Kupffer cells.AM J Phsysiol.1999;276:G591-598.
[15]刘亮,张宗明,张驰等.适于膜片钳技术的大鼠肝Kupffer细胞急性分离和鉴定.世界华人消化杂志,2005;13:202-206.
[16]Catala M,Anton A,Portoles MT.Characterization of the simultaneous binding of Escherichia coli endotoxin to Kupffer and endothelial liver cells by flow cytometry.Cytometry.1999;36:123-130.
[17]Perez R,Johnson J,Winkler JD,et al.Kupffer cell-mediated lymphocyte apoptosis:a PGE2-dependent mechanism of portal venous transfusion-induced immunosuppression? J Surg Res.1998;78:37-41.
[17]李涛,朱继业,柳枫等.RNA干扰供体大鼠库普弗细胞B7分子表达对受体大鼠淋巴细胞激活的影响.世界华人消化杂志,2008;16:39-44.
[18]Xidakis C,Ljumovic D,Manousou P,et al.Production of pro- and anti-fibrotic agents by rat Kupffer cells;the effect of octreotide.Dig Dis Sci.2005;50:935-941.
[19]Xidskis C,Mastrodimou N,Notas G,et al.RT-PCR and immunocytochemistry studies support the presence of somatostatin,cortistatin and somatostatin receptor subtypes in rat Kupffer cells.Regul Pept.2007;143:76-82.
[20]Mawet E,Shiratori Y,Hikiba Y,et al.Cytokine-induced neutrophil chemoattractant release from hepatocytes is modulated by Kupffer cells.Hepatology.1996;23:353-358.
[1]Starzl TE,Demetris Aj.Liver transplantation:a 31-year perspective,Pert Ⅲ.Curr Probl Surg.1990;27:181-240.
[2]Clavien PA,Harvey PR,Strasberg SM.Preservation and reperfusion injuries in liver allografts.An overview and synthesis of current studies.Transplantation.1992;53:957-958.
[3]Fondevila C,Busuttil RW,Kupiec-Weglinski JW,et al.Hepatic ischemia/reperfusion injury-a flesh look.Exp Mol Pathol.2003;74:86-93.
[4]Fan C,Zwacka RM.Therapeutic approaches for ischemia/reperfusion injury in the liver.J Mol Med.1999;77:577-596.
[5]Lemasters JJ,Thurman RG.Hypoxia and reperfusion injury to the liver.Prog Liver Dis.1994; 11:85-114.
[6]Lemasters JJ,Bunzendahl H,Thurman RG Reperfusion injury to donor livers stored for transplantation.Liver Transpl Surg.1995;1:124-138.
[7]Jaeschke H,Gores GJ,Cederbaum AI,et al.Mechanisms of hepatotoxicity.Toxicol Sci.2002;65:166-176.
[8]Wanner GA,Ertel W,Muller P,et al.Liver ischemia and reperfusion induces a systemic inflammatory response through Kupffer cell activation.Shock.1996;5:34-40.
[9]Grace L.SU.Lipopolysaccharides in liver injury:molecular mechanisms of Kupffer cell activation.Am J Physiol Gastrointest Liver Physiol.2002;283:G256-G265.
[10]Nobuyuki Enomoto,Yoshiyuki Takei,Miyoko Hirose,et al.Thalidomide prevents alcoholic liver injury in rats through inhibition of Kupffer cell sensitization.Comp Hepatol.2004;3:S37.
[11]Wang YY,Dahle Mk,Agren J,et al.Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation.Shock.2006;25:141-146.
[12]Choi A,Alam J.Heme oxygenase-1:function,regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury.Am J Respir Cell Mol Biol.1996;15:9-19.
[13]Fujita T,Toda K,Karimova A et al.Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis.Nat Med.2001;7:598-604.
[14]Coito Aj,Buelow R,Shen XD et al.Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury.Transplantation.2002;74:96-102.
[15]Maines MD.The heme oxygenase system:a regulator of second messenger gases.Annu Rev Pharmacol Toxicol.1997;37:517-554.
[16]Kobayashi T,Hirano K,Yamamoto T,et al.Protective role of Kupffer cells in ischemia-reperfused rat liver.Arch Histol Cytol.2002;65:251-261.
[17]Takashi Kobayashi,Yoshinobu Sato,Satoshi Yamamoto,et al.Augmentation of heme oxygenase-1 expression in the graft immediately after implantation in adult living-donor liver transplantation.Transplantation.2005;79:977-980.
[18]Hirohisa Kato,Farin Amersi,Roland Buelow,et al.Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation.Am J Transplant.2001;1:121-128.
[19]Goda,N.,Suzuki,K.,Naito,M.,et al.Distribution of heme oxygenase isoforms in rat liver.Topographic basis for carbon monoxide-mediated microvascular relaxation.J.Clin.Invest.1998;101:604-612.
[20]Bauer,I.,Wanner,.G.A.,et al.Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver.Hepatology.1998;27;829-838.
[21]Kobayashi T,Hirano K,Yamamoto T,et al.The protective role of Kupffer cells in the ischemia-reperfusion rat liver.Arch Histol Cytol.2002;65:251-261.
[22]Erwin Geuken,Carlijn I.Buis,Dorien S.Visser,et al.Expression of heme oxygenase-1 in human livers before transplantation correlates with graft injury and function after transplantation.Am J Transplant.2005;5:1875-1885.
[23]Alexandra K.Kiemer,Tobias Gerwig,Alexander L.Gerbes,et al.Kupffer-cell specific induction of heme oxygenase 1(hsp32) by the atrial natriuretic peptide—role of cGMP.J Hepatol.2003;38:490-498.
[24]Kamada N,Calne RY.A surgical experience with five hundred thirty liver transplants in the rat.Surgery.1983;93:64-69.
[25]Montalvo Jave EE,Escalante Tattersfield T,Ortega Salgado JA,et al.Factors in the pathophysiology of the liver ischemia-reperfusion injury.J Surg Res.2008;147:153-159.
[26]Malhi H,Gores GJ,Lemasters JJ.Apoptosis and necrosis in the liver:a tale of two deaths?Hepatology.2006;43:S31-S44.
[27]Jaeschke H.Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning.Am J Physiol Gastrointest Liver Physiol.2003;284:G15-G26.
[28]Farmer DG,Amersi F,Kupiec-Weglinski JW,et al.Current status of ischemia and reperfusion injury in the liver.Transplant Rev.2000;14:106-126.
[29]Huang Y,Shan J,Wang C,et al.Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation.Transpl Immunol.2009;20:127-131.
[30]Burton JR,Rosen HR.Diagnosis and management of allograft failure.Clin Liver Dis.2006;10:407-35.
[31]Kupiec Weglinski JW,Busuttil RW.Ischemia and reperfusion injury in liver transplantation.Transplant Proc.2005;37:1653-1656.
[32]Selzner N,Rudiger H,Graf R,et al.Protective strategies against ischemic injury of the liver.Gastroenterology 2003;125:917-936.
[33]Suematsu M,Kashiwagi S,Sano T,et al.Carbon monoxide as an endogenous modulator of hepatic vascular perfusion.Biochem Biophys Res Commun.1994;205:1333-1337.
[34]Redaelli CA,Tian YH,Schaffner T,et al.Extended preservation of rat liver graft by induction of heme oxygenase-1.Hepatology.2002;35:1082-1092.
[35]Katori M,Buelow R,Ke B,et al.Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway.Transplantation 2002;73:287-292.
[36]Tullius,S.G.;Nieminen-Kelha,M.;Buelow,R.;et al.Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1.Transplantation.2002;74:591-598.
[37]Bilban M,Haschemi A,Wegiel B,et al.Heme oxygenase and carbon monoxide initiate homeostatic signaling.J Mol Med.2008;86:267-279.
[38]D'Amico G,Lam F,Hagen T,et al.Inhibition of cellular respiration by endogenously produced carbon monoxide.J Cell Sci.2006;119:2291-2298.
[39]Verma A,Hirsch D,Glatt C,et al.Carbon monoxide:a putative neural messenger.Science.1993;259:381-384.
[40]Motterlini R,Mann BE,Johnson T,et al.Bioactivity and pharmacological actions of carbon monoxide-releasing molecules.Curr Pharm Des.2003;9:2525-2539.
[41]Otterbein LE,Zuckerbraun B,Haga M,et al.Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury.Nat Med.2003;9:183-190.
[42]Song R,Kubo M,Morse D,et al.Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via antiinflammatory and anti-apoptotic effects.Am J Pathol.2003;163:231-242.
[43]Zuckerbraun B,Billiar T,Otterbein S,et al.Carbon monoxide protects against liver failure through nitric oxide-induced heme oxygenase 1.J Exp Med.2003;198:1707-1716.
[44]Zuckerbraun S,Chin B,Wegiel B,et al.Carbon monoxide reverses established pulmonary hypertension.J Exp Med.2006;203:2109-2119.
[45]Wagener F,Volk H,Willis D,et al.Different faces of the home-home oxygenase system in inflammation.Pharmacol Rcv.2003;55:551-571.
[46]Caban A,Oczkowicz G,Abdcl Samad O,ct al.Influence of Kupffer cells on the early phase of liver reperfusion.Transplant Proc.2002;34:694-697.
[47]Lcntsch AB,Yoshidome H,Chcadle WG,et al.Chemokine involvement in hepatic ischemia/repcrfusion injury in mice:roles for macrophage inflammatory protein-2 and Kupffer cells.Hepatology.1998;27:507-512.
[48]Takashi Kaizu,Atsunori Nakao,AllanTsung,et al.Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.Surgery 2005;138:229-235.
[49]Tomiyama K,Ikeda A,Ueki S,et al.Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats.Hepatology.2008;48:1608-1620.
[50]Sei-ichiro Tsuchihashi,Yuan Zhai,Qiao Bo,et al.Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury:inhibition of type-1 interferon signaling.Transplantation 2007;83:1628-1634.
[51]Stephen J.McNally,Ewen M.Harrison,James A.Ross,et al.Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury.Transplantation 2006;81:623-626.
[52]Lai IR,Chang KJ,Tsai HW,et al.Pharmacological preconditioning with simvastatin protects liver from ischemia-reperfusion injury by heme oxygenase-1 induction.Transplantation 2008;85:732-738.
[53]Sei-ichiro Tsuchihashi,Masha Livhits,Yuan Zhai,et al.Basal rather than induced heme oxygenase-1 levels are in the antioxidant cytoprotection.J Immunol 2006;177:4749-57.
[54]Cutrn JC,Perrelli MG,Cavalieri B,et al.Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning.Free Radic Biol Med 2002;33:1200-1208.
[55]Tsukamoto H.Redox regulation of cytokine expression in Kupffer cells.Antioxid Redox Signal 2002;4:741-748.
[56]Hanschen M,Zahler S,Krombach F,et al.Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion.Transplantation.2008;86:710-718.
[57]Thomas P,Hayashi H,Lazure D,et al.Inhibition of lipopolysaccharide activation of Kupffer cells by transition metals.J Surg Res.2008;148:116-120.
[58]Kaur H,Hughes MN,Green CJ,et al.Interaction of bilirubin and biliverdin with reactive nitrogen species.FEBS Lett.2003;543:113-119.
[59]Monbaliu D,Van Pelt J,De Vos R,et al.Primary graft nonfunction and Kupffer cell activation after liver transplantation from non-heart-beating donors in pigs.Liver Transpl.2007;13:239-247.
[60]Antal-Szalmas P.Evaluation of CD14 in host defence.Eur J Clin Invest 2000;30:167-179.
[61]Li XH,Gong JP,Shi YJ,et al.In vitro expression of CD14 protein and its gene in Kupffer cells induced by lipopolysaccharide.Hepatobiliary Pancreat Dis Int.2003;2:571-575.
[62]Qiu DK,Hua J,Li JQ,et al.CD14 expression on Kupffer cells during the course of carbon tetrachloride-mediated liver injury.Chin J Dig Dis.2005;6:137-141.
[63]Miyaso H,Morimoto Y,Ozaki M,et al.Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats:possible involvement of CD14 and TLR-4 downregulation on Kupffer cells.Dig Dis Sci.2006;51:2007-2012.
[64]Devey L,Ferenbach D,Mohr E,et al.Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism.Mol Ther.2009;17:65-72.
[1]Makoto Naito,Go Hasegawa,Yusuke Ebe,et al.Differentiation and function of Kupffer cells.Meal Electron Microsc.2004,37:16-28.
[2]Giakoustidis DE,Iliadis S,Tsantilas D,et al.Blockade of Kupffer cells by gadolinium chloride reduces lipid peroxidation and protects liver from ischemia / reperfusion injury.Hcpatogastroenterology.2003,50:1587-1592.
[3]Luis A.Videla,Virginia Fernandez,Gladys Tapia,et al.Oxidative stress-mediated hepatotoxicity of iron and copper:Role of Kupffer cells.Bio Metals.2003,16:103-111.
[4]Ohkochi N,Shibuya H,Tsukamoto M,et al.Kupffer's cells modulate neutrophile activity by superoxide anion and tumor necrosis factor-α in reperfusion injury of liver transplantation mechanisms of radical generation and reperfusion injury after cold ischemia.Transplant Proc.1999,31:1055-1058.
[5]Hidekazu Tsukamoto.Redox regulation of cytokine expression in Kupffer cells.Antioxid.Redox Signal.2002,4:741-748.
[6]Atsushi Kato,Cem Gabay,Tomohisa Okaya,et al.Specific role of intedeukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion.American Journal of Pathology.2002,161:1797-1803.
[7]Ferdinand Serracino-inglott,Nagy A.Habib,Robert T.Mathie,et al.Hepatic ischemiareperfusion injury.The American Journal of Surgery.2001,181:160-166.
[8]Kox W J,Volk T,Kox SN,et al.Immunomodulatory therapies in sepsis.Intensive Care Med.2000,26:S124-S128.
[9]Sun Z,Klein AS,Radaeva S,et al.In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats.Gastroenterology.2003,125:202-215.
[10]Tadashi Matsumoto,Kerri O'Malley,Philip A.Efron,et al.Interleukin-6 and STAT3 protect the liver from hepatic ischemia and reperfusion injury during ischemic preconditioning.Surgery. 2006,140:793-802.
[11]Danielle GSouza,Vanessa Pinho,Adriana C.Soares,et al.Role of PAF receptors during intestinal ischemia and reperfusion injury.A comparative study between PAF receptor-deficient mice and PAF receptor antagonist treatment.British Journal of Pharmacology.2003,139:733-740.
[12]Hulya Ozturk,Hayrettin Ozturk,Yusuf Yagmur.PAF antagonist BN-52021 reduces intercellular adhesion molecule-1 expression and oxidative stress in rats with reperfusion damage due to unilateral testicular torsion.Pediatr Surg Int.2006,22:191-196.
[13]N.Ohkohchi.Suppression of Kupffer cell function is a key for liver transplantation from the non-heart-beating donor.Transplant Proc.2001,33:3728-3731.
[14]Isozaki H,Okajima K,Hara H,et al.The protective effect of thromboxane A2 synthetase inhibitor against ischemic liver injury.Surgery Today.1994,24:435-440.
[15]N.Ohkohchi.Mechanisms of preservation and ischemic/reperfusion injury in liver transplantation.Transplant Proc.2002,34:2670-2673.
[16]Hirano K-I,Kobayashi T,Watanabe T,et al.Role of heme oxygenase-1 and Kupffer cells in the production of bilirubin in the rat liver.Arch Histol Cytol.2001,64:111-120.
[17]Yachie A,Niida Y,Wada T,et al.Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.J Clin Invest.1999,103:129-135.
[18]Yakashi Kobayashi,Ken-ichiro Hirano,Takashi Yamamoto,et al.The protective role of Kupffer cells in the ischemia-reperfused rat liver.Arch Histol Cytol.2002,65:251-261.
[19]Kyokane T,Norimizu S,Taniai H,et al.Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver.Gastroenterology.2001,120:1227-1240.
[20]Robert B Dorman,Mary Lynn Bajt,Anwar Farhood,et al.Heme oxygenase-1 induction in hepatocytes and non-parenchymal cells protects against liver injury during endotoxemia.Comp Hepatol.2004,3:S42.
[21]Wunder C,Brock RW,McCarter SD,et al.Inhibition of heam oxygenase activity increases leukocyte accumulation in the liver following limb ischaemia-reperfusion in mice.J Physiol.2002,540:1013-1021.
[22]Takashi Kobayashi,Yoshinobu Sato,Satoshi Yamamoto,et al.Augmentation of gene oxygenase-1 expression in the graft immediately after implantation in adult living-donor liver transplantation.Transplantation.2005,79:977-980.
[23]Tuzuner E,Liu L,Shimada M,et al.Heme oxygenase-1 protects human hepatocytes in vitro against warm and cold hypoxia.J Hepatol.2004,41:764-772.
[24]McNally SJ,Harrison EM,Ross JA,et al.Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury.Transplantation.2006,81:623-626.
[25]Ebenezer Olatunde Farombi,Young-Joon Surh,et al.Heme oxygenase-1 as a potential therapeutic target for hepatoprotection.Journal of Biochemistry and Molecular Biology.2006,39:479-491.
[26]Gill RG,Coulombe M,Lafferty KJ:Pancreatic islet allograft immunity and tolerance:the two-signal hepothesis revisited.Immuno Rev.1996,149:75-96.
[27]Yorihiro Akamatsu,Nobuhiro Ohkohchi,Hideyuki Doi,et al.Effect of elimination of donor Kupffer cells and / or recipient macrophages on acute rejection in liver transplantation.Hepato Gastroenterology.2003,50:1105-1110.
[28]Y.Akamatsu,N.Ohkohchi,H.Doi,et al.Does elimination of Kupffer cells prolong survival time in liver transplantation? Transplant Proc.1999,31:545-547.
[29]Andrew D.Clouston,Julie R.Jonsson,Glenda A.Balderson,et al.Lymphocyte apoptosis and cell replacement in humen liver allografts.Transplantation.2002,73:1828-1834.
[30]Ulrich T(o｜¨)x,Marcus A Burkhardt,Christine Benz,et al.Expression of apoptosis and apoptosis-related peptides in various stages of rejection in the human transplanted liver.Hepato-Gastroenterology.2001,48:1697-1700.
[31]Yamaguchi Y,Okabe K,Matsumara F,et al.Peroxynitrite formation during rat hepatic allograft rejection.Hepatology.1999,29:777-784.
[32]Svensson G,Friman S,Jacobsson L,et al.Hepatocyte and Kupffer cell function after liver transplantation in the rat in vivo evaluation with dynamic scintigraphy.Liver.1995,15:189-195.
[33]Hua Liu,Hui Cao,Zhi-Yong WU.Isolation of Kupffer cells and their suppressive effects on T lymphocyte growth in rat orthotopic liver transplantation.World J Gastroenterol.2007,13:3133-3136.
[34]Sharland A,Yan Y,Wang C,et al.Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.Transplantation.1999,68:1736-1745.
[35]Zhaoli Sun,Tatehiko Wada,Kosei Maemura,et al.Hepatic allograft-derived Kupffer cells regulate T cell response in rats.Liver Transplantation.2003,9:489-497.
[36]Aya Miyagawa-Hayashino,Tatsuaki Tsuruyama,Hiroto Egawa.FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL~+ Kupffer cells are indicators of rejection activity in human liver allografts.The American Journal of Pathology.2007,171:1499-1508.
[37]Yuichi Nagakawa,Shuji Nomoto,Yukihiko Kato,et al.Over-expression of AIF-1 in liver allografts and peripheral blood correlates with acute rejection after transplantation in rats.American Journal of Transplantation.2004,4:1949-1957.
[38]Nagakawa Y,Williams GM,Zheng Q,et al.Oxidative mitochondrial DNA damage and deletion in hepatocytes of rejecting liver allografts in rats:Role of TNF-alpha.Hepatology.2005,42:208-215.
[39]Guangwei Liu,Haixia Ma,Lingling Jiang,et al.Allograft inflammatory factor-1 and its immune regulation.Autoimmunity.2007,40:95-102.
[40]Aya Miyagawa-Hayashino,Tatsuaki Tsuruyama,Hironori Haga,et al.Arteriopathy in chronic allograft rejection in liver transplantation.Liver Transplantation.2004,10:513-519.
[41]A.S.Gaweco,R.H.Wiesner,S.Yong,et al.Kupffer cell expression of CD40L(CD154) in human chronic liver allograft rejection.Transplantation Proceedings.1999,31:560-561.
[42]Adam S.R.Bartlett,John L.McCall,Rohan Ameratunga,et al.Analysis of intragraft gene and protein expression of the costimulatory molecules,CD80,CD86 and CD154.in orthotopic liver transplant recipients.American Journal of Transplantation.2003,3:1363-1368.
[43]Sun H,Subbotin V,Chen C,et al.Prevention of chronic rejection in mouse aortic allograft by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody.Transplantation.1997,64:1838-1843.
[44]Allan D.Kirk,David M.Harlan,Nicholas N.Armstrong,et al.CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates.Proc.Natl.Acad.Sci.USA.1997,94:8789-8794.
[45]Paola Pontrelli,Michele Ursi,Elena Ranieri,et al.CD40L proinflammatory and profibrotic effects on proximal tubular epithelial cells:Role of NF-κB and Lyn.Journal of the American Society of Nephrology.2006,17:627-636.
[46]Koishi Sato,Kiyotaka Yabuki,Takanori Haba,et al.Role of Kupffer cells in the induction of tolerance after liver transplantation.Journal of Surgical Research.1996,63:433-438.
[47]Savier E,Lemasters JJ,Thurman RG.Kupffer cells participate in rejection following liver transplantation in the rat.Transplant International.1994,7:S183-S186.
[48]Roland CR,Mangino MJ,Duffy BF,et al.Lymphocyte suppression by Kupffer cells prevents portal venous tolerance induction:a study of macrophage function after intravenous gadolinium.Transplantation.1993,55:1151-1158.
[49]Diaz-Peromingo JA,Gonzalez-Quintela A.Influence of gadolinium-induced Kupffer cell blockade on portal venous tolerance in rat skin allograft transplantation.European Surgical Research.2005,37:45-49.
[50]Yong Chen,Zuojin Liu,Shaoyong Liang,et al.Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats.Liver Transplantation.2008,14:823-836.
[51]S.Yamamoto,Y.Sato,T.Suda,et al.Can donor-specific transfusion via the portal vein unfer activated Kupffer cells enhance the beneficial effect of portal venous tolerance for rat small intestinal transplantation? Transplantation Proceedings.2000,32:2485.
[52]Akiko Iwasaki,Ruslan Medzhitov.Toll-like receptor control of the adaptive immune responses.Nature immunology.2004,5:987-995.
[53]Ian N.Crispe,Matthew Giannandrea,Ingo Klein,et al.Cellular and molecular mechanisms of liver tolerance.Immunological Reviews.2006,213:101-118.
[54]Knolle P,Sehlaak J,Uhrig A,et al.Human Kupffer cells secrete IL-10 in response to lipopolysaceharide(LPS) challenge.Journal of Hepatology.1995,22:226-229.
[55]Annette Erhardt,Markus Biburger,Thomas Papadopoulos,et al.IL-10,regulatory T cells,and Kupffer cells mediate tolerance in concanavalon A-induced liver injury in mice.Hepatology.2007,45:475-485.
[56]Sun D,Chen D,Du B,et al.Heat shock response inhibits NF-kappaB activation and cytokine production in murine Kupffer cells.The Journal of surgical research.2005,129:114-121.
[57]Ojaniemi M,Liljeroos M,Harju K,et al.TLR-2 is upregulated and mobilized to the hepatocyte plasma membrane in the space of Disse and to the Kupffer cells TLR-4 dependently during acute endotoxemia in mice.Immunology Letters.2006,102:158-168.
[58]Jahnke C,Mehrabi A,Golling M,et al.Evaluation of microperfusion disturbances in the transplanted liver after Kupffer cell destruction using GdC13:an experimental porcine study.Transplantation Proceedings.2006,38:1588-1595.
[59]Jung JY,Lee SM.The roles of Kupffer cells in hepatic dysfunction induced by ischemia/reperfusion in rats.Archives of Pharmacal Research.2005,28:1386-1391.
[60]Matsue H,Matsue K,Walters M,et al.Induction of antigen-specific immunosuppression by CD95L cDNA-reansfected 'killer' dendritic cells.Nature Medicine.1999,5:930-937.
[61]Zhang HG,SU X,Liu D,et al.Induction of specific T cell tolerance by Fas ligand-expressing antigen-presenting cells.Journal of immunology.1999,162:1423-1430.
[62]Z.-L.Sun,T.Wada,K.Uchikura,et al.Role of Fas/Fasl in Kupffer cell-dependent deletion of alloantigen activated T cells following liver transplantation.Transplantation Proceedings.2001,33:279-282.
[63]Keiichiro Uchikura,Tatehiko Eada,Sumito Hoshino,et al.Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species.Am J Physiol Gastrointest Liver Physiol.2004,287:G620-G626.
[64]Varsha Thakur,Michele T.Pritchard,Megan R.McMullen.Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells:role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-α Production.Journal of Leukocyte Biology.2006,79:1348-1356.
[65]Kosei Maemura,Qizhi Zheng,Tatehiko Wada,et al.Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells.Immunology and Cell Biology.2005,83:336-343.
[66]Mocellin S,Panelli MC,Wang E,et al.The dual role of IL-10.Trands in Immunology.2003,24:36-43.
[67]Maloy K J,Salaun L,Cahill R,et al.CD4~+ CD25~+ T_R cells suppress innate immune pathology through cytokine-dependent mechanisms.J Exp Med.2003,197:111-119.
[68]Zhang X,Koldzic DN,Izikson L,et al.IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25~+CD4~+ regulatory T cells.Int Immunol.2004,16:249-256.
[69]Masaki Ham,Cherry I.Kingsley,Masanori Niimi,et al.IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo.The Journal of Immunology.2001,166:3789-3796.
[70]Li Wei-min,Liu Wei,Gao Cheng,et al.Antigen-specific tolerance induced by IL-10 gene modified immature dendritic cells in experimental autoimmune myocarditis in rats.Chin Med J.2006,119:1646-1652.
[71]Shusen Yang,Weimin Li,Wei Liu,et al.IL-10 gene modified dendritic cells induced antigen-specific tolerance in experimental autoimmune myoearditis.Clinical Immunology.2006,121:63-73.
[72]Yukihiro Yokoyama,William C.Kitehens,Balazs Toth,et al.Role of IL-10 in regulating proinflammatory cytokine release by Kupffer cells following trauma-hemorrhage.Am J Physiol Gastrointest Liver Physiol.2004,286:G942-G946.