天然免疫分子HMGB1在肾脏缺血再灌注损伤和异种移植排斥反应中的作用研究
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摘要
第一部分上调HO-1对缺血再灌注损伤的保护机制与抑制HMGB1释放有关
[目的]本课题组已经发现Copp诱导HO-1高表达能减轻大鼠肾脏缺血再灌注损伤,目前实验为了进一步深入研究保护性基因HO-1在减轻大鼠肾脏缺血再灌注损伤中的作用及其机制,探讨HMGB1在其中是否发挥炎症因子效应。
[方法]课题前期实验以Wistar大鼠为对象,建立大鼠肾脏在体原位缺血再灌注损伤模型,夹闭大鼠左侧肾蒂阻断血供47分钟,恢复血流后切除右肾。实验分三组：1)缺血对照组：缺血再灌后无处理；2)CoPP治疗组：手术前48h和24h分别腹腔内注射CoPP (2.5mg/kg);3)正常组。左肾恢复血供即再灌注24h后检测血清肌酐(Cr)和尿素氮(BUN)值,并取正常及缺血再灌注肾脏标本行HE病理检查,Western-blot检测肾脏组织中HO-1表达,观察CoPP治疗对肾脏长时间缺血(80min)再灌注后大鼠存活的影响。目前实验以免疫组化检测其肾组织内HMGB1、TLR4、MPO、TNF-α的表达情况,以及TUNEL法检测细胞凋亡并计数。
[结果]CoPP治疗组与对照组相比肾功能(Cr和BUN)明显改善(p<0.05),存活实验发现CoPP治疗组5只大鼠全部存活,而对照组6只大鼠中,4只分别于观察第5、5、7、13天死亡,两组具有明显差异(p<0.05)。CoPP治疗组肾组织中HMGB1及TLR4表达明显弱于对照组,且代表单核细胞标志的MPO及细胞因子TNF-α也同样弱于对照组。细胞凋亡情况通过统计后对照组明显高于HO-1保护组,并具有统计学差异(p<0.05)。
[结论]CoPP可效诱导肾脏HO-1高表达保护大鼠肾脏缺血再灌注损伤,其作用机制可能与抑制HMGB1的释放有关,进一步抑制炎症反应,减轻细胞凋亡,进而减少损伤。
第二部分抗HMGB1中和抗体对小鼠肾脏缺血再灌注损伤的保护作用
[目的]探讨高迁移率簇蛋白B1 (HMGB1)在小鼠肾脏缺血再灌注损伤(IRI)模型中的作用,通过抗体阻断HMGB1研究对小鼠肾脏IRI的保护作用。
[方法]以BALB/C小鼠为实验对象,肾缺血前24小时和前30分钟实验组(n=7)分别于腹腔注射兔抗小鼠HMGB1抗体,而对照组(n=7)以等量生理盐水替代作为参照。在体阻断小鼠左肾血流60min,恢复左肾血流的同时切除小鼠右肾,恢复血供再灌注0,3,6或24小时后,在每组每个时间点(n=2)分别取其外周血及左肾。测定血清肌酐(sCr)和尿素氮(BUN)水平,观察肾组织学变化(PAS),免疫组化及Western blot检测肾组织中HMGB1的表达,并检测抗HMGB1抗体的沉积,免疫组化检测肾组织中髓过氧化物酶(MPO)表达,免疫荧光检测TNF-a表达,原位末端脱氧核苷酸转移酶标记法(TUNEL)检测肾组织中细胞凋亡情况。
[结果]正常组肾脏内HMGB1均表达于细胞核内,而对照组HMGB1则在核外明显表达,且在缺血后即有核外表达,随着再灌注时间延长(分别为0,3,6,24小时),HMGB1表达量增多且部位分布更广(细胞外)。对照组肾脏缺血再灌注24小时后血清Cr及BUN分别为(82.46±30.13)μmol/L和(46.46±9.61)μmol/L显著高于实验组的(32.24±22.51)μmol/L和(25.81±11.41)μmol/L(p<0.05)。正常肾及对照组肾组织中未检测到HMGB1抗体沉积,使用抗HMGB1抗体的实验组可见明显HMGB1抗体沉积。PAS显示对照组肾小管细胞大片坏死,管型形成,并有大量出血,与之相比,抗HMGB1治疗组肾组织病变程度明显减轻。对照组肾组织中MPO表达明显强于使用HMGB1的实验组,同时对照组细胞凋亡较实验组显著增多,凋亡细胞数计数具有统计学差异(p<0.05)：对照组肾组织中细胞因子TNF-α也明显强于实验组。
[结论]HMGB1在肾脏IRI中发挥重要作用,而缺血前使用抗HMGB1抗体可明显减轻小鼠IRI,这种保护作用可能通过中和炎性因子HMGB1来抑制肾脏IRI中的炎症反应,并减少炎症导致的凋亡来实现。
第三部分抗HMGB1中和抗体延长大鼠到小鼠异种心脏移植存活的实验研究
[目的]探讨HMGB1对新生大鼠心脏移植到小鼠异种移植心的作用,及其通过抗HMGB1抗体阻断HMGB1能否延长异种移植心存活,并阐明其机制。
[方法]以1周龄SD大鼠为供心供者,BALB/C小鼠为移植心受者,实施颈部心异位心脏移植,抗体治疗组(n=10)于心脏移植前1天起隔天腹腔注射兔抗小鼠HMGB1抗体,而对照组(n=7)不做任何处理。术后观察移植心存活时间,移植心停止搏动即为发生排斥时留取心脏及血清,治疗组另有3例行在第6天留取标本(与对照组进行同期对组),进行病理学检测(HE),免疫组化观察组织中MPO, HMGB1, TLT4的表达及抗体IgG、IgM的沉积,以及补体调节蛋白CD55和CD59,免疫荧光检测JG12表达,TUNEL法检测心脏组织内细胞凋亡情况,流式细胞仪分析循环中抗体IgG、IgM水平。
[结果]对照组心脏存活5-6天,抗体治疗组为7-11天,明显长于对照组(p<0.01)。组织病理上发现对照组排斥心脏呈急性血管性排斥反应特征,而治疗组同期的病变明显轻于前者；同时通过细胞计数显示抗HMGB1抗体治疗组较对照组MPO阳性的浸润细胞显著减少,TUNEL显示细胞凋亡或坏死显著减轻,统计具有显著性差异(p<0.05),而血管内皮完整性的特异性标志JG12则显著强于对照组；另外组化显示抗体治疗组心脏组织内HMGB1及其受体TLR4表达均明显弱于对照组。流式检测以及免疫组化均显示对照组心脏组织内和循环中的异种抗体IgG显著增加,而同期的抗体治疗组IgG的产生和沉积显著减弱。此外,免疫组化显示对照组心脏组织中CD55和CD59明显弱于正常心脏及实验组。
[结论]本研究首次证明,拮抗HMGB1可明显延长大鼠到小鼠异种移植心脏的存活,其可能的机制是通过中和炎性细胞释放的HMGB1,从而抑制一系列炎症反应,阻遏异种抗体的产生并增强补体调节蛋白表达。
PartⅠUpregulation of HO-1 to protect renal ischemia reperfusion injury via inhibiting release of HMGB1.
[Objective] Based on the results of the previous experiments, the mechanism of protection of the protective gene HO-1 on the rat renal ischemia reperfusion injury is studied more thoroughly.
[Method] A dose of 2.5mg/kg of CoPP was administered intraperitoneally into rats 48h and 24h before 47min of renal ischemia. Blood and kidney samples were collected 24h after reperfusion. Serum Cr and BUN were determined to evaluate kidney function. HO-1 expression in kidney was detected by immunohistochemistry and western-blot. Prolongation of renal ischemia time to 80min was undertaken to study the protective effects of CoPP on rat mortality. The expression of HMGB1, TRL4, MPO, and TNF-αwas detected by immunohistochemistry, and the cell apoptosis was detected by TUNEL assay with cell counted.
[Result] The mean serum Cr and BUN levels of the IRI control rats were 134.37±24.26μmol/L and 30.10±3.09mmol/L, CoPP treatment significantly improved renal function after I/R, the mean serum Cr and BUN levels were 48.92±12.92μmol/L and 13.99±5.00mmol/L respectively(p<0.05 vs.IRI control group). CoPP therapy significantly protected rats from lethal kidney ischemia. The expression of HMGB1 and TLR4 in the tissues treated with CoPP was significantly weaker than the control group and the marker of monocyte MPO and cytokine TNF-αin the protected group is also much weaker than the control. The apoptotic cells counted in the HO-1 protected group were statistically less than in the control group.
[Conclusion] Inhibition the release of HMGB1 maybe one of the mechanisms that protective gene HO-1 prevents rat renal ischemia reperfusion injury; furthermore it inhibits the inflammation response and reduces injury.
PartⅡNeutralizing extracellular HMGB1 by using antibody prevents mice from renal ischemia-reperfusion injury
[Objective] To investigate the pattern that High mobility group box 1 (HMGB1) releases during renal ischemia/reperfusion injury (IRI) and relative mechanism that neutralizing the extracellular HMGB1 prevents mice from renal IRI.
[Methods] Renal IRI was induced by clamping the left renal pedicle for 60 min, and some of the kidneys were removed immediately as others collected 24 h later for detection of HMGB1 expression with Immunohistocheistry and Western blot. Rabbit anti-mouse HMGB1 antibody was administered 24 h and 30 min before ischemia as control mice with normal sodium. The therapeutic effects were evaluated in renal function after 24 h of reperfusion, also with histologic examination. Deposits of anti-HMGB1 antibody were detected by Immunohistochemistry and MPO expression was measured by Immunofluorescence. Additionally, TUNEL assays were used to evaluate the apoptosis of renal cells.
[Results] HMGB1 expressed in cell nucleus was passively released by ischemic renal cells as to cytoplasm or even out of cells early as the time prior to reperfusion. When mice were treated, the therapic anti-HMGB1 antibody was detected to deposit at local renal tubules, peritubular capillaries and glomcruli, but no deposits were found in control mice. Consequently, levels of serum creatinine and blood urea nitrogen were significantly decreased in mice treated with anti-HMGB1 antibody ((32.24±22.51)μmol/L, (25.81±11.41)μmol/L, respectively) compared with control mice ((82.46±30.13)μmol/L, (46.46±9.61)μmol/L, respectively,p<0.05). Correspondently, Tissue damage caused by IRI was markedly reduced with less necrosis and hemorrhage as a result of neutralizing antibody treatment. In addition, MPO expression was extremely diminished in treated mice compared with control kidneys, and apoptosis was also significantly decreased (p<0.05).
[Conclusion] HMGB1 may act as a crucial mediator during IRI, and blockage of HMGB1 before ischemia can protect mice against renal IRI, and the mechanism of protection might come from targeting HMGB1 to interfering process of inflammation induce by IRI.
PartⅢAnti-HMGB1 antibody prolongs rat to mouse cardiac xenograft survival xia inhibiting products of anti-donor antibody.
[Objective] To investigate the role of High mobility group box 1 (HMGB1) in the rejection of rat to mouse cardiac xenotransplantation, and relative mechanism that neutralizing the extracellular HMGB1 prolongs xenograft survival.
[Methods] Heterotopic cardiac xenotransplantation was established from One-week-old SD rat to BALB/c mouse. Rabbit anti-mouse HMGB1 antibody was administered by intraperitoneal injection on day-1,0 and every other day until the study end point or graft rejection, while control mice was received control IgG or PBS instead of neutralizing antibody. The therapeutic effects were evaluated by the survival of xenograft, and some of hearts were obtained from recipients which were therapied at day 6 as symotanians control. MPO, CD3, HMGB1, TLR4 expression were measured by Immunohistochemical staining and cytockine TNF, IL2, IL10 were evaluated by RT-PCR. TUNEL assays were used to evaluate the apoptosis of renal cells. Additionally, serum or intra graft IgG and IgM were measured and CRPs alse were avaluated to analyse the mechanism.
[Results] The xenograft survival was significantly prolonged by neutrolizing antibody from 5 days to 9 days. In concurrent control groups, the neutralizing group exibited clear vessels, fewer interstitial hemorrhages, and integrated endothelial cell with mass JG12-positive cells and less apotosis cells. Furthermore, less MPO and CD3 positive cells were observed and HMGB1 with its receptor TLR4 were much weaker than the control group. More interestingly, the FCM and immunohistochemistry showed the less IgG and IgM in the circle and xenograft, and much more expression of CRPs in the treated gourp.
[Conclusion] we have shown that anti-HMGBl antibody efficiently delayed AVR by markedly inhibiting anti-donor xAb production and up-regulating CRPs in the xenograft in rat to mouse cardiac transplantation.
[目的]本课题组已经发现Copp诱导HO-1高表达能减轻大鼠肾脏缺血再灌注损伤,目前实验为了进一步深入研究保护性基因HO-1在减轻大鼠肾脏缺血再灌注损伤中的作用及其机制,探讨HMGB1在其中是否发挥炎症因子效应。
[方法]课题前期实验以Wistar大鼠为对象,建立大鼠肾脏在体原位缺血再灌注损伤模型,夹闭大鼠左侧肾蒂阻断血供47分钟,恢复血流后切除右肾。实验分三组：1)缺血对照组：缺血再灌后无处理；2)CoPP治疗组：手术前48h和24h分别腹腔内注射CoPP (2.5mg/kg);3)正常组。左肾恢复血供即再灌注24h后检测血清肌酐(Cr)和尿素氮(BUN)值,并取正常及缺血再灌注肾脏标本行HE病理检查,Western-blot检测肾脏组织中HO-1表达,观察CoPP治疗对肾脏长时间缺血(80min)再灌注后大鼠存活的影响。目前实验以免疫组化检测其肾组织内HMGB1、TLR4、MPO、TNF-α的表达情况,以及TUNEL法检测细胞凋亡并计数。
[结果]CoPP治疗组与对照组相比肾功能(Cr和BUN)明显改善(p<0.05),存活实验发现CoPP治疗组5只大鼠全部存活,而对照组6只大鼠中,4只分别于观察第5、5、7、13天死亡,两组具有明显差异(p<0.05)。CoPP治疗组肾组织中HMGB1及TLR4表达明显弱于对照组,且代表单核细胞标志的MPO及细胞因子TNF-α也同样弱于对照组。细胞凋亡情况通过统计后对照组明显高于HO-1保护组,并具有统计学差异(p<0.05)。
[结论]CoPP可效诱导肾脏HO-1高表达保护大鼠肾脏缺血再灌注损伤,其作用机制可能与抑制HMGB1的释放有关,进一步抑制炎症反应,减轻细胞凋亡,进而减少损伤。
第二部分抗HMGB1中和抗体对小鼠肾脏缺血再灌注损伤的保护作用
[目的]探讨高迁移率簇蛋白B1 (HMGB1)在小鼠肾脏缺血再灌注损伤(IRI)模型中的作用,通过抗体阻断HMGB1研究对小鼠肾脏IRI的保护作用。
[方法]以BALB/C小鼠为实验对象,肾缺血前24小时和前30分钟实验组(n=7)分别于腹腔注射兔抗小鼠HMGB1抗体,而对照组(n=7)以等量生理盐水替代作为参照。在体阻断小鼠左肾血流60min,恢复左肾血流的同时切除小鼠右肾,恢复血供再灌注0,3,6或24小时后,在每组每个时间点(n=2)分别取其外周血及左肾。测定血清肌酐(sCr)和尿素氮(BUN)水平,观察肾组织学变化(PAS),免疫组化及Western blot检测肾组织中HMGB1的表达,并检测抗HMGB1抗体的沉积,免疫组化检测肾组织中髓过氧化物酶(MPO)表达,免疫荧光检测TNF-a表达,原位末端脱氧核苷酸转移酶标记法(TUNEL)检测肾组织中细胞凋亡情况。
[结果]正常组肾脏内HMGB1均表达于细胞核内,而对照组HMGB1则在核外明显表达,且在缺血后即有核外表达,随着再灌注时间延长(分别为0,3,6,24小时),HMGB1表达量增多且部位分布更广(细胞外)。对照组肾脏缺血再灌注24小时后血清Cr及BUN分别为(82.46±30.13)μmol/L和(46.46±9.61)μmol/L显著高于实验组的(32.24±22.51)μmol/L和(25.81±11.41)μmol/L(p<0.05)。正常肾及对照组肾组织中未检测到HMGB1抗体沉积,使用抗HMGB1抗体的实验组可见明显HMGB1抗体沉积。PAS显示对照组肾小管细胞大片坏死,管型形成,并有大量出血,与之相比,抗HMGB1治疗组肾组织病变程度明显减轻。对照组肾组织中MPO表达明显强于使用HMGB1的实验组,同时对照组细胞凋亡较实验组显著增多,凋亡细胞数计数具有统计学差异(p<0.05)：对照组肾组织中细胞因子TNF-α也明显强于实验组。
[结论]HMGB1在肾脏IRI中发挥重要作用,而缺血前使用抗HMGB1抗体可明显减轻小鼠IRI,这种保护作用可能通过中和炎性因子HMGB1来抑制肾脏IRI中的炎症反应,并减少炎症导致的凋亡来实现。
第三部分抗HMGB1中和抗体延长大鼠到小鼠异种心脏移植存活的实验研究
[目的]探讨HMGB1对新生大鼠心脏移植到小鼠异种移植心的作用,及其通过抗HMGB1抗体阻断HMGB1能否延长异种移植心存活,并阐明其机制。
[方法]以1周龄SD大鼠为供心供者,BALB/C小鼠为移植心受者,实施颈部心异位心脏移植,抗体治疗组(n=10)于心脏移植前1天起隔天腹腔注射兔抗小鼠HMGB1抗体,而对照组(n=7)不做任何处理。术后观察移植心存活时间,移植心停止搏动即为发生排斥时留取心脏及血清,治疗组另有3例行在第6天留取标本(与对照组进行同期对组),进行病理学检测(HE),免疫组化观察组织中MPO, HMGB1, TLT4的表达及抗体IgG、IgM的沉积,以及补体调节蛋白CD55和CD59,免疫荧光检测JG12表达,TUNEL法检测心脏组织内细胞凋亡情况,流式细胞仪分析循环中抗体IgG、IgM水平。
[结果]对照组心脏存活5-6天,抗体治疗组为7-11天,明显长于对照组(p<0.01)。组织病理上发现对照组排斥心脏呈急性血管性排斥反应特征,而治疗组同期的病变明显轻于前者；同时通过细胞计数显示抗HMGB1抗体治疗组较对照组MPO阳性的浸润细胞显著减少,TUNEL显示细胞凋亡或坏死显著减轻,统计具有显著性差异(p<0.05),而血管内皮完整性的特异性标志JG12则显著强于对照组；另外组化显示抗体治疗组心脏组织内HMGB1及其受体TLR4表达均明显弱于对照组。流式检测以及免疫组化均显示对照组心脏组织内和循环中的异种抗体IgG显著增加,而同期的抗体治疗组IgG的产生和沉积显著减弱。此外,免疫组化显示对照组心脏组织中CD55和CD59明显弱于正常心脏及实验组。
[结论]本研究首次证明,拮抗HMGB1可明显延长大鼠到小鼠异种移植心脏的存活,其可能的机制是通过中和炎性细胞释放的HMGB1,从而抑制一系列炎症反应,阻遏异种抗体的产生并增强补体调节蛋白表达。
PartⅠUpregulation of HO-1 to protect renal ischemia reperfusion injury via inhibiting release of HMGB1.
[Objective] Based on the results of the previous experiments, the mechanism of protection of the protective gene HO-1 on the rat renal ischemia reperfusion injury is studied more thoroughly.
[Method] A dose of 2.5mg/kg of CoPP was administered intraperitoneally into rats 48h and 24h before 47min of renal ischemia. Blood and kidney samples were collected 24h after reperfusion. Serum Cr and BUN were determined to evaluate kidney function. HO-1 expression in kidney was detected by immunohistochemistry and western-blot. Prolongation of renal ischemia time to 80min was undertaken to study the protective effects of CoPP on rat mortality. The expression of HMGB1, TRL4, MPO, and TNF-αwas detected by immunohistochemistry, and the cell apoptosis was detected by TUNEL assay with cell counted.
[Result] The mean serum Cr and BUN levels of the IRI control rats were 134.37±24.26μmol/L and 30.10±3.09mmol/L, CoPP treatment significantly improved renal function after I/R, the mean serum Cr and BUN levels were 48.92±12.92μmol/L and 13.99±5.00mmol/L respectively(p<0.05 vs.IRI control group). CoPP therapy significantly protected rats from lethal kidney ischemia. The expression of HMGB1 and TLR4 in the tissues treated with CoPP was significantly weaker than the control group and the marker of monocyte MPO and cytokine TNF-αin the protected group is also much weaker than the control. The apoptotic cells counted in the HO-1 protected group were statistically less than in the control group.
[Conclusion] Inhibition the release of HMGB1 maybe one of the mechanisms that protective gene HO-1 prevents rat renal ischemia reperfusion injury; furthermore it inhibits the inflammation response and reduces injury.
PartⅡNeutralizing extracellular HMGB1 by using antibody prevents mice from renal ischemia-reperfusion injury
[Objective] To investigate the pattern that High mobility group box 1 (HMGB1) releases during renal ischemia/reperfusion injury (IRI) and relative mechanism that neutralizing the extracellular HMGB1 prevents mice from renal IRI.
[Methods] Renal IRI was induced by clamping the left renal pedicle for 60 min, and some of the kidneys were removed immediately as others collected 24 h later for detection of HMGB1 expression with Immunohistocheistry and Western blot. Rabbit anti-mouse HMGB1 antibody was administered 24 h and 30 min before ischemia as control mice with normal sodium. The therapeutic effects were evaluated in renal function after 24 h of reperfusion, also with histologic examination. Deposits of anti-HMGB1 antibody were detected by Immunohistochemistry and MPO expression was measured by Immunofluorescence. Additionally, TUNEL assays were used to evaluate the apoptosis of renal cells.
[Results] HMGB1 expressed in cell nucleus was passively released by ischemic renal cells as to cytoplasm or even out of cells early as the time prior to reperfusion. When mice were treated, the therapic anti-HMGB1 antibody was detected to deposit at local renal tubules, peritubular capillaries and glomcruli, but no deposits were found in control mice. Consequently, levels of serum creatinine and blood urea nitrogen were significantly decreased in mice treated with anti-HMGB1 antibody ((32.24±22.51)μmol/L, (25.81±11.41)μmol/L, respectively) compared with control mice ((82.46±30.13)μmol/L, (46.46±9.61)μmol/L, respectively,p<0.05). Correspondently, Tissue damage caused by IRI was markedly reduced with less necrosis and hemorrhage as a result of neutralizing antibody treatment. In addition, MPO expression was extremely diminished in treated mice compared with control kidneys, and apoptosis was also significantly decreased (p<0.05).
[Conclusion] HMGB1 may act as a crucial mediator during IRI, and blockage of HMGB1 before ischemia can protect mice against renal IRI, and the mechanism of protection might come from targeting HMGB1 to interfering process of inflammation induce by IRI.
PartⅢAnti-HMGB1 antibody prolongs rat to mouse cardiac xenograft survival xia inhibiting products of anti-donor antibody.
[Objective] To investigate the role of High mobility group box 1 (HMGB1) in the rejection of rat to mouse cardiac xenotransplantation, and relative mechanism that neutralizing the extracellular HMGB1 prolongs xenograft survival.
[Methods] Heterotopic cardiac xenotransplantation was established from One-week-old SD rat to BALB/c mouse. Rabbit anti-mouse HMGB1 antibody was administered by intraperitoneal injection on day-1,0 and every other day until the study end point or graft rejection, while control mice was received control IgG or PBS instead of neutralizing antibody. The therapeutic effects were evaluated by the survival of xenograft, and some of hearts were obtained from recipients which were therapied at day 6 as symotanians control. MPO, CD3, HMGB1, TLR4 expression were measured by Immunohistochemical staining and cytockine TNF, IL2, IL10 were evaluated by RT-PCR. TUNEL assays were used to evaluate the apoptosis of renal cells. Additionally, serum or intra graft IgG and IgM were measured and CRPs alse were avaluated to analyse the mechanism.
[Results] The xenograft survival was significantly prolonged by neutrolizing antibody from 5 days to 9 days. In concurrent control groups, the neutralizing group exibited clear vessels, fewer interstitial hemorrhages, and integrated endothelial cell with mass JG12-positive cells and less apotosis cells. Furthermore, less MPO and CD3 positive cells were observed and HMGB1 with its receptor TLR4 were much weaker than the control group. More interestingly, the FCM and immunohistochemistry showed the less IgG and IgM in the circle and xenograft, and much more expression of CRPs in the treated gourp.
[Conclusion] we have shown that anti-HMGBl antibody efficiently delayed AVR by markedly inhibiting anti-donor xAb production and up-regulating CRPs in the xenograft in rat to mouse cardiac transplantation.
引文
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