诱导受体产生一氧化碳减轻小鼠移植心缺血再灌注损伤和排斥反应的机制研究
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摘要
第一部分
应用Tail-cuff技术改良小鼠颈部异位心脏移植模型
目的小鼠颈部心脏移植模型是研究移植缺血再灌注损伤和排斥反应的理想模型,由于显微血管吻合的技术问题,限制了其在医学研究中的广泛应用。在本实验室既往应用套管法(cuff technique)建立该模型的基础上,本研究应用Tail-cuff技术(带尾套管法)改良小鼠颈部异位心脏移植模型。方法昆明小鼠用作预实验,C57BL/6和BALB/c小鼠用作正式试验。应用24G和22G静脉内导管制作成带有尾巴的动脉或静脉套管(Tail-cuff),在准备受体血管时,Tail-cuff通过右颈外静脉或右颈总动脉近心端后,用显微血管夹一起固定其近心端和Tail-cuff管的尾巴,翻转血管并固定后分别与供心的肺动脉主干和升主动脉连接固定。
结果应用这种改良技术,预实验手术成功率为72.2%(13/18),总操作时间为56.2±8.9min。正式实验总操作时间为49.6±7.4 min,血管翻转和与供心连接时间分别为3.6±1.4min和4.1±1.1 min,正式实验(12例同系移植,24例同种移植)的成功率为100%(36/36)。
结论应用Tail-cuff技术建立小鼠颈部异位心脏移植模型显示出一定的优越性,是一种理想的方法。
第二部分
诱导受体产生一氧化碳减轻小鼠移植心的冷缺血再灌注损伤
目的一氧化碳(carbon monoxide, CO)是血红素加氧酶催化亚铁血红素生成的代谢产物之一,对大鼠肝、肺、肾和小肠的缺血再灌注损伤(ischemia/reperfusion injury, IRI)具有明显的保护作用。本研究在小鼠心脏移植模型的基础上,观察以二氯甲烷(methylene chloride, MC)诱导受体小鼠产生CO对移植心冷IRI的影响,并探讨其可能的机制。
方法以Balb/c小鼠作为供、受者,建立颈部异位心脏移植模型。实验共分为4组,分别为MC100mg组(n=10)、MC500mg组(n=12)、橄榄油组(IR组,n=10)和正常对照组(N,n=5)。前3组在麻醉前3 h分别用经橄榄油稀释的MC100mg/kg、MC500mg/kg以及单纯橄榄油0.15ml(IR组)对受者进行灌胃处理,然后行颈部异位心脏移植；N组小鼠仅作麻醉处理,不进行心脏移植。分别于灌胃后0、1、3、6、12和24 h剪尾采血,测定血液中CO的含量[用碳氧血红蛋白(COHb)占总血红蛋白的百分比表示],并于相应时间点取心肌组织,检测心肌组织中CO的含量；各组移植后3h和24 h分别处死半数受者,检测移植后3h和24 h血清中肌钙蛋白I(cTnI)、心肌组织中肿瘤坏死因子α(TNF-α)、白细胞介素10(IL-10)、细胞凋亡与相关基因Bcl-2和Bax mRNA以及核因子κB(NF-κB)的表达,并观察移植心心肌的超微结构。
结果与橄榄油灌胃比较,以MC100 mg和MC500 mg灌胃受者血液中COHb浓度与心肌组织中CO含量明显升高,均在灌胃后3 h达到峰值(P<0.01)。与IR组比较,MC100 mg和MC500 mg组受者心脏移植后3h和24 h,能显著降低血清中cTnI水平(P<0.01),并以MC500 mg组降低最为明显;可明显下调促炎症基因TNF-a mRNA水平(P<0.01),而抗炎症基因IL-10 mRNA上调不明显(P>0.05),同时可以显著上调抗凋亡基因Bcl-2 mRNA水平(P<0.01),并抑制促凋亡基因Bax mRNA的转录(P<0.01)；心肌超微结构损伤明显减轻,以MC500mg组最为显著。正常对照组可见少量NF-κB表达,而IR组、MC100mg组和MC500 mg组NF-κB活性均显著增强(P<0.01),但后三组之间在相同时间点的NF-κB活性无明显区别(P>0.05)。
结论诱导受体小鼠产生CO明显减轻小鼠移植心冷IRI,其主要机理与CO的抗炎和抗凋亡作用有关,且不受NF-κB信号转导通路的调节。第三部分
诱导受体产生一氧化碳经PI3K/Akt信号途径抑制冷缺血再灌注诱导的移植心细胞凋亡
目的CO是体内的一种重要信号分子。外源性低浓度的CO具有缓解血管损伤、排斥反应和急性肺损伤等功能,但涉及到的信号机理尚未完全阐明。本研究在小鼠心脏移植的基础上,观察诱导受体产生CO对移植心冷IRI中细胞凋亡的影响,并探讨其可能的信号机制。
方法以Balb/c小鼠建立同系移植心冷IRI模型。受体用二氯甲烷(MC,500mg/kg体重)灌胃诱导受体小鼠产生CO(MC组,n=12),或用橄榄油灌胃(IR组,n=12),在MC组的基础上受体在移植心恢复血供前1h腹腔注射PI3K抑制剂LY294002(40mg/kg,LY组,n=10)或二甲亚砜(DMSO组,n=10)；检测移植后3h和24h(每一时间点n=5～6／组)移植心细胞凋亡并计算凋亡指数(AI)、磷酸化Akt(p-Akt)蛋白、Bcl-2与Bax蛋白的表达及Caspase-3蛋白酶活性;设立正常对照组(N组,n=5)。
结果受体以MC灌胃后血液中COHb浓度与心肌组织CO含量均在3h达到峰值,分别为(9.82±0.84)%和2.25±0.08 pmol/mg；与IR组比较,MC组明显降低移植心AI[3h:(8.65±2.01)％vs.(19.28±4.94)％,P<0.01；24h:(5.82±2.36)％vs.(10.54±3.66)％,P<0.05].激活Akt蛋白(3h:P<0.01；24h:P<0.05).抑制Caspase-3蛋白酶活性(3h:2.19±0.18 vs.3.31±0.36,P<0.05)、上调Bcl.2/Bax比值(3h：1.97±0.16比0.46±0.07,P<0.01；24h：1.89±0.10比0.51±0.04,P<0.01)；而与MC组比较,LY组明显增加AI[3h:(17.95±4.92)％,P<0.01:24h:(9.75±3.14)%；P<0.01]、抑制Akt蛋白激活(3h：P<0.01；24：P<0.05)、增强Caspase-3蛋白酶活性(3h：3.27±0.24,P<0.05)、下调Bcl.2/Bax比值(3h：0.47±0.06,P<0.01；24h:0.52±0.03,P<0.01),从而逆转其抗凋亡作用；DMSO组与MC组的各个指标无明显统计学意义(P>0.05)。
结论诱导受体产生CO能明显抑制冷缺血再灌注诱导的移植心的细胞凋亡,其机理可能与通过P13K/Akt信号途径对凋亡相关蛋白Caspase-3、Bcl-2和Bax的调节有关。
第四部分
诱导受体产生一氧化碳减轻同种移植心排斥反应不依赖于Foxp3表达的上调
目的CO由于具有强大的干扰体内氧运输的特性而通常被认为是一种有害的废弃物。事实上,低浓度的CO通过调节血管张力、抗炎、抗凋亡等作用缓解移植物缺血再灌注损伤。本研究在小鼠心脏移植的基础上,观察诱导受体小鼠产生CO对同种移植排斥反应和移植心存活时间的影响,并探讨其可能的机制。
方法建立小鼠颈部异位心脏移植模型(C57BL/6→Balb/c小鼠)。受体小鼠自移植前1d至移植后第6d(MC1w组,n=11)或至第13d(MC2w组,n=10)以含二氯甲烷(MC)100mg/kg体重灌胃,或以同体积不含MC的橄榄油灌胃(Tx组,n=6)。观测移植心存活时间,并于移植后6d、10d分别检测受体血清TNF-α、IL-10的含量、心脏移植物和受体脾脏TNF-α、IL-10、Foxp3 mRNA及Foxp3蛋白的表达、心脏移植物ICAM-1(细胞间粘附分子-1)及Caspase-3蛋白的表达；观察移植后6d、10d或移植物心跳停止时移植心胶原纤维增生程度及组织病理学变化。
结果受体以MC灌胃后血液中COHb浓度在3h达到峰值,为(5.24±0.45)%；受体诱导CO可以明显延长移植心存活时间[Tx:(6.33±0.56)d; MC1w: (12.14±0.87)d, P<0.01vs.Tx; MC2w组：(19.38±0.95)d,P<0.01vs.Tx and MC1w];降低血清TNF-a的含量(MC1w组：P<0.01vs.Tx; MC2w组:P<0.01vs.Tx and P<0.05 vs. MC1w);抑制心脏移植物和受体脾脏TNF-αmRNA的表达(MC1w组：P<0.01vs.Tx; MC2w组：P<0.01vs.Tx and MC1w);抑制心脏移植物ICAM-1 (MC1w组及MC2w组：P<0.01vs.Tx)及Caspase-3的表达(MC1w组：P<0.01vs.Tx; MC2w组：P<0.01vs.Tx and MC1w);减轻移植物内胶原纤维增生及淋巴细胞和单核细胞侵润的程度,以MC2w组最为明显；各组血清IL-10含量、心脏移植物和受体脾脏IL-10mRNA、Foxp3 mRNA及Foxp3蛋白的表达无统计学意义(P>0.05)。
结论受体小鼠诱导CO明显减轻同种移植排斥反应并延长移植心的存活时间,其主要机制与可能与CO的抗炎症和抗凋亡功能密切相关,而并不依赖于移植物和受体脾脏内Foxp3表达的上调。
PartⅠ
Improvements of mouse cervical heterotopic heart transplantation model using the tail-cuff technique
Objective The model of mouse cervical heart transplantation is an ideal medical research tool for study of transplant-induced ischemia/reperfusion injury and immunological rejection. However, technical problems have limited the widespread use of mouse cervical vascularized heart transplantation. The aim of this study is to describe an improved method for performing cervical heterotopic heart transplantation by the tail-cuff technique.
Methods The kunming mice were used for preliminary experiment. And for formal experiment, inbred male C57BL/6 mice and Balb/c mice were used for isogeneic transplantation from BALB/c to BALB/c mice and allogeneic transplantation from C57BL/6 to BALB/c mice. The right common carotid artery and the external jugular vein of the recipient were equipped with a tail cuff made from 24G and 22G intravenous catheter, and everted over the cuff, and then connected with the aorta and the pulonary artery of donor heart, respectively.
Results For preliminary experiment, the successful rate was 72.2%(13/18) and the the total surgical procedures took 56.2±8.9min. For formal experiment, the total surgical procedures took 49.6±7.4 min, the average time for evert and reconnection of both vessels was 3.6±1.4min and 4.1±1.1 min, and the successful rate was 100%(36/36).
Conclusions This improved cuff technique shows its superiority, and can serve as an ideal method for the establishment of mouse cervical heterotopic heart transplantation model.
Part II
Induction of carbon monoxide in recipients ameliorates cold ischemia/reperfusion injury in a murine heart transplantation model
Objective Carbon monoxide (CO), a product of heme degradation by heme oxygenase, induces cytoprotection against ischemia/reperfusion (I/R) injury in a variety of organs such as the liver, lung, kidney, and small intestine. The aim of this study is to examine whether induction of carbon monoxide (CO) with methylene chloride (MC) in recipients would protect heart grafts against cold I/R injury associated with transplantation and explore the possible mechanisam in a murine heart transplantation model..
Methods Inbred male Balb/c mice were used as donors and recipients to establish transplant-induced cold I/R injury model with 2 hours cold preservation. Recipients were treated with either methylene chloride (MC) (100mg/kg or 500mg/kg, per os)(Group MC100mg, n=10; Group MC 500mg, n=12) or olive oil(0.15ml, per os, Group IR, n=10) 3h prior to anesthesia. Age-matched normal mice served as controls(Group N, n=5). The serum COHb and the CO content of myocardial tissue were measured at Oh, 1h,3h,6h,12h, 24h after oral MC administration. Half of Recipients mice were killed at 3h and 24h after transplantation for serum or cardiac graft samples(n=5-6 per time point). Recipients mice were killed at 3h and 24h after transplantation for serum or cardiac graft samples. The serum cTnI levels, the mRNA levels of TNF-α、IL-10、Bcl-2、Bax, the protein of NF-κB and the ultrastructure of myocardium were measured, respectively.
Results The serum COHb and tissue CO increased significantly and peaked within 3h in Group MC100mg and Group MC 500mg(P<0.01 vs Olive oil). Compared with Group IR, The serum cTnI levels in Group MC100mg and Group 500mg were significantly decreased(P<0.01), especially in Group 500mg. Induction of CO in recipients in Group MC100mg and Group MC 500mg significantly inhibited the pro-inflammatory gene expression of TNF-a mRNA and the pro-apoptotic gene expression of Bax mRNA(P<0.01), and increased the anti-apoptotic gene expression of Bcl-2 mRNA(P<0.01), but did not increase the anti-inflammatory gene expression of IL-10 mRNA(P>0.05) in cardiac grafts. Compared with Group N, the myocardial NF-κB activation increased significantly in Group Olive, Group MC100mg and Group MC500mg(P<0.01), but did not differ between the later three groups at the same point(P>0.05).The myocardial ultrastructure was also improved significantly in Group MC100mg and Group MC500mg, especially in Group MC500mg.
Conclusions Induction of CO in recipients with MC suppresses pro-inflammatory and pro-apoptotic gene expression and efficiently ameliorates transplant-induced heart cold I/R injury. The possible mechanism does not seem to be associated with down-regulation of the NF-κB signaling pathway.
Part III
Induction of carbon monoxide in recipient mice inhibits cold ischemia/reperfusion-induced apoptosis of cardiac grafts via PI3K/Akt signal pathway
Objective Carbon monoxide (CO) is emerging as an important gaseous molecule. And exogenous low-dose CO protects against vascular injury, transplant rejection and acute lung injury. However, little is known regarding the precise signaling mechanisms of CO. The aim of this study is to observe whether induction of carbon monoxide in recipients could inhibit cold ischemia/reperfusion(I/R)-induced apoptosis of cardiac grafts and to explore the possible anti-apoptotic signaling mechanisms in a murine heart transplantation model.
Methods Inbred Balb/c mice were used as donors and recipients to establish transplant-induced cold I/R injury model. Recipients were treated with either methylene chloride (500mg/kg, per os, Group MC, n=12) or olive oil(Group IR, n=12) 3h prior to anesthesia, or treated with MC plus either LY294002 of PI3K inhibitor (40mg/kg, i.p, Group LY, n=10) or DMSO(Group DMSO, n=10) lh prior to reperfusion of cardiac grafts. Recipients mice were killed at 3h and 24h after transplantation for cardiac graft samples(n=5-6 for each time point). The apoptosis index(AI), the protein of phosphorylated, the activities of Caspase-3, the protein of Bcl-2 and Bax were measured, respectively. Age-matched normal mice served as controls(Group N).
Results Following MC application serum COHb[(9.82±0.84)%]and tissue CO (2.25±0.08 pmol/mg) peaked within 3h in recipients. Compared with Group IR, induction of CO in recipients decreased significantly the level of AI [3h:(8.65±2.01)%vs. (19.28±4.94)%, P<0.01; 24h:(5.82±2.36)%vs.(10.54±3.66)%, P<0.05], increased the Akt phosphorylation (3h:P<0.01; 24h:P<0.05), inhibited the activities of Caspase-3(3h:2.19±0.18 vs.3.31±0.36, P<0.05)and up-regulated the ratios of Bcl-2/Bax(3h:1.97±0.16 vs.0.46±0.07, P<0.01; 24h:1.89±0.10 vs.0.51±0.04, P<0.01) in cardiac grafts. However, compared with Group MC, recipients pretreated with LY294002 could reverse the anti-apoptotic effects of MC by increasing the level of AI[3h:(17.95±4.92)%, P<0.01; 24h:(9.75±3.14)%, P<0.01], inhibiting the Akt phosphorylation(3h:P<0.01; 24:P<0.05), activating Caspase-3(3h:3.27±0.24, P<0.05) and down-regulating the ratio of Bcl-2/Bax (3h:0.47±0.06, P<0.01; 24h:0.52±0.03, P<0.01). And the DMSO had no impact on the anti-apoptotic effects of MC(P>0.05).
Conclusion Induction of carbon monoxide in recipient mice inhibits cold I/R-induced apoptosis of cardiac grafts by regulating caspase-3, Bcl-2 and Bax proteins via the activation of PI3K/Akt signal pathway.
Part IV
Amelioration of cardiac allograft rejection by induction of carbon monoxide with methylene chloride in recipients is independent of up-regulation of Foxp3 expression in mice
Objective Carbon monoxide (CO) is commonly viewed as a poison in high concentrations due to its ability to interfere with oxygen delivery. However, exogenous low-dose carbon monoxide inhibits transplant-induced ischemia/reperfusion injury via its vasodilation, anti-inflammatory and anti-apoptotic effects in various models. The aim of this study is to investigate the protective effects of induction of CO in recipients on amelioration of allograft rejection and prolongation of allograft survival and the possible mechanisms in a mouse heart transplantation model.
Methods Inbred male C57BL/6 mice were used as donors and inbred male Balb/c mice were used as recipients to establish allogenic heart transplantation model. Recipients were treated with either methylene chloride (100mg/kg, per os, Group MC) or olive oil(Group Tx, n=6) day 1 prior to transplantation to day 6 posttransplantation (Group MC1w, n=11) or to day 13 posttransplantation (Group MC2w, n=10). The survival of cardiac grafts was recorded. Recipients mice were killed at day 6 and day 10 or the time of non-heartbeating after transplantation for serum, cardiac graft and spleen samples(n=5-6 for each time point). The serum TNF-a and IL-10, the TNF-a mRNA and IL-10 mRNA, the Foxp3 mRNA and Foxp3 protein in cardiac grafts and spleen were measured, respectively. The intercellular adhesion molecule-1(ICAM-1) and Caspase-3 protein in cardiac grafts, the proliferation of collagen fibers and histopathologic changes of cardiac grafts were also recorded.
Results Following MC application serum COHb peaked within 3h in recipients[(5.24±0.45)%]. Induction of CO in recipients prolonged significantly the cardiac graft survival(median survival time, MST) [Tx:(6.33±0.56)d; MC1w: (12.14±0.87)d, P<0.01vs.Tx; MC2w:(19.38±0.95)d, P<0.01vs.Tx and MC1w], down-regulated the levels of serum TNF-a(MC1w:P<0.01vs.Tx; MC2w: P<0.01vs.Tx and P<0.05 vs. MC1w)and TNF-a mRNA (MC1w:P<0.01vs.Tx; MC2w: P<0.01vs.Tx and MC1w)of cardiac grafts and spleen in recipient mice, inhibited the protein expression of ICAM-1(MC1w and MC2w: P<0.01vs.Tx) and Caspase-3(MC1w:P<0.01vs.Tx; MC2w:P<0.01vs.Tx and MC1w) of cardiac grafts, and inhibited, especially in Group MC2w, the proliferation of collagen fibers and lymphocyte and monocyte infiltration in cardiac grafts. The levels of serum IL-10, the IL-10 mRNA, the Foxp3 mRNA and the Foxp3 protein in cardiac grafts and spleen of recipients did not differ between the groups(P>0.05).
Conclusions Induction of carbon monoxide in recipients could relieve cardiac allograft rejection and prolong cardiac allograft survival via its anti-inflammation and anti-apoptotic effects, not via up-regulation of Foxp3 mRNA and Foxp3 protein in cardiac grafts and spleen in recipient mice.
应用Tail-cuff技术改良小鼠颈部异位心脏移植模型
目的小鼠颈部心脏移植模型是研究移植缺血再灌注损伤和排斥反应的理想模型,由于显微血管吻合的技术问题,限制了其在医学研究中的广泛应用。在本实验室既往应用套管法(cuff technique)建立该模型的基础上,本研究应用Tail-cuff技术(带尾套管法)改良小鼠颈部异位心脏移植模型。方法昆明小鼠用作预实验,C57BL/6和BALB/c小鼠用作正式试验。应用24G和22G静脉内导管制作成带有尾巴的动脉或静脉套管(Tail-cuff),在准备受体血管时,Tail-cuff通过右颈外静脉或右颈总动脉近心端后,用显微血管夹一起固定其近心端和Tail-cuff管的尾巴,翻转血管并固定后分别与供心的肺动脉主干和升主动脉连接固定。
结果应用这种改良技术,预实验手术成功率为72.2%(13/18),总操作时间为56.2±8.9min。正式实验总操作时间为49.6±7.4 min,血管翻转和与供心连接时间分别为3.6±1.4min和4.1±1.1 min,正式实验(12例同系移植,24例同种移植)的成功率为100%(36/36)。
结论应用Tail-cuff技术建立小鼠颈部异位心脏移植模型显示出一定的优越性,是一种理想的方法。
第二部分
诱导受体产生一氧化碳减轻小鼠移植心的冷缺血再灌注损伤
目的一氧化碳(carbon monoxide, CO)是血红素加氧酶催化亚铁血红素生成的代谢产物之一,对大鼠肝、肺、肾和小肠的缺血再灌注损伤(ischemia/reperfusion injury, IRI)具有明显的保护作用。本研究在小鼠心脏移植模型的基础上,观察以二氯甲烷(methylene chloride, MC)诱导受体小鼠产生CO对移植心冷IRI的影响,并探讨其可能的机制。
方法以Balb/c小鼠作为供、受者,建立颈部异位心脏移植模型。实验共分为4组,分别为MC100mg组(n=10)、MC500mg组(n=12)、橄榄油组(IR组,n=10)和正常对照组(N,n=5)。前3组在麻醉前3 h分别用经橄榄油稀释的MC100mg/kg、MC500mg/kg以及单纯橄榄油0.15ml(IR组)对受者进行灌胃处理,然后行颈部异位心脏移植；N组小鼠仅作麻醉处理,不进行心脏移植。分别于灌胃后0、1、3、6、12和24 h剪尾采血,测定血液中CO的含量[用碳氧血红蛋白(COHb)占总血红蛋白的百分比表示],并于相应时间点取心肌组织,检测心肌组织中CO的含量；各组移植后3h和24 h分别处死半数受者,检测移植后3h和24 h血清中肌钙蛋白I(cTnI)、心肌组织中肿瘤坏死因子α(TNF-α)、白细胞介素10(IL-10)、细胞凋亡与相关基因Bcl-2和Bax mRNA以及核因子κB(NF-κB)的表达,并观察移植心心肌的超微结构。
结果与橄榄油灌胃比较,以MC100 mg和MC500 mg灌胃受者血液中COHb浓度与心肌组织中CO含量明显升高,均在灌胃后3 h达到峰值(P<0.01)。与IR组比较,MC100 mg和MC500 mg组受者心脏移植后3h和24 h,能显著降低血清中cTnI水平(P<0.01),并以MC500 mg组降低最为明显;可明显下调促炎症基因TNF-a mRNA水平(P<0.01),而抗炎症基因IL-10 mRNA上调不明显(P>0.05),同时可以显著上调抗凋亡基因Bcl-2 mRNA水平(P<0.01),并抑制促凋亡基因Bax mRNA的转录(P<0.01)；心肌超微结构损伤明显减轻,以MC500mg组最为显著。正常对照组可见少量NF-κB表达,而IR组、MC100mg组和MC500 mg组NF-κB活性均显著增强(P<0.01),但后三组之间在相同时间点的NF-κB活性无明显区别(P>0.05)。
结论诱导受体小鼠产生CO明显减轻小鼠移植心冷IRI,其主要机理与CO的抗炎和抗凋亡作用有关,且不受NF-κB信号转导通路的调节。第三部分
诱导受体产生一氧化碳经PI3K/Akt信号途径抑制冷缺血再灌注诱导的移植心细胞凋亡
目的CO是体内的一种重要信号分子。外源性低浓度的CO具有缓解血管损伤、排斥反应和急性肺损伤等功能,但涉及到的信号机理尚未完全阐明。本研究在小鼠心脏移植的基础上,观察诱导受体产生CO对移植心冷IRI中细胞凋亡的影响,并探讨其可能的信号机制。
方法以Balb/c小鼠建立同系移植心冷IRI模型。受体用二氯甲烷(MC,500mg/kg体重)灌胃诱导受体小鼠产生CO(MC组,n=12),或用橄榄油灌胃(IR组,n=12),在MC组的基础上受体在移植心恢复血供前1h腹腔注射PI3K抑制剂LY294002(40mg/kg,LY组,n=10)或二甲亚砜(DMSO组,n=10)；检测移植后3h和24h(每一时间点n=5～6／组)移植心细胞凋亡并计算凋亡指数(AI)、磷酸化Akt(p-Akt)蛋白、Bcl-2与Bax蛋白的表达及Caspase-3蛋白酶活性;设立正常对照组(N组,n=5)。
结果受体以MC灌胃后血液中COHb浓度与心肌组织CO含量均在3h达到峰值,分别为(9.82±0.84)%和2.25±0.08 pmol/mg；与IR组比较,MC组明显降低移植心AI[3h:(8.65±2.01)％vs.(19.28±4.94)％,P<0.01；24h:(5.82±2.36)％vs.(10.54±3.66)％,P<0.05].激活Akt蛋白(3h:P<0.01；24h:P<0.05).抑制Caspase-3蛋白酶活性(3h:2.19±0.18 vs.3.31±0.36,P<0.05)、上调Bcl.2/Bax比值(3h：1.97±0.16比0.46±0.07,P<0.01；24h：1.89±0.10比0.51±0.04,P<0.01)；而与MC组比较,LY组明显增加AI[3h:(17.95±4.92)％,P<0.01:24h:(9.75±3.14)%；P<0.01]、抑制Akt蛋白激活(3h：P<0.01；24：P<0.05)、增强Caspase-3蛋白酶活性(3h：3.27±0.24,P<0.05)、下调Bcl.2/Bax比值(3h：0.47±0.06,P<0.01；24h:0.52±0.03,P<0.01),从而逆转其抗凋亡作用；DMSO组与MC组的各个指标无明显统计学意义(P>0.05)。
结论诱导受体产生CO能明显抑制冷缺血再灌注诱导的移植心的细胞凋亡,其机理可能与通过P13K/Akt信号途径对凋亡相关蛋白Caspase-3、Bcl-2和Bax的调节有关。
第四部分
诱导受体产生一氧化碳减轻同种移植心排斥反应不依赖于Foxp3表达的上调
目的CO由于具有强大的干扰体内氧运输的特性而通常被认为是一种有害的废弃物。事实上,低浓度的CO通过调节血管张力、抗炎、抗凋亡等作用缓解移植物缺血再灌注损伤。本研究在小鼠心脏移植的基础上,观察诱导受体小鼠产生CO对同种移植排斥反应和移植心存活时间的影响,并探讨其可能的机制。
方法建立小鼠颈部异位心脏移植模型(C57BL/6→Balb/c小鼠)。受体小鼠自移植前1d至移植后第6d(MC1w组,n=11)或至第13d(MC2w组,n=10)以含二氯甲烷(MC)100mg/kg体重灌胃,或以同体积不含MC的橄榄油灌胃(Tx组,n=6)。观测移植心存活时间,并于移植后6d、10d分别检测受体血清TNF-α、IL-10的含量、心脏移植物和受体脾脏TNF-α、IL-10、Foxp3 mRNA及Foxp3蛋白的表达、心脏移植物ICAM-1(细胞间粘附分子-1)及Caspase-3蛋白的表达；观察移植后6d、10d或移植物心跳停止时移植心胶原纤维增生程度及组织病理学变化。
结果受体以MC灌胃后血液中COHb浓度在3h达到峰值,为(5.24±0.45)%；受体诱导CO可以明显延长移植心存活时间[Tx:(6.33±0.56)d; MC1w: (12.14±0.87)d, P<0.01vs.Tx; MC2w组：(19.38±0.95)d,P<0.01vs.Tx and MC1w];降低血清TNF-a的含量(MC1w组：P<0.01vs.Tx; MC2w组:P<0.01vs.Tx and P<0.05 vs. MC1w);抑制心脏移植物和受体脾脏TNF-αmRNA的表达(MC1w组：P<0.01vs.Tx; MC2w组：P<0.01vs.Tx and MC1w);抑制心脏移植物ICAM-1 (MC1w组及MC2w组：P<0.01vs.Tx)及Caspase-3的表达(MC1w组：P<0.01vs.Tx; MC2w组：P<0.01vs.Tx and MC1w);减轻移植物内胶原纤维增生及淋巴细胞和单核细胞侵润的程度,以MC2w组最为明显；各组血清IL-10含量、心脏移植物和受体脾脏IL-10mRNA、Foxp3 mRNA及Foxp3蛋白的表达无统计学意义(P>0.05)。
结论受体小鼠诱导CO明显减轻同种移植排斥反应并延长移植心的存活时间,其主要机制与可能与CO的抗炎症和抗凋亡功能密切相关,而并不依赖于移植物和受体脾脏内Foxp3表达的上调。
PartⅠ
Improvements of mouse cervical heterotopic heart transplantation model using the tail-cuff technique
Objective The model of mouse cervical heart transplantation is an ideal medical research tool for study of transplant-induced ischemia/reperfusion injury and immunological rejection. However, technical problems have limited the widespread use of mouse cervical vascularized heart transplantation. The aim of this study is to describe an improved method for performing cervical heterotopic heart transplantation by the tail-cuff technique.
Methods The kunming mice were used for preliminary experiment. And for formal experiment, inbred male C57BL/6 mice and Balb/c mice were used for isogeneic transplantation from BALB/c to BALB/c mice and allogeneic transplantation from C57BL/6 to BALB/c mice. The right common carotid artery and the external jugular vein of the recipient were equipped with a tail cuff made from 24G and 22G intravenous catheter, and everted over the cuff, and then connected with the aorta and the pulonary artery of donor heart, respectively.
Results For preliminary experiment, the successful rate was 72.2%(13/18) and the the total surgical procedures took 56.2±8.9min. For formal experiment, the total surgical procedures took 49.6±7.4 min, the average time for evert and reconnection of both vessels was 3.6±1.4min and 4.1±1.1 min, and the successful rate was 100%(36/36).
Conclusions This improved cuff technique shows its superiority, and can serve as an ideal method for the establishment of mouse cervical heterotopic heart transplantation model.
Part II
Induction of carbon monoxide in recipients ameliorates cold ischemia/reperfusion injury in a murine heart transplantation model
Objective Carbon monoxide (CO), a product of heme degradation by heme oxygenase, induces cytoprotection against ischemia/reperfusion (I/R) injury in a variety of organs such as the liver, lung, kidney, and small intestine. The aim of this study is to examine whether induction of carbon monoxide (CO) with methylene chloride (MC) in recipients would protect heart grafts against cold I/R injury associated with transplantation and explore the possible mechanisam in a murine heart transplantation model..
Methods Inbred male Balb/c mice were used as donors and recipients to establish transplant-induced cold I/R injury model with 2 hours cold preservation. Recipients were treated with either methylene chloride (MC) (100mg/kg or 500mg/kg, per os)(Group MC100mg, n=10; Group MC 500mg, n=12) or olive oil(0.15ml, per os, Group IR, n=10) 3h prior to anesthesia. Age-matched normal mice served as controls(Group N, n=5). The serum COHb and the CO content of myocardial tissue were measured at Oh, 1h,3h,6h,12h, 24h after oral MC administration. Half of Recipients mice were killed at 3h and 24h after transplantation for serum or cardiac graft samples(n=5-6 per time point). Recipients mice were killed at 3h and 24h after transplantation for serum or cardiac graft samples. The serum cTnI levels, the mRNA levels of TNF-α、IL-10、Bcl-2、Bax, the protein of NF-κB and the ultrastructure of myocardium were measured, respectively.
Results The serum COHb and tissue CO increased significantly and peaked within 3h in Group MC100mg and Group MC 500mg(P<0.01 vs Olive oil). Compared with Group IR, The serum cTnI levels in Group MC100mg and Group 500mg were significantly decreased(P<0.01), especially in Group 500mg. Induction of CO in recipients in Group MC100mg and Group MC 500mg significantly inhibited the pro-inflammatory gene expression of TNF-a mRNA and the pro-apoptotic gene expression of Bax mRNA(P<0.01), and increased the anti-apoptotic gene expression of Bcl-2 mRNA(P<0.01), but did not increase the anti-inflammatory gene expression of IL-10 mRNA(P>0.05) in cardiac grafts. Compared with Group N, the myocardial NF-κB activation increased significantly in Group Olive, Group MC100mg and Group MC500mg(P<0.01), but did not differ between the later three groups at the same point(P>0.05).The myocardial ultrastructure was also improved significantly in Group MC100mg and Group MC500mg, especially in Group MC500mg.
Conclusions Induction of CO in recipients with MC suppresses pro-inflammatory and pro-apoptotic gene expression and efficiently ameliorates transplant-induced heart cold I/R injury. The possible mechanism does not seem to be associated with down-regulation of the NF-κB signaling pathway.
Part III
Induction of carbon monoxide in recipient mice inhibits cold ischemia/reperfusion-induced apoptosis of cardiac grafts via PI3K/Akt signal pathway
Objective Carbon monoxide (CO) is emerging as an important gaseous molecule. And exogenous low-dose CO protects against vascular injury, transplant rejection and acute lung injury. However, little is known regarding the precise signaling mechanisms of CO. The aim of this study is to observe whether induction of carbon monoxide in recipients could inhibit cold ischemia/reperfusion(I/R)-induced apoptosis of cardiac grafts and to explore the possible anti-apoptotic signaling mechanisms in a murine heart transplantation model.
Methods Inbred Balb/c mice were used as donors and recipients to establish transplant-induced cold I/R injury model. Recipients were treated with either methylene chloride (500mg/kg, per os, Group MC, n=12) or olive oil(Group IR, n=12) 3h prior to anesthesia, or treated with MC plus either LY294002 of PI3K inhibitor (40mg/kg, i.p, Group LY, n=10) or DMSO(Group DMSO, n=10) lh prior to reperfusion of cardiac grafts. Recipients mice were killed at 3h and 24h after transplantation for cardiac graft samples(n=5-6 for each time point). The apoptosis index(AI), the protein of phosphorylated, the activities of Caspase-3, the protein of Bcl-2 and Bax were measured, respectively. Age-matched normal mice served as controls(Group N).
Results Following MC application serum COHb[(9.82±0.84)%]and tissue CO (2.25±0.08 pmol/mg) peaked within 3h in recipients. Compared with Group IR, induction of CO in recipients decreased significantly the level of AI [3h:(8.65±2.01)%vs. (19.28±4.94)%, P<0.01; 24h:(5.82±2.36)%vs.(10.54±3.66)%, P<0.05], increased the Akt phosphorylation (3h:P<0.01; 24h:P<0.05), inhibited the activities of Caspase-3(3h:2.19±0.18 vs.3.31±0.36, P<0.05)and up-regulated the ratios of Bcl-2/Bax(3h:1.97±0.16 vs.0.46±0.07, P<0.01; 24h:1.89±0.10 vs.0.51±0.04, P<0.01) in cardiac grafts. However, compared with Group MC, recipients pretreated with LY294002 could reverse the anti-apoptotic effects of MC by increasing the level of AI[3h:(17.95±4.92)%, P<0.01; 24h:(9.75±3.14)%, P<0.01], inhibiting the Akt phosphorylation(3h:P<0.01; 24:P<0.05), activating Caspase-3(3h:3.27±0.24, P<0.05) and down-regulating the ratio of Bcl-2/Bax (3h:0.47±0.06, P<0.01; 24h:0.52±0.03, P<0.01). And the DMSO had no impact on the anti-apoptotic effects of MC(P>0.05).
Conclusion Induction of carbon monoxide in recipient mice inhibits cold I/R-induced apoptosis of cardiac grafts by regulating caspase-3, Bcl-2 and Bax proteins via the activation of PI3K/Akt signal pathway.
Part IV
Amelioration of cardiac allograft rejection by induction of carbon monoxide with methylene chloride in recipients is independent of up-regulation of Foxp3 expression in mice
Objective Carbon monoxide (CO) is commonly viewed as a poison in high concentrations due to its ability to interfere with oxygen delivery. However, exogenous low-dose carbon monoxide inhibits transplant-induced ischemia/reperfusion injury via its vasodilation, anti-inflammatory and anti-apoptotic effects in various models. The aim of this study is to investigate the protective effects of induction of CO in recipients on amelioration of allograft rejection and prolongation of allograft survival and the possible mechanisms in a mouse heart transplantation model.
Methods Inbred male C57BL/6 mice were used as donors and inbred male Balb/c mice were used as recipients to establish allogenic heart transplantation model. Recipients were treated with either methylene chloride (100mg/kg, per os, Group MC) or olive oil(Group Tx, n=6) day 1 prior to transplantation to day 6 posttransplantation (Group MC1w, n=11) or to day 13 posttransplantation (Group MC2w, n=10). The survival of cardiac grafts was recorded. Recipients mice were killed at day 6 and day 10 or the time of non-heartbeating after transplantation for serum, cardiac graft and spleen samples(n=5-6 for each time point). The serum TNF-a and IL-10, the TNF-a mRNA and IL-10 mRNA, the Foxp3 mRNA and Foxp3 protein in cardiac grafts and spleen were measured, respectively. The intercellular adhesion molecule-1(ICAM-1) and Caspase-3 protein in cardiac grafts, the proliferation of collagen fibers and histopathologic changes of cardiac grafts were also recorded.
Results Following MC application serum COHb peaked within 3h in recipients[(5.24±0.45)%]. Induction of CO in recipients prolonged significantly the cardiac graft survival(median survival time, MST) [Tx:(6.33±0.56)d; MC1w: (12.14±0.87)d, P<0.01vs.Tx; MC2w:(19.38±0.95)d, P<0.01vs.Tx and MC1w], down-regulated the levels of serum TNF-a(MC1w:P<0.01vs.Tx; MC2w: P<0.01vs.Tx and P<0.05 vs. MC1w)and TNF-a mRNA (MC1w:P<0.01vs.Tx; MC2w: P<0.01vs.Tx and MC1w)of cardiac grafts and spleen in recipient mice, inhibited the protein expression of ICAM-1(MC1w and MC2w: P<0.01vs.Tx) and Caspase-3(MC1w:P<0.01vs.Tx; MC2w:P<0.01vs.Tx and MC1w) of cardiac grafts, and inhibited, especially in Group MC2w, the proliferation of collagen fibers and lymphocyte and monocyte infiltration in cardiac grafts. The levels of serum IL-10, the IL-10 mRNA, the Foxp3 mRNA and the Foxp3 protein in cardiac grafts and spleen of recipients did not differ between the groups(P>0.05).
Conclusions Induction of carbon monoxide in recipients could relieve cardiac allograft rejection and prolong cardiac allograft survival via its anti-inflammation and anti-apoptotic effects, not via up-regulation of Foxp3 mRNA and Foxp3 protein in cardiac grafts and spleen in recipient mice.
引文
1. Schmauss D, Weis M. Cardiac allograft vasculopathy:recent developments. Circulation,2008,117(16):2131-2141.
2. Vassalli G, Gallino A, Weis M, et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J,2003,24(13):1180-1188.
3. Land WG. The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation, 2005,79(5):505-514.
4. Andrade CF, Waddell TK, Keshavjee S,et al. Innate immunity and organ transplantation:the potential role of toll-like receptors. Am J Transplant,2005, 5(5):969-975.
5. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant,2006,6(4):652-658.
6. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
7. Tsuchihashi S, Fondevila C, Kupiec-Weglinski JW. Heme oxygenase system in ischemia and reperfusion injury. Ann Transplant,2004,9(1):84-87.
8. Soares MP, Bach FH. Heme oxygenase-1 in organ transplantation. Front Biosci,2007, 12:4932-4945.
9. Lee SS, Gao W, Mazzola S, et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J,2007,21(13):3450-3457.
10. Otterbein LE. The evolution of carbon monoxide into medicine. Respir Care.2009, 54(7):925-932
11. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
12. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J, 2004,18(6):771-772.
13. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
14.高开柱,孙宗全,杜心灵,等.套管法建立小鼠颈部心脏移植模型的探讨.华中科技大学学报(医学版),2006,35(5)：638-640.
15.冯剑锷,孙宗全.应用Cuff技术建立小鼠异位心脏移植模型.中华实验外科杂志,2005,22(12)：1576-1577.
16.吴龙,孙宗全.小鼠心脏移植缺血再灌注诱导细胞凋亡的机制.中国心血管杂志,2004,9(5)：313-315.
1. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant,2006,6(4):652-658.
2. Land WG The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation, 2005,79(5):505-514.
3. Schmauss D, Weis M. Cardiac allograft vasculopathy:recent developments. Circulation,2008,117(16):2131-2141.
4. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
5. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
6. Otterbein LE. The evolution of carbon monoxide into medicine. Respir Care.2009, 54(7):925-932.
7. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation,2006,82(7):938-944.
8. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
9. Nakao A, Toyokawa H, Tsung A,et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am-J Transplant,2006,6(10):2243-2255.
10. Overbergh L, Giulietti A, Valckx D, et al. The use of real-time reverse transcriptase PCR for the quantification of cytokine gene expression. J Biomol Tech,2003, 14(1):33-43.
11. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
12. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
13. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
14. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
15. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
16. Kaizu T, Ikeda A, Nakao A, et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am J Physiol Gastrointest Liver Physiol,2008,294(1):G236-244.
17. Nakao A, Kimizuka K, Stolz DB, et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol,2003,163(4): 1587-1598.
18. Kaczorowski DJ, Nakao A, Mollen KP,et al.Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion. Transplantation,2007,84(10): 1279-1287.
19. Kaizu T, Nakao A, Tsung A, et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery,2005,138(2): 229-235.
20.吴龙,孙宗全.小鼠心脏移植缺血再灌注诱导细胞凋亡的机制.中国心血管杂志,2004,9(5)：313-315.
21. Rentsch M, Kienle K, Mueller T, et al. Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation. Transplantation,2005,80(10):1461-1467.
22. Neto JS, Nakao A, Kimizuka, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol,2004, 287(5):F979-989.
23. Mishra S,Fujita T,Lama VN,et al.Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. Proc Natl Acad Sci USA,2006,103(13):5191-5196.
24. Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH. Molecular biology of apoptosis in ischemia and reperfusion. J Invest Surg,2005,18(6):335-350.
25. Sardy JK, Zuckerbraun BS, Bilban M, et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J, 2004,18(7):854-856.
1. Land WG. The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation,2005,79(5): 505-514.
2. Vassalli G, Gallino A, Weis M,et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J,2003,24(13):1180-1188.
3. 吴龙,孙宗全.小鼠心脏移植缺血再灌注诱导细胞凋亡的机制.中国心血管杂志,2004,9(5)：313-315.
4. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J, 2004,18(6):771-772.
5. Kaizu T, Nakao A, Tsung A, et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery,2005,138(2): 229-235.
6. Song R, Kubo M, Morse D, et al. Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. Am J Pathol,2003,163(1):231-242.
7. Neto JS, Nakao A, Kimizuka, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol,2004, 287(5):F979-989.
8. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
9. Kotsch K, Martins PN, Klemz R, et al. Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal,2007,9(12):2049-2063.
10. Braudeau C, Bouchet D, Tesson L, et al. Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther,2004, 11(8):701-710.
11. Clarke HM, Shrivastava S, Motterlini R, et al. Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients:a potential role for CD8+ T-cell modulation by carbon monoxide. Transplantation,2009,88(5):653-661.
12. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet
allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
13. Tulis DA, Durante W, Liu X, et al.Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation. Circulation.2001, 104(22):2710-2715.
14. Zhang X, Shan P, Otterbein LE, et al. Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem,2003,278(2):1248-1258.
15. Zhang X, Shan P, Alam J, et al. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alphamitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J Biol Chem,2003,278(24):22061-22070.
16. Achouh PE, Simonet S, Fabiani JN, Verbeuren TJ. Carbon monoxide induces relaxation of human internal thoracic and radial arterial grafts. Interact Cardiovasc Thorac Surg,2008,7(6):959-962.
17. Kohmoto J, Nakao A, Kaizu T, et al. Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery,2006,140(2): 179-185.
18. Kaizu T, Ikeda A, Nakao A, et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am J Physiol Gastrointest Liver Physiol,2008,294(1):G236-244.
19. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation,2006,82(7):938-944.
20. Nakao A, Toyokawa H, Tsung A,et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am J Transplant,2006,6(10):2243-2255.
21. Ha T, Hua F, Liu X, et al. Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism. Cardiovasc Res.2008,78(3):546-553.
22. Kosieradzki M, Rowinski W. Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention. Transplant Proc,2008,40(10):3279-3288.
23. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
24. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
25. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
26. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
27. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
28. Zhang X, Shan P, Alam J,et al. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem, 2005,280(10):8714-8721.
29. Nakao A, Kimizuka K, Stolz DB, et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol,2003,163(4): 1587-1598.
30. Williams DL, Ozment-Skelton T, Li C. Modulation of the phosphoinositide 3-kinase signaling pathway alters host response to sepsis, inflammation, and ischemia/reperfusion injury. Shock,2006,25(5):432-439.
31. Jin YC, Lee YS, Kim YM, et al. (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(CKD712)reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. J Pharmacol Exp Ther,2009, 330(2):440-448.
32. Song JQ, Teng X, Cai Y, et al. Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1-53) protection against myocardial apoptosis induced by ischemia/reperfusion. Apoptosis.2009,14(11):1299-1307.
33. Jeong JJ, Ha YM, Jin YC, et al. Rutin from Lonicera japonica inhibits myocardial ischemia/reperfusion-induced apoptosis in vivo and protects H9c2 cells against hydrogen peroxide-mediated injury via ERK1/2 and PI3K/Akt signals in vitro. Food Chem Toxicol,2009,47(7):1569-1576.
34. Yeh CH, Hsu SP, Yang CC, et al. Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci,2010,86(3-4):115-123.
35. Wang HY, Wang GL, Yu YH, et al. The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats. Brain Res.2009,1297(2):177-184.
36. Faubel S, Edelstein CL. Caspases as drug targets in ischemic organ injury. Curr Drug Targets Immune Endocr Metabol Disord,2005,5(3):269-287.
37. Shiva S, Darley-Usmar VM. Control of the nitric oxide-cytochrome c oxidase signaling pathway under pathological and physiological conditions. IUBMB Life.2003, 55(10-11):585-590.
38. Wong WW, Puthalakath H. Bcl-2 family proteins:the sentinels of the mitochondrial apoptosis pathway. IUBMB Life,2008,60(6):390-397.
39. Goldberg A, Parolini M, Chin BY, et al.Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J,2007,21(11):2840-2848.
1. Schmauss D, Weis M. Cardiac allograft vasculopathy:recent developments. Circulation,2008,117(16):2131-2141.
2. Vassalli G, Gallino A, Weis M,et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J,2003,24(13):1180-1188.
3. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
4. Land WG The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation, 2005,79(5):505-514.
5. Pan PY, Ozao J, Zhou Z,et al. Advancements in immune tolerance. Adv Drug Deliv Rev,2008,60(2):91-105.
6. Sakaguchi S, Yamaguchi T, Nomura T,et al. Regulatory T cells and immune tolerance. Cell,2008,133(5):775-787.
7. Taflin C, Nochy D, Hill Qet al. Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft function. Transplantation,2010, 89(2):194-199.
8. Abe Y, Urakami H, Ostanin D,et al. Induction of Foxp3-expressing regulatory T-cells by donor blood transfusion is required for tolerance to rat liver allografts. PLoS One, 2009,4(11):e7840.
9. Zhang Q, Nakaki T, Iwami D,et al. Induction of regulatory T cells and indefinite survival of fully allogeneic cardiac grafts by ursodeoxycholic acid in mice. Transplantation,2009,88(12):1360-1370.
10. Akiyoshi T, Zhang Q, Inoue F, et al. Induction of indefinite survival of fully mismatched cardiac allografts and generation of regulatory cells by sarpogrelate hydrochloride. Transplantation,2006,82(8):1051-1059.
11. Nik Tavakoli N, Hambly BD,et al. Forkhead box protein 3:essential immune regulatory role. Int J Biochem Cell Biol,2008,40(11):2369-2373.
12. Buckner JH, Ziegler SF. Functional analysis of FOXP3. Ann N Y Acad Sci,2008, 1143:151-169.
13. Workman CJ, Szymczak-Workman AL, Collison LW,et al. The development and function of regulatory T cells. Cell Mol Life Sci,2009,66(16):2603-2622.
14. Feuerer M, Hill JA, Mathis D,et al. Foxp3+ regulatory T cells:differentiation, specification, subphenotypes. Nat Immunol,2009,10(7):689-695.
15. Schnickel GT, Hsieh GR, Kachikwu EL,et al. Cytoprotective gene HO-1 and chronic rejection in heart transplantation. Transplant Proc,2006,38(10):3259-3262.
16. Choi BM, Pae HO, Jeong YR,et al. Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression. Biochem Biophys Res Commun,2005, 327(4):1066-1071.
17. George JF, Braun A, Brusko TM, et al. Suppression by CD4+CD25+ regulatory T cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol,2008,173(1):154-160.
18. Lee SS, Gao W, Mazzola S, et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J,2007,21(13):3450-3457.
19. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell MolMed,2006,10(3):650-671.
20. Pae HO, Oh GS, Choi BM, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol,2004, 172(8):4744-4751.
21. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic
allograft dysfunction. Transplantation,2006,82(7):938-944.
22. Overbergh L, Giulietti A, Valckx D,et al. The use of real-time reverse transcriptase PCR for the quantification of cytokine gene expression. J Biomol Tech,2003, 14(1):33-43.
23. Dahlberg PE, Schartner JM, Timmel A,et al. Daily subcutaneous injections of peptide induce CD4+ CD25+ T regulatory cells. Clin Exp Immunol,2007,149(2):226-234.
24. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
25. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
26. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
27. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
28. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
29. Nakao A, Toyokawa H, Tsung A,et al.Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am J Transplant,2006,6(10):2243-2255.
30. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
31. Song R, Mahidhara RS, Zhou Z,et al. Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway. J Immunol,2004,172(2):1220-1226.
32. Clarke HM, Shrivastava S, Motterlini R,et al.Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients:a potential role for CD8+ T-cell modulation by carbon monoxide. Transplantation,2009,88(5):653-661.
33. Xia J, Xu L, Yang C. Expression of Cytokines in Acute Heart Transplantation Rejection. J Huazhong Univ Sci Technol(Med Sci),2006,26(5):583-586.
34. Salom RN, Maguire JA, Hancock WW. Endothelial activation and cytokine expression in human acute cardiac allograft rejection. Pathology,1998,30(1):24-29.
35. Buhaescu I, Segall L, Goldsmith D, Covic A. New immunosuppressive therapies in renal transplantation:monoclonal antibodies. J Nephrol,2005,18(5):529-536.
36. Ozden H, Kabay B, Guven G, et al. Interleukin-10 Gene Transfection of Donor Pancreas Grafts Protects against Rejection after Heterotopic Pancreas Transplantation in a Rat Model. Eur Surg Res 2005;37(4):220-227.
37. Giinther L, Berberat PO, Haga M, et al. Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation.Diabetes,2002,51(4):994-999.
38. Goldberg A, Parolini M, Chin BY, et al.Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J,2007,21(11):2840-2848.
39. Song R, Kubo M, Morse D, et al. Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects. Am J Pathol,2003,163(1):231-242.
40. Neto JS, Nakao A, Toyokawa H, et al. Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. Am J Physiol Renal Physiol,2006, 290(2):F324-334.
41. Diaz JA, Booth AJ, Lu G, et al. Critical role for IL-6 in hypertrophy and fibrosis in chronic cardiac allograft rejection. Am J Transplant,2009,9(8):1773-1783.
42. Faust SM, Lu G, Marini BL, et al. Role of T cell TGF beta signaling and IL-17 in allograft acceptance fibrosis associated with chronic rejection. J Immunol, 2009,183(11):7297-7306.
1. Andrade CF, Waddell TK, Keshavjee S,et al. Innate immunity and organ transplantation:the potential role of toll-like receptors. Am J Transplant,2005,5(5): 969-975.
2. Land WG The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation,2005,79(5): 505-514.
3. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
4. Tsoyi K, Lee TY, Lee YS, et al.Heme-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group box 1 release in vitro and improve survival of mice in LPS-and cecal ligation and puncture-induced sepsis model in vivo. Mol Pharmacol,2009,76(1):173-182.
5. Vallabhaneni R, Kaczorowski DJ, Yaakovian MD, et al. Heme oxygenase 1 protects against hepatic hypoxia and injury from hemorrhage via regulation of cellular respiration. Shock,2010,33(3):274-281.
6. Bernuzzi F, Recalcati S, Alberghini A, et al. Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes:role for heme oxygenase-1 down-modulation. Chem Biol Interact,2009,177(1):12-20.
7. Jamieson RW, Friend PJ. Organ reperfusion and preservation. Front Biosci,2008, 13:221-235.
8. Clarke HM, Shrivastava S, Motterlini R, et al. Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients:a potential role for CD8+ T-cell modulation by carbon monoxide. Transplantation,2009,88(5):653-661.
9. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
10. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J, 2004,18(6):771-772.
11. Braudeau C, Bouchet D, Tesson L, et al. Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther,2004, 11(8):701-710.
12. Obtterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med,2000, 6(4):422-428.
13. Zhang X, Shan P, Alam J,et al. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem, 2005,280(10):8714-8721.
14. Song R, Mahidhara RS, Zhou Z,et al. Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway. J Immunol,2004,172(2):1220-1226.
15. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
16. Otterbein LE. The evolution of carbon monoxide into medicine. Respir Care.2009, 54(7):925-932.
17. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A,1968,61(2):748-755.
18. McCoubrey WK Jr, Huang TJ, Maines MD. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem,1997, 247(2):725-732.
19. Otterbein LE, Choi AM. Heme oxygenase:colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol,2000,279(6):L1029-1037.
20. Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A ,1997,94(20):10919-10924.
21. Kapturczak MH, Wasserfall C, Brusko T, et al. Heme oxygenase-1 modulates early inflammatory responses:evidence from the heme oxygenase-1-deficient mouse. Am J Pathol.2004 Sep;165(3):1045-1053.
22. 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(1):129-135.
23. Chen B, Guo L, Fan C, et al. Carbon monoxide rescues heme oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation. Am J Pathol,2009, 175(1):422-429.
24. Von Burg R. Carbon monoxide. J Appl Toxicol,1999,19(5):379-386.
25. Stupfel M, Bouley G Physiological and biochemical effects on rats and mice exposed to small concentrations of carbon monoxide for long periods. Ann N Y Acad Sci,1970, 174(1):342-368.
26. Soares MP, Bach FH. Heme oxygenase-1 in organ transplantation. Front Biosci, 2007,12:4932-4945.
27. Sass G, Soares MC, Yamashita K, et al. Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. Hepatology,2003,38(4):909-918.
28. Lamon BD, Zhang FF, Puri N, et al. Dual pathways of carbon monoxide-mediated vasoregulation:modulation by redox mechanisms. Circ Res,2009,105(8):775-783.
29. Van Landeghem L, Laleman W, Vander Elst I, et al. Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver Int,2009,29(5):650-660.
30. Faleo G, Neto JS, Kohmoto J, et al. Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor. Transplantation,2008,85(12):1833-1840.
31. Matsumoto H, Ishikawa K, Itabe H, et al. Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator
inhibitor-1 induction. Mol Cell Biochem,2006,291(1-2):21-28.
32. Brouard S, Otterbein LE, Anrather J, et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med,2000,192(7): 1015-1026.
33. Bernardini C, Zannoni A, Bacci ML, et al. Protective effect of carbon monoxide pre-conditioning on LPS-induced endothelial cell stress. Cell Stress Chaperones,2010, 15(2):219-224.
34. Christova T, Diankova Z, Setchenska M. Heme oxygenase-carbon monoxide signalling pathway as a physiological regulator of vascular smooth muscle cells. Acta Physiol Pharmacol Bulg,2000,25(1):9-17.
35. Hoenicka M, Schmid C. Cardiovascular effects of modulators of soluble guanylyl cyclase activity. Cardiovasc Hematol Agents Med Chem,2008,6(4):287-301.
36. Nakao A, Kaczorowski DJ, Wang Y, et al. Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant,2010,29(5):544-553.
37. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
38. Kaizu T, Ikeda A, Nakao A, et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am J Physiol Gastrointest Liver Physiol,2008,294(1):G236-244.
39. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
40. Kohmoto J, Nakao A, Kaizu T, et al. Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery,2006,140(2): 179-185.
41. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
42. Vadori M, Seveso M, Besenzon F, et al.In vitro and in vivo effects of the carbon monoxide-releasing molecule, CORM-3, in the xenogeneic pig-to-primate context.
Xenotransplantation,2009,16(2):99-114.
43. Clark JE, Naughton P, Shurey S, et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res,2003,93(2):e2-8.
44. Bagul A, Hosgood SA, Kaushik M, et al. Carbon monoxide protects against ischemia-reperfusion injury in an experimental model of controlled nonheartbeating donor kidney. Transplantation,2008,85(4):576-581.
45. Hosgood SA, Bagul A, Kaushik M, et al. Application of nitric oxide and carbon monoxide in a model of renal preservation. Br J Surg,2008,95(8):1060-1067.
46. Motterlini R, Mann BE, Foresti R. Therapeutic applications of carbon monoxide-releasing molecules. Expert Opin Investig Drugs,2005,14(11):1305-1318.
47. Katada K, Bihari A, Mizuguchi S, et al. Carbon Monoxide Liberated from CO-Releasing Molecule (CORM-2)Attenuates Ischemia/Reperfusion (I/R)-Induced Inflammation in the Small Intestine. Inflammation,2010,33(2):92-100.
48. Urquhart P, Rosignoli G, Cooper D, et al. Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow. J Pharmacol Exp Ther,2007, 321(2):656-662.
49. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
50. Scapens D, Adams H, Johnson TR, et al. [(η-C5H4R)Fe(CO)2X], X= Cl, Br, I, NO3, CO2Me and [(η-C5H4R)Fe(CO)3]+, R= (CH2)nCO2Me (n= 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules. Dalton Trans,2007,(43):4962-4973.
51. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation,2006,82(7):938-944.
52. Ke B, Buelow R, Shen XD, et al. Heme oxygenase 1 gene transfer prevents CD95/Fas ligand-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway. Hum Gene Ther,2002,13(10):1189-1199.
53. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
54. Nakao A, Schmidt J, Harada T, et al. A single intraperitoneal dose of carbon
monoxide-saturated ringer's lactate solution ameliorates postoperative ileus in mice. J Pharmacol Exp Ther,2006,319(3):1265-1275.
55. Nakao A, Toyokawa H, Tsung A,et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am J Transplant,2006,6(10):2243-2255.
56. Kohmoto J, Nakao A, Sugimoto R, et al. Carbon monoxide-saturated preservation solution protects lung grafts from ischemia-reperfusion injury. J Thorac Cardiovasc Surg,2008,136(4):1067-1075.
57. Ikeda A, Ueki S, Nakao A, et al. Liver graft exposure to carbon monoxide during cold storage protects sinusoidal endothelial cells and ameliorates reperfusion injury in rats. Liver Transpl,2009,15(11):1458-1468.
58. Nakao A, Faleo Q Shimizu H, et al. Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts. Kidney Int, 2008,74(8):1009-1016.
59. Vreman HJ, Baxter LM, Stone RT, et al. Evaluation of a fully automated end-tidal carbon monoxide instrument for breath analysis. Clin Chem,1996,42(1):50-56.
60. Mikhalski D, Wissing KM, Ghisdal L, et al. Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunosuppression. Transplantation,2008,85(7 Suppl):S3-9.
61. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant,2006,6(4):652-658.
62. Piantadosi CA. Carbon monoxide, reactive oxygen signaling, and oxidative stress. Free Radic Biol Med,2008,45(5):562-569.
63. Nakao A, Kaczorowski DJ, Sugimoto R, et al. Application of heme oxygenase-1, carbon monoxide and biliverdin for the prevention of intestinal ischemia/reperfusion injury. J Clin Biochem Nutr,2008,42(2):78-88.
64. Kaczorowski DJ, Nakao A, Vallabhaneni R, et al. Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation,2009,87(10):1455-1463.
65. Kaczorowski DJ, Nakao A, Mollen KP, et al. Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion.Transplantation,2007,84(10): 1279-1287.
66. Shen XD, Ke B, Zhai Y,et al. Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl,2007,13(10):1435-1443.
67. Neto JS, Nakao A, Kimizuka, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol,2004, 287(5):F979-989.
68. Wegiel B, Gallo DJ, Raman KG, et al. Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation,2010,121(4):537-548.
69. Lin HH, Chen YH, Yet SF, et al. After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells. J Thromb Haemost,2009,7(8):1401-1408.
70. Zhang X, Shan P, Otterbein LE, et al. Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem,2003,278(2):1248-1258.
71. Nakao A, Toyokawa H, Abe M, et al. Heart allograft protection with low-dose carbon monoxide inhalation:effects on inflammatory mediators and alloreactive T-cell responses. Transplantation,2006,81(2):220-230.
72. Nakao A, Neto JS, Kanno S, et al. Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both. Am J Transplant,2005,5(2):282-291.
73. Achouh PE, Simonet S, Fabiani JN, Verbeuren TJ. Carbon monoxide induces relaxation of human internal thoracic and radial arterial grafts. Interact Cardiovasc Thorac Surg,2008,7(6):959-962.
74. Amersi F, Shen XD, Anselmo D,et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology, 2002,35(4):815-823.
75. 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(5): 598-604.
76. Mishra S,Fujita T,Lama VN,et al.Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. Proc Natl Acad Sci USA,2006,103(13):5191-5196.
77. Zhou HC, Ding WG, Cui XQ et al. Carbon monoxide inhalation ameliorates conditions of lung grafts from rat brain death donors. Chin Med J (Engl),2008; 121(15): 1411-1419.
78. 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(5):1608-1620.
79. Kotsch K, Martins PN, Klemz R,et al. Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal,2007,9(12):2049-2063.
80. Kaizu T, Nakao A, Tsung A, et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery,2005,138(2): 229-235.
81. Sarady JK, Zuckerbraun BS, Bilban M, et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J, 2004,18(7):854-856.
82. Otterbein LE, Otterbein SL, Ifedigbo E, et al. MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Am J Pathol,2003,163(6):2555-2563.
83. Rentsch M, Kienle K, Mueller T, et al. Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation. Transplantation,2005,80(10):1461-1467.
84. Song R, Kubo M, Morse D, et al. Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. Am J Pathol,2003,163(1):231-242.
85. Nakao A, Kimizuka K, Stolz DB, et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol,2003,163(4): 1587-1598.
86. Zhang X, Shan P, Alam J, et al. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alphamitogen-activated protein kinase pathway during ischemia-reperfusion lung injury.J Biol Chem,2003,278(24):22061-22070.
87. Srisook K, Han SS, Choi HS, et al. CO from enhanced HO activity or from CORM-2
inhibits both 02-and NO production and downregulates HO-1 expression in LPS-stimulated macrophages. Biochem Pharmacol.2006,71(3):307-318.
88. True AL, Olive M, Boehm M, et al. Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium,which is rescued by inhaled carbon monoxide. Circ Res.2007,101(9):893-901.
89. Zuckerbraun BS, Chin BY, Bilban M, et al. Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J,2007,21(4):1099-1106.
90. Kim BS, Lim SW, Li C, et al. Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation,2005,79(10):1370-1377.
91. Pae HO, Oh GS, Choi BM, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol,2004, 172(8):4744-4751.
92. Morita T, Mitsialis SA, Koike H, et al. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem,1997,272(52):32804-32809.
93. Peyton KJ, Reyna SV, Chapman GB, et al. Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood,2002, 99(12):4443-4448.
94. Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med,2003,9(2):183-190.
95. Li C, Yang CW. The pathogenesis and treatment of chronic allograft nephropathy. Nat Rev Nephrol,2009,5(9):513-519.
96. Neto JS, Nakao A, Toyokawa H, et al. Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. Am J Physiol Renal Physiol,2006, 290(2):F324-334.
97. Song R, Mahidhara RS, Liu F, et al. Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Am J Respir Cell Mol Biol,2002,27(5):603-610.
98. Brar SS, Kennedy TP, Sturrock AB, et al. NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol,2002,282(4):L782-795.
99. Minamoto K, Harada H, Lama VN, et al. Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase. J Exp Med,2005,202(2):283-294.
100.Djamali A, Samaniego M. Fibrogenesis in kidney transplantation:potential targets for prevention and therapy. Transplantation,2009,88(10):1149-1156.
101.Zhou Z, Song R, Fattman CL, et al. Carbon monoxide suppresses bleomycin-induced lung fibrosis. Am J Pathol,2005,166(1):27-37.
102.Gunther L, Berberat PO, Haga M, et al. Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation. Diabetes,2002,51(4):994-999.
103.Goldberg A, Parolini M, Chin BY, et al.Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J,2007,21(11):2840-2848.
104.Lee SS, Gao W, Mazzola S, et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J,2007,21(13):3450-3457.
105.Soares MP, Lin Y, Anrather J, et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med.1998,4(9):1073-1077.
106.Sato K, Balla J, Otterbein L, et al. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J Immunol,2001,166(6): 4185-4194.
107.Shennib H, Adoumie R, Fraser R. Successful transplantation of a lung allograft from a carbon monoxide-poisoning victim. J Heart Lung Transplant,1992,11(1 Pt 1):68-71.
108.Luckraz H, Tsui SS, Parameshwar J, et al. Improved outcome with organs from carbon monoxide poisoned donors for intrathoracic transplantation. Ann Thorac Surg,2001, 72(3):709-713.
109.Verran D, Chui A, Painter D, et al. Use of liver allografts from carbon monoxide poisoned cadaveric donors. Transplantation,1996,62(10):1514-1515.
110.Hantson P, Vekemans MC, Squifflet JP, et al. Outcome following organ removal from poisoned donors:experience with 12 cases a review of the literature. Transpl Int,1995, 8(3):185-189.
111.Bojakowski K, Gaciong Z, Grochowiecki T, et al. Carbon monoxide may reduce ischemia reperfusion injury:a case report of complicated kidney transplantation from a carbon monoxide poisoned donor. Transplant Proc,2007,39(9):2928-2929.
112.Karwande SV, Hopfenbeck JA, Renlund DQ et al. An avoidable pitfall in donor selection for heart transplantation. Utah Heart Transplant Program. J Heart Transplant, 1989,8(5):422-424.
113.Roberts JR, Bain M, Klachko MN, et al. Successful heart transplantation from a victim of carbon monoxide poisoning. Ann Emerg Med,1995,26(5):652-655.
114.Martin-Suarez S, Mikus E, Pilato E, et al. Cardiac transplantation from a carbon monoxide intoxicated donor. Transplant Proc,2008,40(5):1563-1565.
115.Sezgin A, Akay TH, Ozkan S, et al. Successful cardiac transplantation from donor with carbon monoxide intoxication:a case report. Transplant Proc,2008,40(1):324-325.
116.Wood DM, Dargan PI, Jones AL. Poisoned patients as potential organ donors:postal survey of transplant centres and intensive care units. Crit Care,2003,7(2):147-154.
117.Bathoorn E, Slebos DJ, Postma DS, et al. Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD:a pilot study. Eur Respir J,2007,30(6):1131-1137.
118.Mayr FB, Spiel A, Leitner J, et al. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med,2005,171(4): 354-360.
119.Vos R, Cordemans C, Vanaudenaerde BM, et al. Exhaled carbon monoxide as a noninvasive marker of airway neutrophilia after lung transplantation. Transplantation, 2009,87(10):1579-1583.
120. Van Muylem A, Knoop C, Estenne M. Early detection of chronic pulmonary allograft dysfunction by exhaled biomarkers. Am J Respir Crit Care Med,2007,175(7): 731-736.
121.Matsusaki T, Morimatsu H, Takahashi T, et al. Increased exhaled carbon monoxide concentration during living donor liver transplantation. Int J Mol Med,2008, 21(1):75-81.
2. Vassalli G, Gallino A, Weis M, et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J,2003,24(13):1180-1188.
3. Land WG. The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation, 2005,79(5):505-514.
4. Andrade CF, Waddell TK, Keshavjee S,et al. Innate immunity and organ transplantation:the potential role of toll-like receptors. Am J Transplant,2005, 5(5):969-975.
5. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant,2006,6(4):652-658.
6. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
7. Tsuchihashi S, Fondevila C, Kupiec-Weglinski JW. Heme oxygenase system in ischemia and reperfusion injury. Ann Transplant,2004,9(1):84-87.
8. Soares MP, Bach FH. Heme oxygenase-1 in organ transplantation. Front Biosci,2007, 12:4932-4945.
9. Lee SS, Gao W, Mazzola S, et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J,2007,21(13):3450-3457.
10. Otterbein LE. The evolution of carbon monoxide into medicine. Respir Care.2009, 54(7):925-932
11. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
12. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J, 2004,18(6):771-772.
13. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
14.高开柱,孙宗全,杜心灵,等.套管法建立小鼠颈部心脏移植模型的探讨.华中科技大学学报(医学版),2006,35(5)：638-640.
15.冯剑锷,孙宗全.应用Cuff技术建立小鼠异位心脏移植模型.中华实验外科杂志,2005,22(12)：1576-1577.
16.吴龙,孙宗全.小鼠心脏移植缺血再灌注诱导细胞凋亡的机制.中国心血管杂志,2004,9(5)：313-315.
1. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant,2006,6(4):652-658.
2. Land WG The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation, 2005,79(5):505-514.
3. Schmauss D, Weis M. Cardiac allograft vasculopathy:recent developments. Circulation,2008,117(16):2131-2141.
4. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
5. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
6. Otterbein LE. The evolution of carbon monoxide into medicine. Respir Care.2009, 54(7):925-932.
7. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation,2006,82(7):938-944.
8. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
9. Nakao A, Toyokawa H, Tsung A,et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am-J Transplant,2006,6(10):2243-2255.
10. Overbergh L, Giulietti A, Valckx D, et al. The use of real-time reverse transcriptase PCR for the quantification of cytokine gene expression. J Biomol Tech,2003, 14(1):33-43.
11. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
12. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
13. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
14. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
15. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
16. Kaizu T, Ikeda A, Nakao A, et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am J Physiol Gastrointest Liver Physiol,2008,294(1):G236-244.
17. Nakao A, Kimizuka K, Stolz DB, et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol,2003,163(4): 1587-1598.
18. Kaczorowski DJ, Nakao A, Mollen KP,et al.Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion. Transplantation,2007,84(10): 1279-1287.
19. Kaizu T, Nakao A, Tsung A, et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery,2005,138(2): 229-235.
20.吴龙,孙宗全.小鼠心脏移植缺血再灌注诱导细胞凋亡的机制.中国心血管杂志,2004,9(5)：313-315.
21. Rentsch M, Kienle K, Mueller T, et al. Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation. Transplantation,2005,80(10):1461-1467.
22. Neto JS, Nakao A, Kimizuka, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol,2004, 287(5):F979-989.
23. Mishra S,Fujita T,Lama VN,et al.Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. Proc Natl Acad Sci USA,2006,103(13):5191-5196.
24. Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH. Molecular biology of apoptosis in ischemia and reperfusion. J Invest Surg,2005,18(6):335-350.
25. Sardy JK, Zuckerbraun BS, Bilban M, et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J, 2004,18(7):854-856.
1. Land WG. The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation,2005,79(5): 505-514.
2. Vassalli G, Gallino A, Weis M,et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J,2003,24(13):1180-1188.
3. 吴龙,孙宗全.小鼠心脏移植缺血再灌注诱导细胞凋亡的机制.中国心血管杂志,2004,9(5)：313-315.
4. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J, 2004,18(6):771-772.
5. Kaizu T, Nakao A, Tsung A, et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery,2005,138(2): 229-235.
6. Song R, Kubo M, Morse D, et al. Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. Am J Pathol,2003,163(1):231-242.
7. Neto JS, Nakao A, Kimizuka, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol,2004, 287(5):F979-989.
8. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
9. Kotsch K, Martins PN, Klemz R, et al. Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal,2007,9(12):2049-2063.
10. Braudeau C, Bouchet D, Tesson L, et al. Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther,2004, 11(8):701-710.
11. Clarke HM, Shrivastava S, Motterlini R, et al. Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients:a potential role for CD8+ T-cell modulation by carbon monoxide. Transplantation,2009,88(5):653-661.
12. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet
allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
13. Tulis DA, Durante W, Liu X, et al.Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation. Circulation.2001, 104(22):2710-2715.
14. Zhang X, Shan P, Otterbein LE, et al. Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem,2003,278(2):1248-1258.
15. Zhang X, Shan P, Alam J, et al. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alphamitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J Biol Chem,2003,278(24):22061-22070.
16. Achouh PE, Simonet S, Fabiani JN, Verbeuren TJ. Carbon monoxide induces relaxation of human internal thoracic and radial arterial grafts. Interact Cardiovasc Thorac Surg,2008,7(6):959-962.
17. Kohmoto J, Nakao A, Kaizu T, et al. Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery,2006,140(2): 179-185.
18. Kaizu T, Ikeda A, Nakao A, et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am J Physiol Gastrointest Liver Physiol,2008,294(1):G236-244.
19. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation,2006,82(7):938-944.
20. Nakao A, Toyokawa H, Tsung A,et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am J Transplant,2006,6(10):2243-2255.
21. Ha T, Hua F, Liu X, et al. Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism. Cardiovasc Res.2008,78(3):546-553.
22. Kosieradzki M, Rowinski W. Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention. Transplant Proc,2008,40(10):3279-3288.
23. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
24. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
25. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
26. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
27. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
28. Zhang X, Shan P, Alam J,et al. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem, 2005,280(10):8714-8721.
29. Nakao A, Kimizuka K, Stolz DB, et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol,2003,163(4): 1587-1598.
30. Williams DL, Ozment-Skelton T, Li C. Modulation of the phosphoinositide 3-kinase signaling pathway alters host response to sepsis, inflammation, and ischemia/reperfusion injury. Shock,2006,25(5):432-439.
31. Jin YC, Lee YS, Kim YM, et al. (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(CKD712)reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. J Pharmacol Exp Ther,2009, 330(2):440-448.
32. Song JQ, Teng X, Cai Y, et al. Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1-53) protection against myocardial apoptosis induced by ischemia/reperfusion. Apoptosis.2009,14(11):1299-1307.
33. Jeong JJ, Ha YM, Jin YC, et al. Rutin from Lonicera japonica inhibits myocardial ischemia/reperfusion-induced apoptosis in vivo and protects H9c2 cells against hydrogen peroxide-mediated injury via ERK1/2 and PI3K/Akt signals in vitro. Food Chem Toxicol,2009,47(7):1569-1576.
34. Yeh CH, Hsu SP, Yang CC, et al. Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci,2010,86(3-4):115-123.
35. Wang HY, Wang GL, Yu YH, et al. The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats. Brain Res.2009,1297(2):177-184.
36. Faubel S, Edelstein CL. Caspases as drug targets in ischemic organ injury. Curr Drug Targets Immune Endocr Metabol Disord,2005,5(3):269-287.
37. Shiva S, Darley-Usmar VM. Control of the nitric oxide-cytochrome c oxidase signaling pathway under pathological and physiological conditions. IUBMB Life.2003, 55(10-11):585-590.
38. Wong WW, Puthalakath H. Bcl-2 family proteins:the sentinels of the mitochondrial apoptosis pathway. IUBMB Life,2008,60(6):390-397.
39. Goldberg A, Parolini M, Chin BY, et al.Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J,2007,21(11):2840-2848.
1. Schmauss D, Weis M. Cardiac allograft vasculopathy:recent developments. Circulation,2008,117(16):2131-2141.
2. Vassalli G, Gallino A, Weis M,et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J,2003,24(13):1180-1188.
3. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
4. Land WG The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation, 2005,79(5):505-514.
5. Pan PY, Ozao J, Zhou Z,et al. Advancements in immune tolerance. Adv Drug Deliv Rev,2008,60(2):91-105.
6. Sakaguchi S, Yamaguchi T, Nomura T,et al. Regulatory T cells and immune tolerance. Cell,2008,133(5):775-787.
7. Taflin C, Nochy D, Hill Qet al. Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft function. Transplantation,2010, 89(2):194-199.
8. Abe Y, Urakami H, Ostanin D,et al. Induction of Foxp3-expressing regulatory T-cells by donor blood transfusion is required for tolerance to rat liver allografts. PLoS One, 2009,4(11):e7840.
9. Zhang Q, Nakaki T, Iwami D,et al. Induction of regulatory T cells and indefinite survival of fully allogeneic cardiac grafts by ursodeoxycholic acid in mice. Transplantation,2009,88(12):1360-1370.
10. Akiyoshi T, Zhang Q, Inoue F, et al. Induction of indefinite survival of fully mismatched cardiac allografts and generation of regulatory cells by sarpogrelate hydrochloride. Transplantation,2006,82(8):1051-1059.
11. Nik Tavakoli N, Hambly BD,et al. Forkhead box protein 3:essential immune regulatory role. Int J Biochem Cell Biol,2008,40(11):2369-2373.
12. Buckner JH, Ziegler SF. Functional analysis of FOXP3. Ann N Y Acad Sci,2008, 1143:151-169.
13. Workman CJ, Szymczak-Workman AL, Collison LW,et al. The development and function of regulatory T cells. Cell Mol Life Sci,2009,66(16):2603-2622.
14. Feuerer M, Hill JA, Mathis D,et al. Foxp3+ regulatory T cells:differentiation, specification, subphenotypes. Nat Immunol,2009,10(7):689-695.
15. Schnickel GT, Hsieh GR, Kachikwu EL,et al. Cytoprotective gene HO-1 and chronic rejection in heart transplantation. Transplant Proc,2006,38(10):3259-3262.
16. Choi BM, Pae HO, Jeong YR,et al. Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression. Biochem Biophys Res Commun,2005, 327(4):1066-1071.
17. George JF, Braun A, Brusko TM, et al. Suppression by CD4+CD25+ regulatory T cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol,2008,173(1):154-160.
18. Lee SS, Gao W, Mazzola S, et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J,2007,21(13):3450-3457.
19. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell MolMed,2006,10(3):650-671.
20. Pae HO, Oh GS, Choi BM, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol,2004, 172(8):4744-4751.
21. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic
allograft dysfunction. Transplantation,2006,82(7):938-944.
22. Overbergh L, Giulietti A, Valckx D,et al. The use of real-time reverse transcriptase PCR for the quantification of cytokine gene expression. J Biomol Tech,2003, 14(1):33-43.
23. Dahlberg PE, Schartner JM, Timmel A,et al. Daily subcutaneous injections of peptide induce CD4+ CD25+ T regulatory cells. Clin Exp Immunol,2007,149(2):226-234.
24. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
25. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
26. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
27. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
28. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
29. Nakao A, Toyokawa H, Tsung A,et al.Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am J Transplant,2006,6(10):2243-2255.
30. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
31. Song R, Mahidhara RS, Zhou Z,et al. Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway. J Immunol,2004,172(2):1220-1226.
32. Clarke HM, Shrivastava S, Motterlini R,et al.Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients:a potential role for CD8+ T-cell modulation by carbon monoxide. Transplantation,2009,88(5):653-661.
33. Xia J, Xu L, Yang C. Expression of Cytokines in Acute Heart Transplantation Rejection. J Huazhong Univ Sci Technol(Med Sci),2006,26(5):583-586.
34. Salom RN, Maguire JA, Hancock WW. Endothelial activation and cytokine expression in human acute cardiac allograft rejection. Pathology,1998,30(1):24-29.
35. Buhaescu I, Segall L, Goldsmith D, Covic A. New immunosuppressive therapies in renal transplantation:monoclonal antibodies. J Nephrol,2005,18(5):529-536.
36. Ozden H, Kabay B, Guven G, et al. Interleukin-10 Gene Transfection of Donor Pancreas Grafts Protects against Rejection after Heterotopic Pancreas Transplantation in a Rat Model. Eur Surg Res 2005;37(4):220-227.
37. Giinther L, Berberat PO, Haga M, et al. Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation.Diabetes,2002,51(4):994-999.
38. Goldberg A, Parolini M, Chin BY, et al.Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J,2007,21(11):2840-2848.
39. Song R, Kubo M, Morse D, et al. Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects. Am J Pathol,2003,163(1):231-242.
40. Neto JS, Nakao A, Toyokawa H, et al. Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. Am J Physiol Renal Physiol,2006, 290(2):F324-334.
41. Diaz JA, Booth AJ, Lu G, et al. Critical role for IL-6 in hypertrophy and fibrosis in chronic cardiac allograft rejection. Am J Transplant,2009,9(8):1773-1783.
42. Faust SM, Lu G, Marini BL, et al. Role of T cell TGF beta signaling and IL-17 in allograft acceptance fibrosis associated with chronic rejection. J Immunol, 2009,183(11):7297-7306.
1. Andrade CF, Waddell TK, Keshavjee S,et al. Innate immunity and organ transplantation:the potential role of toll-like receptors. Am J Transplant,2005,5(5): 969-975.
2. Land WG The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation. Transplantation,2005,79(5): 505-514.
3. Abouna GM. Organ Shortage Crisis:Problems and Possible Solutions. Transplant Proc, 2008,40(1):34-38.
4. Tsoyi K, Lee TY, Lee YS, et al.Heme-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group box 1 release in vitro and improve survival of mice in LPS-and cecal ligation and puncture-induced sepsis model in vivo. Mol Pharmacol,2009,76(1):173-182.
5. Vallabhaneni R, Kaczorowski DJ, Yaakovian MD, et al. Heme oxygenase 1 protects against hepatic hypoxia and injury from hemorrhage via regulation of cellular respiration. Shock,2010,33(3):274-281.
6. Bernuzzi F, Recalcati S, Alberghini A, et al. Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes:role for heme oxygenase-1 down-modulation. Chem Biol Interact,2009,177(1):12-20.
7. Jamieson RW, Friend PJ. Organ reperfusion and preservation. Front Biosci,2008, 13:221-235.
8. Clarke HM, Shrivastava S, Motterlini R, et al. Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients:a potential role for CD8+ T-cell modulation by carbon monoxide. Transplantation,2009,88(5):653-661.
9. Wang H, Lee SS, Gao W, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes,2005,54(5):1400-1406.
10. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J, 2004,18(6):771-772.
11. Braudeau C, Bouchet D, Tesson L, et al. Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther,2004, 11(8):701-710.
12. Obtterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med,2000, 6(4):422-428.
13. Zhang X, Shan P, Alam J,et al. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem, 2005,280(10):8714-8721.
14. Song R, Mahidhara RS, Zhou Z,et al. Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway. J Immunol,2004,172(2):1220-1226.
15. Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med,2006,10(3):650-671.
16. Otterbein LE. The evolution of carbon monoxide into medicine. Respir Care.2009, 54(7):925-932.
17. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A,1968,61(2):748-755.
18. McCoubrey WK Jr, Huang TJ, Maines MD. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem,1997, 247(2):725-732.
19. Otterbein LE, Choi AM. Heme oxygenase:colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol,2000,279(6):L1029-1037.
20. Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A ,1997,94(20):10919-10924.
21. Kapturczak MH, Wasserfall C, Brusko T, et al. Heme oxygenase-1 modulates early inflammatory responses:evidence from the heme oxygenase-1-deficient mouse. Am J Pathol.2004 Sep;165(3):1045-1053.
22. 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(1):129-135.
23. Chen B, Guo L, Fan C, et al. Carbon monoxide rescues heme oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation. Am J Pathol,2009, 175(1):422-429.
24. Von Burg R. Carbon monoxide. J Appl Toxicol,1999,19(5):379-386.
25. Stupfel M, Bouley G Physiological and biochemical effects on rats and mice exposed to small concentrations of carbon monoxide for long periods. Ann N Y Acad Sci,1970, 174(1):342-368.
26. Soares MP, Bach FH. Heme oxygenase-1 in organ transplantation. Front Biosci, 2007,12:4932-4945.
27. Sass G, Soares MC, Yamashita K, et al. Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. Hepatology,2003,38(4):909-918.
28. Lamon BD, Zhang FF, Puri N, et al. Dual pathways of carbon monoxide-mediated vasoregulation:modulation by redox mechanisms. Circ Res,2009,105(8):775-783.
29. Van Landeghem L, Laleman W, Vander Elst I, et al. Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver Int,2009,29(5):650-660.
30. Faleo G, Neto JS, Kohmoto J, et al. Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor. Transplantation,2008,85(12):1833-1840.
31. Matsumoto H, Ishikawa K, Itabe H, et al. Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator
inhibitor-1 induction. Mol Cell Biochem,2006,291(1-2):21-28.
32. Brouard S, Otterbein LE, Anrather J, et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med,2000,192(7): 1015-1026.
33. Bernardini C, Zannoni A, Bacci ML, et al. Protective effect of carbon monoxide pre-conditioning on LPS-induced endothelial cell stress. Cell Stress Chaperones,2010, 15(2):219-224.
34. Christova T, Diankova Z, Setchenska M. Heme oxygenase-carbon monoxide signalling pathway as a physiological regulator of vascular smooth muscle cells. Acta Physiol Pharmacol Bulg,2000,25(1):9-17.
35. Hoenicka M, Schmid C. Cardiovascular effects of modulators of soluble guanylyl cyclase activity. Cardiovasc Hematol Agents Med Chem,2008,6(4):287-301.
36. Nakao A, Kaczorowski DJ, Wang Y, et al. Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant,2010,29(5):544-553.
37. Nakao A, Faleo G, Nalesnik MA, et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am J Physiol Renal Physiol,2009,297(1):F19-26.
38. Kaizu T, Ikeda A, Nakao A, et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am J Physiol Gastrointest Liver Physiol,2008,294(1):G236-244.
39. Kohmoto J, Nakao A, Stolz DB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant,2007,7(10):2279-2290.
40. Kohmoto J, Nakao A, Kaizu T, et al. Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery,2006,140(2): 179-185.
41. Pizarro MD, Rodriguez JV, Mamprin ME, et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3)during hepatic cold preservation. Cryobiology, 2009,58(3):248-255.
42. Vadori M, Seveso M, Besenzon F, et al.In vitro and in vivo effects of the carbon monoxide-releasing molecule, CORM-3, in the xenogeneic pig-to-primate context.
Xenotransplantation,2009,16(2):99-114.
43. Clark JE, Naughton P, Shurey S, et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res,2003,93(2):e2-8.
44. Bagul A, Hosgood SA, Kaushik M, et al. Carbon monoxide protects against ischemia-reperfusion injury in an experimental model of controlled nonheartbeating donor kidney. Transplantation,2008,85(4):576-581.
45. Hosgood SA, Bagul A, Kaushik M, et al. Application of nitric oxide and carbon monoxide in a model of renal preservation. Br J Surg,2008,95(8):1060-1067.
46. Motterlini R, Mann BE, Foresti R. Therapeutic applications of carbon monoxide-releasing molecules. Expert Opin Investig Drugs,2005,14(11):1305-1318.
47. Katada K, Bihari A, Mizuguchi S, et al. Carbon Monoxide Liberated from CO-Releasing Molecule (CORM-2)Attenuates Ischemia/Reperfusion (I/R)-Induced Inflammation in the Small Intestine. Inflammation,2010,33(2):92-100.
48. Urquhart P, Rosignoli G, Cooper D, et al. Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow. J Pharmacol Exp Ther,2007, 321(2):656-662.
49. Motterlini R. Carbon monoxide-releasing molecules (CO-RMs):vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans,2007,35(Pt 5):1142-1146.
50. Scapens D, Adams H, Johnson TR, et al. [(η-C5H4R)Fe(CO)2X], X= Cl, Br, I, NO3, CO2Me and [(η-C5H4R)Fe(CO)3]+, R= (CH2)nCO2Me (n= 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules. Dalton Trans,2007,(43):4962-4973.
51. Martins PN, Reutzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction. Transplantation,2006,82(7):938-944.
52. Ke B, Buelow R, Shen XD, et al. Heme oxygenase 1 gene transfer prevents CD95/Fas ligand-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway. Hum Gene Ther,2002,13(10):1189-1199.
53. Chauveau C, Bouchet D, Roussel JC, et al. Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant.2002,2(7): 581-592.
54. Nakao A, Schmidt J, Harada T, et al. A single intraperitoneal dose of carbon
monoxide-saturated ringer's lactate solution ameliorates postoperative ileus in mice. J Pharmacol Exp Ther,2006,319(3):1265-1275.
55. Nakao A, Toyokawa H, Tsung A,et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am J Transplant,2006,6(10):2243-2255.
56. Kohmoto J, Nakao A, Sugimoto R, et al. Carbon monoxide-saturated preservation solution protects lung grafts from ischemia-reperfusion injury. J Thorac Cardiovasc Surg,2008,136(4):1067-1075.
57. Ikeda A, Ueki S, Nakao A, et al. Liver graft exposure to carbon monoxide during cold storage protects sinusoidal endothelial cells and ameliorates reperfusion injury in rats. Liver Transpl,2009,15(11):1458-1468.
58. Nakao A, Faleo Q Shimizu H, et al. Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts. Kidney Int, 2008,74(8):1009-1016.
59. Vreman HJ, Baxter LM, Stone RT, et al. Evaluation of a fully automated end-tidal carbon monoxide instrument for breath analysis. Clin Chem,1996,42(1):50-56.
60. Mikhalski D, Wissing KM, Ghisdal L, et al. Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunosuppression. Transplantation,2008,85(7 Suppl):S3-9.
61. Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant,2006,6(4):652-658.
62. Piantadosi CA. Carbon monoxide, reactive oxygen signaling, and oxidative stress. Free Radic Biol Med,2008,45(5):562-569.
63. Nakao A, Kaczorowski DJ, Sugimoto R, et al. Application of heme oxygenase-1, carbon monoxide and biliverdin for the prevention of intestinal ischemia/reperfusion injury. J Clin Biochem Nutr,2008,42(2):78-88.
64. Kaczorowski DJ, Nakao A, Vallabhaneni R, et al. Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation,2009,87(10):1455-1463.
65. Kaczorowski DJ, Nakao A, Mollen KP, et al. Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion.Transplantation,2007,84(10): 1279-1287.
66. Shen XD, Ke B, Zhai Y,et al. Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl,2007,13(10):1435-1443.
67. Neto JS, Nakao A, Kimizuka, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol,2004, 287(5):F979-989.
68. Wegiel B, Gallo DJ, Raman KG, et al. Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation,2010,121(4):537-548.
69. Lin HH, Chen YH, Yet SF, et al. After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells. J Thromb Haemost,2009,7(8):1401-1408.
70. Zhang X, Shan P, Otterbein LE, et al. Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem,2003,278(2):1248-1258.
71. Nakao A, Toyokawa H, Abe M, et al. Heart allograft protection with low-dose carbon monoxide inhalation:effects on inflammatory mediators and alloreactive T-cell responses. Transplantation,2006,81(2):220-230.
72. Nakao A, Neto JS, Kanno S, et al. Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both. Am J Transplant,2005,5(2):282-291.
73. Achouh PE, Simonet S, Fabiani JN, Verbeuren TJ. Carbon monoxide induces relaxation of human internal thoracic and radial arterial grafts. Interact Cardiovasc Thorac Surg,2008,7(6):959-962.
74. Amersi F, Shen XD, Anselmo D,et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology, 2002,35(4):815-823.
75. 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(5): 598-604.
76. Mishra S,Fujita T,Lama VN,et al.Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. Proc Natl Acad Sci USA,2006,103(13):5191-5196.
77. Zhou HC, Ding WG, Cui XQ et al. Carbon monoxide inhalation ameliorates conditions of lung grafts from rat brain death donors. Chin Med J (Engl),2008; 121(15): 1411-1419.
78. 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(5):1608-1620.
79. Kotsch K, Martins PN, Klemz R,et al. Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal,2007,9(12):2049-2063.
80. Kaizu T, Nakao A, Tsung A, et al. Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery,2005,138(2): 229-235.
81. Sarady JK, Zuckerbraun BS, Bilban M, et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J, 2004,18(7):854-856.
82. Otterbein LE, Otterbein SL, Ifedigbo E, et al. MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Am J Pathol,2003,163(6):2555-2563.
83. Rentsch M, Kienle K, Mueller T, et al. Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation. Transplantation,2005,80(10):1461-1467.
84. Song R, Kubo M, Morse D, et al. Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. Am J Pathol,2003,163(1):231-242.
85. Nakao A, Kimizuka K, Stolz DB, et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol,2003,163(4): 1587-1598.
86. Zhang X, Shan P, Alam J, et al. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alphamitogen-activated protein kinase pathway during ischemia-reperfusion lung injury.J Biol Chem,2003,278(24):22061-22070.
87. Srisook K, Han SS, Choi HS, et al. CO from enhanced HO activity or from CORM-2
inhibits both 02-and NO production and downregulates HO-1 expression in LPS-stimulated macrophages. Biochem Pharmacol.2006,71(3):307-318.
88. True AL, Olive M, Boehm M, et al. Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium,which is rescued by inhaled carbon monoxide. Circ Res.2007,101(9):893-901.
89. Zuckerbraun BS, Chin BY, Bilban M, et al. Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J,2007,21(4):1099-1106.
90. Kim BS, Lim SW, Li C, et al. Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation,2005,79(10):1370-1377.
91. Pae HO, Oh GS, Choi BM, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol,2004, 172(8):4744-4751.
92. Morita T, Mitsialis SA, Koike H, et al. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem,1997,272(52):32804-32809.
93. Peyton KJ, Reyna SV, Chapman GB, et al. Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood,2002, 99(12):4443-4448.
94. Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med,2003,9(2):183-190.
95. Li C, Yang CW. The pathogenesis and treatment of chronic allograft nephropathy. Nat Rev Nephrol,2009,5(9):513-519.
96. Neto JS, Nakao A, Toyokawa H, et al. Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. Am J Physiol Renal Physiol,2006, 290(2):F324-334.
97. Song R, Mahidhara RS, Liu F, et al. Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Am J Respir Cell Mol Biol,2002,27(5):603-610.
98. Brar SS, Kennedy TP, Sturrock AB, et al. NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol,2002,282(4):L782-795.
99. Minamoto K, Harada H, Lama VN, et al. Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase. J Exp Med,2005,202(2):283-294.
100.Djamali A, Samaniego M. Fibrogenesis in kidney transplantation:potential targets for prevention and therapy. Transplantation,2009,88(10):1149-1156.
101.Zhou Z, Song R, Fattman CL, et al. Carbon monoxide suppresses bleomycin-induced lung fibrosis. Am J Pathol,2005,166(1):27-37.
102.Gunther L, Berberat PO, Haga M, et al. Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation. Diabetes,2002,51(4):994-999.
103.Goldberg A, Parolini M, Chin BY, et al.Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J,2007,21(11):2840-2848.
104.Lee SS, Gao W, Mazzola S, et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J,2007,21(13):3450-3457.
105.Soares MP, Lin Y, Anrather J, et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med.1998,4(9):1073-1077.
106.Sato K, Balla J, Otterbein L, et al. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J Immunol,2001,166(6): 4185-4194.
107.Shennib H, Adoumie R, Fraser R. Successful transplantation of a lung allograft from a carbon monoxide-poisoning victim. J Heart Lung Transplant,1992,11(1 Pt 1):68-71.
108.Luckraz H, Tsui SS, Parameshwar J, et al. Improved outcome with organs from carbon monoxide poisoned donors for intrathoracic transplantation. Ann Thorac Surg,2001, 72(3):709-713.
109.Verran D, Chui A, Painter D, et al. Use of liver allografts from carbon monoxide poisoned cadaveric donors. Transplantation,1996,62(10):1514-1515.
110.Hantson P, Vekemans MC, Squifflet JP, et al. Outcome following organ removal from poisoned donors:experience with 12 cases a review of the literature. Transpl Int,1995, 8(3):185-189.
111.Bojakowski K, Gaciong Z, Grochowiecki T, et al. Carbon monoxide may reduce ischemia reperfusion injury:a case report of complicated kidney transplantation from a carbon monoxide poisoned donor. Transplant Proc,2007,39(9):2928-2929.
112.Karwande SV, Hopfenbeck JA, Renlund DQ et al. An avoidable pitfall in donor selection for heart transplantation. Utah Heart Transplant Program. J Heart Transplant, 1989,8(5):422-424.
113.Roberts JR, Bain M, Klachko MN, et al. Successful heart transplantation from a victim of carbon monoxide poisoning. Ann Emerg Med,1995,26(5):652-655.
114.Martin-Suarez S, Mikus E, Pilato E, et al. Cardiac transplantation from a carbon monoxide intoxicated donor. Transplant Proc,2008,40(5):1563-1565.
115.Sezgin A, Akay TH, Ozkan S, et al. Successful cardiac transplantation from donor with carbon monoxide intoxication:a case report. Transplant Proc,2008,40(1):324-325.
116.Wood DM, Dargan PI, Jones AL. Poisoned patients as potential organ donors:postal survey of transplant centres and intensive care units. Crit Care,2003,7(2):147-154.
117.Bathoorn E, Slebos DJ, Postma DS, et al. Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD:a pilot study. Eur Respir J,2007,30(6):1131-1137.
118.Mayr FB, Spiel A, Leitner J, et al. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med,2005,171(4): 354-360.
119.Vos R, Cordemans C, Vanaudenaerde BM, et al. Exhaled carbon monoxide as a noninvasive marker of airway neutrophilia after lung transplantation. Transplantation, 2009,87(10):1579-1583.
120. Van Muylem A, Knoop C, Estenne M. Early detection of chronic pulmonary allograft dysfunction by exhaled biomarkers. Am J Respir Crit Care Med,2007,175(7): 731-736.
121.Matsusaki T, Morimatsu H, Takahashi T, et al. Increased exhaled carbon monoxide concentration during living donor liver transplantation. Int J Mol Med,2008, 21(1):75-81.