修回日期: 2015-03-04
接受日期: 2015-03-12
在线出版日期: 2015-04-28
肝移植被公认为目前治疗终末期肝病最有效的手段, 但术后缺血再灌注损伤(ischemia- reperfusion injury, I/RI)及急慢性免疫排斥反应(immune rejection response, IRR)仍是影响预后及生存率的重要因素, 遗憾的是, 目前临床上的对症方案效果差强人意, 且在当前供体紧缺的背景下, 探索改善肝脏移植术后I/RI及急慢性IRR的有效方法, 具有重要的临床意义. Kupffer细胞(Kupffer cells, KCs)是定居于肝脏的体内最大的抗原呈递细胞群, 作为肝内第一防线, 在移植后I/RI及IRR中具有多样性效能, 但其在影响肝移植术后的病理进展中的具体机制目前尚未完全明了, 故此将我们的研究发现及目前最新的研究结果做一综述.
核心提示: Kupffer细胞(Kupffer cells, KCs)在肝移植术后缺血再灌注损伤(ischemia-reperfusion injury)期及免疫排斥反应(immune rejection response)期的病理生理中起着关键作用. 我们认为调节KCs极性、调节Th细胞分化倾向以及凋亡细胞清除这三者在术后病理生理中最为重要, 故结合我们的研究及最新研究进展做出综述.
引文著录: 张安元, 刘一鸣, 龚建平. Kupffer细胞与肝脏移植的研究进展. 世界华人消化杂志 2015; 23(12): 1917-1923
Revised: March 4, 2015
Accepted: March 12, 2015
Published online: April 28, 2015
Nowadays, liver transplantation is globally considered the most effective treatment for end-stage liver diseases. Ischemia-reperfusion (I/R) injury and immune rejection response (IRR) are the two major imperfections which severely affect the recipients' prognosis and survival rate without satisfactory clinical management strategies. Therefore, exploring effective methods to improve I/R injury and IRR have important clinical significance under circumstances of shortage of donor livers. Kupffer cells (KCs) are the largest population of antigen representing cells (APCs) which settle in the liver. As the first defensive line of the live, KCs exhibit various biological effects. However, the exact mechanisms responsible for the role of KCs in I/R injury and IRR remain elusive. We hereby review the current finding about the role of KCs in I/R injury and IRR.
- Citation: Zhang AY, Liu YM, Gong JP. Kupffer cells and liver transplantation. Shijie Huaren Xiaohua Zazhi 2015; 23(12): 1917-1923
- URL: https://www.wjgnet.com/1009-3079/full/v23/i12/1917.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i12.1917
肝移植被公认为目前治疗终末期肝病最有效的手段, 经过大半个世纪的发展, 已取得初步成果[1-7]. 但术后缺血再灌注损伤(ischemia- reperfusion injury, I/RI)和免疫排斥反应(immune rejection response, IRR)仍然是其无法回避的两大难题[8-13]. 持续性的I/RI是术后发生原发性移植物功能障碍、脓毒症休克、多器官功能衰竭等并发症的主要原因之一; 而除外供体和受体是同卵双生或者受体接受免疫抑制治疗, 绝大多数移植肝脏在1-2 wk内都会发生IRR[14-19]. 在当前供体紧缺的背景下, 探索改善肝移植后I/RI及避免IRR的有效办法, 具有重要的临床意义. Kupffer细胞(Kupffer cells, KCs)作为肝内第一防线, 具备很强的吞噬清除及呈递能力, 在I/RI及IRR中扮演着重要的角色[20,21].
I/RI是肝移植术后一个常见而又复杂的过程, 涉及微循环障碍, 炎症细胞的激活与浸润, 促炎因子通路传导、活性氧族、活性氮族介质的释放等诸多环节[22,23]. 在肝脏移植手术中, 在无肝期肠道明显淤血、肿胀. 在缺血缺氧的环境下, 肠道菌群失调, 产生大量有毒物质; 上皮细胞通透性增加, 毒素入血; 而处于冷缺血期的肝脏KCs同样因缺血缺氧而处于对有毒物质敏感性增强的预激活状态[24-26]. 当肝脏恢复灌注时, 肠道有害物质随门静脉血流汇入肝血窦, 预激活状态的KCs被其活化并大量吞噬清除肠源有害物质, 产生多效作用.
脂多糖(lipopolysaccharide, LPS)是I/RI肠源性有毒物质的主要组成部分, 也是KCs活化的主要刺激源. KCs上LPS受体CD14与LPS连接蛋白(LPS binding protein, LBP)结合后经细胞内Toll样受体4(Toll-like receptor 4, TLR4)信号通路触发级联反应, 经经典途径激活并上调核因子κB(nuclear factor κB, NF-κB)转录活性, 并使其下游受调控的炎症因子肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)、白介素(interleukin, IL)-1、6、8等过度表达, 参与I/RI[27]. 近年来研究[28]证实缺氧状况下引起的NF-κB活性增强主要是通过经典途径; 而I/RI本身就包含缺血缺氧的过程. 因此, NF-κB经经典途径过度激活可能是缺血再灌注过程中的关键因素. 然而我们在实验中却发现, 用抗-CD14单克隆抗体阻断CD14与LBP的结合, 仅能一定程度降低NF-κB转录活性, 提示还有其他通路(非经典途径)参与了这一过程[29]. 我们通过建立内毒素耐受(endotoxin tolerance, ET)的SD大鼠移植后I/RI模型, 发现ET组术后I/RI情况得到明显的改善. NF-κB转录活性受抑制的同时TNF-α表达下调, 并伴有人白介素受体相关激酶4(interleukin receptor-associated kinase 4, IRAK-4)的表达减少[30,31]. TNF-α作为在肝内主要由KCs表达的强效促炎因子, 具有诱导黏附因子集聚、激活补体促进细胞凋亡坏死等效应. 但另有研究[32]显示, TNF-α也有诱导肝细胞增殖及再生以及诱导Th0向CD4+CD25+Foxp3+Treg分化等作用. IRAK-4是TLR-4信号通路中的"桥梁因子", 也是调节NF-κB活性的关键上游因子. 由于ET模型无法运用于临床, 我们从信号通路着手, 发现经过氨基乙磺酸(taurine)预处理的大鼠肝移植后I/RI水平较对照组明显减弱, IRAK-4的表达及NF-κB转录活性明显受抑制伴TNF-α、IL-6表达减少, 且IL-6的浓度与移植肝功能紊乱程度成正相关. 而IL-10表达则上调. 但上述处理因素均不能完全消除NF-κB的过度激活效应[32-37]. 前期文献报道[38], 氨基乙酸(glycine)在LPS诱导的肝损伤中起着负性调节作用, 其通过激活氨基乙酸门控氯离子通道(glycine-gated chloride channel)抑制胞外Ca2+内流, 阻断胞内第二信使作用. 我们在术前1 h用glycine预处理供肝, 发现预处理组中glycine可有效抑制MAPK的磷酸化及阻碍NF-κB的核转位, 进而导致下游信号级联反应中断, TNF-α等细胞因子表达明显减少[39]. 同时, 我们也观察到, 完全阻断NF-κB的功能具有肝不良反应, 反而加重I/RI以及IRR. 因此, 如何能抑制KCs中NF-κB的过度激活而不影响其基础功能呢? 我们实验[40]证实: NBD多肽可通过竞争性抑制IKK复合物的形成, 抑制移植术后LPS刺激下的NF-κB过度激活, 导致TNF-α、IL-6等促炎因子分泌减少; 而在生理状态下NBD多肽则对下游细胞因子无影响. 提示NBD多肽能消除NF-κB的过度激活同时又保有其基础功能, 同时减轻I/RI, 但其分子机制仍有待于进一步阐明.
此外, 活化的KCs可产生过量的活性氧族(reactive oxygen species, ROS)以及活性氮族(reactive nitrogen species, RNS). 其能直接导致肝细胞膜通透性增加甚至溶解坏死并抑制线粒体氧化磷酸化效能, 减少肝内能量物质的产生和传递. 活化的KCs还可通过分泌血小板活化因子(platelet-activating factor, PAF)和血栓素A2(thromboxane A2, TXA2)等介质激活趋化中性粒细胞、诱导细胞间黏附分子表达以及促进血小板黏附等效应协同加重I/RI的程度. 但也有文献报道活化的KCs在I/RI过程中可上调具有细胞保护作用的血红素加氧酶-1(heme oxygenase-1, HO-1)的表达, 通过清除促炎因子在移植肝脏微循环中的积聚, 进而保护I/RI对移植肝的破坏[41-44]. I/RI的进展是一种复杂的多细胞多因子多层面协同效应, KCs在这一过程中表现出"两面性", 故如何调节KCs功能应是I/RI研究领域重要的研究方向.
移植后急性排斥反应(acute rejection response, AcR)是影响患者术后生存率及生存质量的关键因素. 鉴于非特异性免疫抑制剂的诸多并发症, 诱导术后移植物免疫耐受成为避免慢性失功及长期服用免疫抑制剂的最佳途径. 免疫耐受是指机体免疫系统接受供体抗原后产生的特异性的免疫无应答状态. 当机体再次接触同一抗原刺激后, 不会发生免疫应答但机体对其他抗原仍具有正常的提呈及免疫应答能力[45]. 目前, 移植领域研究广泛认为AcR实质是由活化的T淋巴细胞及各类细胞因子协同作用介导的炎症反应, 移植肝脏术后, 大量的供体抗原进入受体, 激活肝脏内部具有高效呈递功能的KCs细胞及树突状细胞等, 活化的抗原呈递细胞在呈递抗原并活化初始T细胞的同时, 还有诱导大量黏附因子、趋化因子向肝脏集聚, 使移植肝脏长期处于炎症浸润状态, 容易诱发肝脏细胞死亡/凋亡、肝脏纤维化、胆管压力过大、血栓形成等病理改变, 破坏移植肝脏的功能, 导致肝脏移植失败和排斥. T细胞活化是造成上述现象的主要原因, 其活化需要APC上主要组织相容性复合体(major histocompatibility complex, MHC)Ⅱ类抗原与T细胞上的T细胞受体(T cell receptor, TCR)的结合和APC上共刺激分子(如CD80、CD86及CD40等)与相应受体结合的双信号刺激. 因此, APC和T细胞在AcR中发挥着关键作用[46].
前文提到, KCs作为体内数量最大的APC群, 具备很强的抗原呈递潜能. 活化的KCs可明显上调其细胞膜表面MHCⅡ类抗原以及共刺激分子的表达, 高效呈递同种异体抗原, 激活初始T细胞. 活化的T细胞在各种信号通路的调控下进一步分化为Th1/Th2/Th17/Treg等亚型, 各亚型的T细胞具有分泌不同细胞因子, 调节机体免疫应答, 维持机体稳态等多种功能, 在移植免疫中发挥重要作用. 我们前期研究证实[47,48]: 在LEW-BN肝移植AcR模型中, 受体移植肝及外周血中Th1类细胞因子干扰素-γ(interferon-γ, IFN-γ)、IL-2及Th17类细胞因子IL-17、IL-6及IL-23的表达明显增高, Th1类细胞因子主要通过增加移植物血管黏附性等方式促进炎症细胞积聚, 进而协同增强Th17细胞及其分泌的细胞因子对移植物的持续性破坏, 同时抑制Th0细胞向Th2/Treg类细胞分化, 致使移植肝脏组织大量炎症因子浸润, 促进AcR的发生. 而在BN-LEW自发耐受模型中, Th2及Treg类细胞因子IL-10、IL-4、转化增长因子β1(transforming growth factor β1, TGF-β1)等抑炎因子较Th1/Th17类细胞因子的表达显著增高. 此外我们还观察到在耐受组移植肝汇管区炎症细胞浸润程度较排斥组明显减轻, 减少且有大量浸润T淋巴细胞凋亡, 肝脏功能明显改善, 提示免疫耐受的形成可能与移植物局部活化T细胞凋亡密切相关.
活化KCs可经过不同信号通路调控, 表达多种凋亡诱导因子, 因此对活化的T细胞增殖具有很强的抑制效应. 我们的研究显示, KCs可经NF-κB途径上调其表面FasL的表达, 从而诱导Fas+ T细胞凋亡伴IL-4的表达增高, 促炎因子分泌降低, 明显延长AcR模型大鼠术后生存率. 而我们用GdCl3阻断KCs内NF-κB的活性, 可破坏已经形成的免疫耐受状态, 且IFN-γ和TNF-α的表达上调. 提示Fas-FasL通路是诱导移植后免疫耐受的重要通路[49]. 近来也有文献报道, FasL已成为监测人体肝移植后AcR的重要观测指标[50]. 此外我们还发现, 通过上调KCs中半乳凝集素(galectin, Gal)1和9的表达, 与表达于Th细胞表面的各自配体结合后可特异性诱导Th1/Th17细胞凋亡, 同时维持Th2/Treg细胞的数量及功能, 诱导免疫平衡向Th2/Treg偏移, 延长移植肝存活时间[51]. 可我们在研究[52,53]中还发现: (1)在体外共培养实验中, 应用多级浓度anti-FasL抗体或转染Gal-1/9过表达质粒并不能完全消除KCs对T细胞的抑制作用; (2)在动物试验中, 单一减少Th1型细胞因子IL-2分泌、阻断ICOS共刺激通路及GITRL通路或增强肝再生增强因子(augmenter of liver regeneration, ALR)表达等, 虽能延长移植物存活时间, 但都较难获得移植物的长期存活. 提示诱导长期、稳定的免疫耐受应从调节KCs极性、功能及T细胞分化凋亡等多层面进行.
KCs细胞可因所处局部微环境不同, 极化为不同的亚型(M1/M2). M1型KCs表型特点为IL-12high、IL-23high、IL-10low, 其可分泌多种炎症因子(IL-1、IL-6、IL-12、IL-23、TNF-α等)也表达大量的MHC-Ⅱ和B7共刺激分子, 高效呈递抗原, 参与Th1/Th17型免疫应答. M2型KCs表型特点为IL-12low, IL-23low, IL-10high. MHC-Ⅱ和共刺激分子表达减少并分泌大量IL-4、IL-10、TGF-β等抑炎因子, 介导Th2型活化及免疫调控[54-57]. 组蛋白去乙酰化酶11(histone deacetylase 11, HDAC11)是第Ⅳ类HDACs成员, 我们研究[58]发现: 在LEW-BN肝移植AcR模型中, 沉默KCs中HDAC11的表达, 可上调KCs自分泌IL-10的能力. 同时MHC-Ⅱ类抗原及B7等共刺激分子的表达显著下降, 诱导KCs向M2型极化, 明显改善移植肝脏情况. 此外, 有文献报道[59], microRNA(miRNA)在免疫调节中起着重要的作用. 我们也发现, 抑制KCs细胞中miR-155表达可下调其表面分子MHCⅡ, CD86和CD40的表达, 减弱其抗原呈递功能, 并抑制SOCS1/JAK/STAT炎症通路, 减少KCs分泌促炎细胞因子, 还可抑制T淋巴细胞增殖, 增加T淋巴细胞凋亡, 其机制与KCs上调FasL表达有关; 同时, KCs分泌IFN-γ减少而IL-10表达增加, 局部炎症反应受到抑制, 有利于免疫耐受微环境的诱导形成.
近来有研究[60]显示: 在肝移植后, 及时有效清除凋亡细胞能减少吞噬细胞促炎因子(如TNF-α、IL-1β、IFN-γ等)的释放, 增加其抗炎因子(如IL-10、TGF-β、IDO等)的分泌或诱导初始Th0细胞向Treg分化, 负向调控免疫反应. 但若凋亡细胞清除障碍, 凋亡细胞继发性坏死则可致抗原特异性免疫反应, 大量分泌诸如IFN-γ、IL-2等强效促炎因子, 破坏移植肝脏结构及功能, 诱发排斥反应或破坏已形成的免疫耐受. 我们发现Tim-4(T cell immunoglobulin domain and mucin domain-4)能促进Th2型细胞因子的分泌和凋亡T细胞的吞噬清除, 并使KCs向M2型极化, 具有较高的研究价值, 但其具体分子机制尚在研究之中.
肝移植后IRI及IRR是决定受体生存率及生活质量的核心因素. 两类反应呈序列式及重叠式发展, 是一个复杂的多机制, 多因素协同作用效应, KCs在其中扮演着不可或缺的角色. 在缺血再灌注阶段, 活化的KCs可经过TLR4通路激活NF-κB, 导致大量炎症细胞蓄积同时可诱导Ca2+内流使细胞死亡, 加重损伤, 但KCs也可通过上调HO-1等因子的表达, 清除蓄积的炎症因子. 在AcR期, KCs在不同的因子诱导活化后, 根据不同的极化结果, 既可分泌促炎因子也能分泌抑炎因子, 并诱导初始T细胞向不同的方向分化, 即有促进排斥反应的作用也具有诱导移植肝脏免疫耐受的效能. 但其完整分子机制仍不清楚. 因此, 以KCs细胞为靶细胞, 阐明以及利用其在肝脏移植后病理生理中的双重效用机制具有重要的研究价值及临床意义.
肝移植是目前治疗终末期肝病最有效的手段, 但术后缺血再灌注损伤(ischemia- reperfusion injury, I/RI)及急慢性免疫排斥反应(immune rejection response, IRR)仍是影响预后及生存率的重要因素.目前临床上的对症方案效果不佳. 因此, 探索改善肝脏移植术后I/RI及急慢性IRR的有效方法, 具有重要的临床意义. Kupffer细胞(Kupffer cells, KCs)作为肝内第一防线, 在移植后的病理生理中具有多样性效能, 明确其具体机制具有重要的意义.
孙星, 副教授, 副主任医师, 上海交通大学附属第一人民医院普外科
如何减轻移植术后I/RI及诱导特异性免疫耐受是目前肝移植研究领域的两大难点及热点, 因机体系统极其复杂而精密, 如何调控上述两个病理过程并未清楚阐明. 而对源头初始诱发因素的研究亟待加强.
目前器官移植领域针对I/RI及急性排斥反应的研究主要通过不同的靶细胞/靶点针对终末端效应细胞及细胞因子进行"对症"调控, 虽能一定程度上改善上述两个病理改变的进展, 但最终维持效果均不理想, 因此目前研究趋势倾向于向上游挖掘, 争取从源头解决这些问题.
本文综述以我们课题组多年研究成果为基础, 结合目前最新研究进展进行总结. 我们认为在移植后的病理生理中, 调节KCs极性、调控效应T细胞及其相关细胞因子分泌谱以及增强局部凋亡的炎症细胞吞噬清除三者缺一不可, 而在这其中KCs的状态又居中心位置. 同时协调这三者, 可能诱导移植肝脏在术后处于一个比较理想的状态.
通过明确KCs在肝移植术后的病理生理中的具体分子机制, 以期为临床肝移植提供足量的实验依据, 并提供一个有价值的治疗靶点.
Kupffer细胞(KCs): 是定居于肝脏肝血窦内的非实质性细胞, 是体内最大的巨噬细胞群, 也是体内最大的抗原呈递细胞群. 作为肝内第一防线, 在不同刺激源刺激下, 可活化为M1型及M2型KCs, 在移植后I/RI及IRR扮演着"双刃剑"的角色, 具有很高的科研价值及临床意义.
本文主要探讨KCs与肝移植术后I/RI以及抑制免疫排斥的关系, 从分子水平来探究KCs在肝移植后的作用机制.
编辑:郭鹏 电编:闫晋利
| 1. | Song AT, Avelino-Silva VI, Pecora RA, Pugliese V, D'Albuquerque LA, Abdala E. Liver transplantation: fifty years of experience. World J Gastroenterol. 2014;20:5363-5374. [PubMed] |
| 2. | Liou IW. Management of end-stage liver disease. Med Clin North Am. 2014;98:119-152. [PubMed] |
| 3. | Akamatsu N, Sugawara Y, Kokudo N. Budd-Chiari syndrome and liver transplantation. Intractable Rare Dis Res. 2015;4:24-32. [PubMed] [DOI] |
| 4. | Londoño MC, Abraldes JG, Altamirano J, Deacens T, Forns X. Clinical trial watch: reports from the Liver Meeting (American Association for the Study of Liver Diseases), Boston, November 2014. J Hepatol. 2015; Jan 31. [Epub ahead of print]. [PubMed] [DOI] |
| 5. | Salvadori M, Bertoni E. What's new in clinical solid organ transplantation by 2013. World J Transplant. 2014;4:243-266. [PubMed] [DOI] |
| 6. | Miro JM, Stock P, Teicher E, Duclos-Vallée JC, Terrault N, Rimola A. Outcome and management of HCV/HIV coinfection pre- and post-liver transplantation. A 2015 update. J Hepatol. 2015;62:701-711. [PubMed] [DOI] |
| 7. | Akamatsu N, Sugawara Y, Kokudo N. Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma. World J Hepatol. 2014;6:626-631. [PubMed] [DOI] |
| 8. | Cunningham EC, Sharland AF, Bishop GA. Liver transplant tolerance and its application to the clinic: can we exploit the high dose effect? Clin Dev Immunol. 2013;2013:419692. [PubMed] [DOI] |
| 9. | Akhtar MZ, Henderson T, Sutherland A, Vogel T, Friend PJ. Novel approaches to preventing ischemia-reperfusion injury during liver transplantation. Transplant Proc. 2013;45:2083-2092. [PubMed] [DOI] |
| 10. | Karatzas T, Neri AA, Baibaki ME, Dontas IA. Rodent models of hepatic ischemia-reperfusion injury: time and percentage-related pathophysiological mechanisms. J Surg Res. 2014;191:399-412. [PubMed] [DOI] |
| 11. | Nastos C, Kalimeris K, Papoutsidakis N, Tasoulis MK, Lykoudis PM, Theodoraki K, Nastou D, Smyrniotis V, Arkadopoulos N. Global consequences of liver ischemia/reperfusion injury. Oxid Med Cell Longev. 2014;2014:906965. [PubMed] [DOI] |
| 12. | Chen XB, Xu MQ. Primary graft dysfunction after liver transplantation. Hepatobiliary Pancreat Dis Int. 2014;13:125-137. [PubMed] |
| 13. | Zhai Y, Petrowsky H, Hong JC, Busuttil RW, Kupiec-Weglinski JW. Ischaemia-reperfusion injury in liver transplantation--from bench to bedside. Nat Rev Gastroenterol Hepatol. 2013;10:79-89. [PubMed] [DOI] |
| 14. | Kong X, Sun R, Chen Y, Wei H, Tian Z. γδT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance. J Immunol. 2014;193:1645-1653. [PubMed] [DOI] |
| 15. | Waterfield M, Khan IS, Cortez JT, Fan U, Metzger T, Greer A, Fasano K, Martinez-Llordella M, Pollack JL, Erle DJ. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat Immunol. 2014;15:258-265. [PubMed] [DOI] |
| 16. | Sood S, Testro AG. Immune monitoring post liver transplant. World J Transplant. 2014;4:30-39. [PubMed] [DOI] |
| 17. | Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am J Transplant. 2011;11:1563-1569. [PubMed] [DOI] |
| 18. | Lentsch AB. Regulatory mechanisms of injury and repair after hepatic ischemia/reperfusion. Scientifica (Cairo). 2012;2012:513192. [PubMed] [DOI] |
| 19. | Macedo FI, Miranda LE. Role of ischemic preconditioning in liver transplant: a review of literature. Exp Clin Transplant. 2010;8:1-3. [PubMed] |
| 20. | Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. Kupffer cells in the liver. Compr Physiol. 2013;3:785-797. [PubMed] [DOI] |
| 21. | Huang HF, Zeng Z, Chen MQ. Roles of Kupffer cells in liver transplantation. Hepatogastroenterology. 2012;59:1251-1257. [PubMed] [DOI] |
| 22. | Tamura T, Kondo T, Pak S, Nakano Y, Murata S, Fukunaga K, Ohkohchi N. Interaction between Kupffer cells and platelets in the early period of hepatic ischemia-reperfusion injury--an in vivo study. J Surg Res. 2012;178:443-451. [PubMed] [DOI] |
| 23. | Halldorson JB, Bakthavatsalam R, Montenovo M, Dick A, Rayhill S, Perkins J, Reyes J. Differential rates of ischemic cholangiopathy and graft survival associated with induction therapy in DCD liver transplantation. Am J Transplant. 2015;15:251-258. [PubMed] [DOI] |
| 24. | Jia JJ, Li JH, Jiang L, Lin BY, Wang L, Su R, Zhou L, Zheng SS. Liver protection strategies in liver transplantation. Hepatobiliary Pancreat Dis Int. 2015;14:34-42. [PubMed] |
| 25. | Quesnelle KM, Bystrom PV, Toledo-Pereyra LH. Molecular responses to ischemia and reperfusion in the liver. Arch Toxicol. 2015; Jan 8. [Epub ahead of print]. [PubMed] |
| 26. | Ali JM, Davies SE, Brais RJ, Randle LV, Klinck JR, Allison ME, Chen Y, Pasea L, Harper SF, Pettigrew GJ. Analysis of ischaemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes. Liver Transpl. 2014; Dec 26. [Epub ahead of print]. [PubMed] [DOI] |
| 27. | Katsargyris A, Klonaris C, Alexandrou A, Giakoustidis AE, Vasileiou I, Theocharis S. Toll-like receptors in liver ischemia reperfusion injury: a novel target for therapeutic modulation? Expert Opin Ther Targets. 2009;13:427-442. [PubMed] [DOI] |
| 28. | Howell J, Gow P, Angus P, Visvanathan K. Role of toll-like receptors in liver transplantation. Liver Transpl. 2014;20:270-280. [PubMed] [DOI] |
| 29. | Peng Y, Liu ZJ, Gong JP, Liu HZ, Gan L, Li SB. [Expression of CD14 and Toll-like receptor 4 on Kupffer cells and its role in ischemia-reperfusion injury on rat liver graft]. Zhonghua Wai Ke Za Zhi. 2005;43:274-276. [PubMed] |
| 30. | Li JD, Peng Y, Peng XY, Li QL, Li Q. Suppression of nuclear factor-kappaB activity in Kupffer cells protects rat liver graft from ischemia-reperfusion injury. Transplant Proc. 2010;42:1582-1586. [PubMed] [DOI] |
| 31. | Cheng MX, Chen ZZ, Cai YL, Liu CA, Tu B. Astragaloside IV protects against ischemia reperfusion in a murine model of orthotopic liver transplantation. Transplant Proc. 2011;43:1456-1461. [PubMed] [DOI] |
| 32. | Taki-Eldin A, Zhou L, Xie HY, Zheng SS. Liver regeneration after liver transplantation. Eur Surg Res. 2012;48:139-153. [PubMed] [DOI] |
| 33. | Luan X, Liu Y, Li M. The role of CD14 and Toll-like receptor 4 of Kupffer cells in hepatic ischemia-reperfusion injury in rats. Transplant Proc. 2012;44:937-941. [PubMed] [DOI] |
| 34. | Li J, Lai X, Chen Y, Niu B, Gong J. Endotoxin tolerance attenuates liver ischemia/reperfusion injury by down-regulation of interleukin-1 receptor-associated kinase 4 in kupffer cells. Transplant Proc. 2011;43:2531-2535. [PubMed] [DOI] |
| 35. | Langdale LA, Hoagland V, Benz W, Riehle KJ, Campbell JS, Liggitt DH, Fausto N. Suppressor of cytokine signaling expression with increasing severity of murine hepatic ischemia-reperfusion injury. J Hepatol. 2008;49:198-206. [PubMed] [DOI] |
| 36. | Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89:1269-1339. [PubMed] [DOI] |
| 37. | Sun K, Chen Y, Liang SY, Liu ZJ, Liao WY, Ou ZB, Tu B, Gong JP. Effect of taurine on IRAK4 and NF-kappa B in Kupffer cells from rat liver grafts after ischemia-reperfusion injury. Am J Surg. 2012;204:389-395. [PubMed] [DOI] |
| 38. | Yamashina S, Ikejima K, Enomoto N, Takei Y, Sato N. Glycine as a therapeutic immuno-nutrient for alcoholic liver disease. Alcohol Clin Exp Res. 2005;29:162S-165S. [PubMed] |
| 39. | Liu ZJ, Yan LN, Li SW, You HB, Gong JP. Glycine blunts transplantative liver ischemia-reperfusion injury by downregulating interleukin 1 receptor associated kinase-4. Acta Pharmacol Sin. 2006;27:1479-1486. [PubMed] |
| 40. | Cheng MX, Gong JP, Chen Y, Liu ZJ, Tu B, Liu CA. NBD peptides protect against ischemia reperfusion after orthotopic liver transplantation in rats. J Surg Res. 2012;176:666-671. [PubMed] [DOI] |
| 41. | Bhogal RH, Sutaria R, Afford SC. Hepatic liver ischemia/reperfusion injury: processes in inflammatory networks--a review. Liver Transpl. 2011;17:95; author reply 96. [PubMed] [DOI] |
| 42. | Ruan Z, Shibamoto T, Shimo T, Koizumi T, Tsuchida H, Kurata Y, Ogura T, Kubo K. Effects of platelet-activating factor and thromboxane A2 on isolated perfused guinea pig liver. Prostaglandins Other Lipid Mediat. 2004;73:73-85. [PubMed] |
| 43. | Karidis NP, Kouraklis G, Theocharis SE. Platelet-activating factor in liver injury: a relational scope. World J Gastroenterol. 2006;12:3695-3706. [PubMed] |
| 44. | Tsuchihashi S, Fondevila C, Kupiec-Weglinski JW. Heme oxygenase system in ischemia and reperfusion injury. Ann Transplant. 2004;9:84-87. [PubMed] |
| 45. | Knechtle SJ, Kwun J. Unique aspects of rejection and tolerance in liver transplantation. Semin Liver Dis. 2009;29:91-101. [PubMed] [DOI] |
| 46. | Carambia A, Herkel J. CD4 T cells in hepatic immune tolerance. J Autoimmun. 2010;34:23-28. [PubMed] [DOI] |
| 47. | Chen Y, Chen J, Liu Z, Liang S, Luan X, Long F, Peng Y, Yan L, Gong J. Relationship between TH1/TH2 cytokines and immune tolerance in liver transplantation in rats. Transplant Proc. 2008;40:2691-2695. [PubMed] [DOI] |
| 48. | Li J, Lai X, Liao W, He Y, Liu Y, Gong J. The dynamic changes of Th17/Treg cytokines in rat liver transplant rejection and tolerance. Int Immunopharmacol. 2011;11:962-967. [PubMed] [DOI] |
| 49. | Chen Y, Liu Z, Liang S, Luan X, Long F, Chen J, Peng Y, Yan L, Gong J. Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats. Liver Transpl. 2008;14:823-836. [PubMed] [DOI] |
| 50. | Miyagawa-Hayashino A, Tsuruyama T, Egawa H, Haga H, Sakashita H, Okuno T, Toyokuni S, Tamaki K, Yamabe H, Manabe T. 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. Am J Pathol. 2007;171:1499-1508. [PubMed] |
| 51. | Chen Y, Yan T, Shi LJ, Liu Z, Liang SY, Luan XF, Long FW, Chen J, Peng Y, Yan LN. Knockdown of interleukin-2 by shRNA-mediated RNA interference prolongs liver allograft survival. J Surg Res. 2010;159:582-587. [PubMed] [DOI] |
| 52. | Chen Y, Liu H, Liu Z, Liang S, Chen J, Long F, Peng Y, Yan L, Gong J. Blockade of inducible costimulator pathway to prevent acute rejection in rat liver transplantation. Am J Surg. 2009;198:244-249. [PubMed] [DOI] |
| 53. | Liang S, Chen Y, Long F, Li J, Cheng M, Shi Y, Gong J. Correlation between augmenter of liver regeneration and IFN-γ expression in graft after rat orthotopic liver transplantation. J Surg Res. 2012;178:968-973. [PubMed] [DOI] |
| 54. | Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology. 2014;59:2034-2042. [PubMed] [DOI] |
| 55. | Ivashkiv LB. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 2013;34:216-223. [PubMed] [DOI] |
| 56. | Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750-761. [PubMed] [DOI] |
| 57. | Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593-604. [PubMed] [DOI] |
| 58. | Lian ZR, Xu YF, Wang XB, Gong JP, Liu ZJ. Suppression of histone deacetylase 11 promotes expression of IL-10 in Kupffer cells and induces tolerance following orthotopic liver transplantation in rats. J Surg Res. 2012;174:359-368. [PubMed] [DOI] |
| 59. | Li J, Gong J, Li P, Li M, Liu Y, Liang S, Gong J. Knockdown of microRNA-155 in Kupffer cells results in immunosuppressive effects and prolongs survival of mouse liver allografts. Transplantation. 2014;97:626-635. [PubMed] [DOI] |
| 60. | Kuchroo VK, Dardalhon V, Xiao S, Anderson AC. New roles for TIM family members in immune regulation. Nat Rev Immunol. 2008;8:577-580. [PubMed] [DOI] |