前列腺素E1及低分子肝素对大鼠肾缺血再灌注损伤的免疫调节作用及机制研究
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摘要
[目的]
通过建立大鼠肾缺血再灌注损伤(ischemia reperfusion injury,IRI)造成的缺血性急性肾衰竭(ischemia acute renal failure,iARF)模型,观察iARF不同阶段血清致炎(TNF-α、IFN-γ)和抗炎细胞因子(IL-4、IL-10)的表达水平变化,以及对中性粒细胞细胞间黏附分子-1(intercellular adhesion molecular-1,ICAM-1)、单核细胞趋化蛋白-1(MCP-1)、核因子-κB(NF-κB)、肾损伤分子-1(Kidney injury molecule 1,KIM-1)、血管紧张素Ⅱ(AngiotensinⅡ,ANGⅡ)、血管紧张素Ⅱ1型受体(AngiotensinⅡreceptorⅠ,AT I R)、血栓调节蛋白(Thrombomodulin,TM)表达的影响,以探讨前列腺素E1(Prostaglandin E1,PGE1)及低分子量肝素(low molecularweight heparin,LMWH)在改善iARF时肾脏免疫反应紊乱、肾脏病理损伤中的作用。
[方法]
第一部分:45只健康Wistar大鼠(8周龄)随机分为假手术对照组(Sham)、模型组(IRI)和PGE1治疗组。假手术对照组只行麻醉、开腹、不阻断肾动脉;模型组与治疗组均行右侧肾切除,在夹闭左肾动脉5 min后经下腔静脉给PGE1治疗组的大鼠注射PGE1(5 ng/kg),模型组则注射等剂量的生理盐水。按不同再灌注时间(1、3、6、24 h)再分为4组,并于相应时间点采集标本。RT-PCR法检测TNF-α、IL-10、ICAM-1、KIM-1、ANGⅡ、AT I R、MCP-1、NF-κB的mRNA水平变化。测定血清Cr、BUN,ELISA法检测各组血清TNF-α及IL-10的含量。免疫组织化学方法检测肾脏组织MCP-1、NF-κB、TM的表达。光学显微镜同步观察肾脏病理改变。
第二部分:65只健康Wistar大鼠(8周龄)按照相同的方法分组,除假手术组外其他两组均切除右肾,左侧肾动脉夹闭60 min肾缺血后再灌注制备动物模型;LMWH治疗组于再灌注前30 min经下腔静脉注射低分子肝素500 U/kg进行干预治疗,模型组和正常对照组给予等量生理盐水注射。各组按不同再灌注时间(1、3、6、24、48、72 h)再分为6组,并于相应时间点处死大鼠。采血测定血肌酐(Cr)、尿素氮(BUN),应用酶联免疫吸附试验(ELISA)方法检测各组血清TNF-α、IFN-γ、IL-4及IL-10含量。RT-PCR法检测TNF-α、IL-10、ICAM-1、KIM-1、ANGⅡ、AT I R、MCP-1、NF-κB的mRNA水平。用流式细胞仪(flow cytometry)测定ICAM-1的表达。免疫组织化学方法检测肾脏组织MCP-1、NF-κB、TM的表达。光学显微镜同步观察肾脏病理改变。
[结果]
1.建模后5 min进行PGE1的注射干预,结果显示TNF-α在3 h和6 h;IL-10、MCP-1在1 h和3 h同非治疗组差异有统计学意义,而治疗组内3 h和6 h差异无统计学意义。
2.与模型组形态学比较,PGE1治疗组小管上皮肿胀较轻,蛋白管型较少;再灌注24 h模型组可见小球扩张充血,小管上皮肿胀,间质血管扩张充血及细胞管型。免疫组织化学方法显示PGE1治疗组MCP-1表达较模型组明显减少,差异有统计学意义(P＜0.01)。
3.缺血再灌注24 h时模型组和治疗组的血Cr、BUN水平明显升高,与假手术组相比,差异有统计学意义(P＜0.01),而治疗组和模型组之间差异无统计学意义(P＞0.05)。
4.LMWH治疗组ICAM-1的表达较模型组在缺血再灌注6 h、24 h降低了72.2%、48.3%,差异有统计学意义(P＜0.01),治疗组48 h较模型组降低61.4%。
5.模型组单核巨噬细胞分泌的血清致炎细胞因子(TNF-α、IFN-γ)浓度较假手术组增加,血清抗炎性细胞因子(IL-4、IL-10)浓度降低;经LMWH治疗后总体变化趋势是:TNF-α、IFN-γ浓度较模型组降低,IL-4、IL-10浓度升高。
6.缺血再灌注早期,光镜下可见模型组肾小管上皮细胞肿胀,空泡样变性,出现不同程度变性和坏死。缺血再灌注24 h时,模型组可见肾髓质高度充血,细胞核固缩、溶解、消失,肾外髓质大部分肾小管上皮细胞坏死脱落,远端肾小管及集合管内可见细胞管型。LMWH治疗后肾脏组织损伤明显减轻。
7.免疫组织化学方法显示,模型组中MCP-1蛋白主要分布在外髓质带的近端肾小管上皮细胞内和肾间质中,肾小球系膜区及毛细血管有少量表达,其中以肾小管上皮细胞中表达为主;肾组织NF-KB表达在缺血再灌注3 h表达增加,缺血再灌注24 h达最高峰,主要在肾小球及肾小管及肾间质中,LMWH治疗组MCP-1、NF-KB表达均较模型组明显减少,差异有统计学意义(P＜0.01),AT I R则表达显著增高。
[结论]
1.本研究在成功地建立大鼠缺血性急性肾衰竭模型的基础上,证明缺血再灌注引起的炎症级联反应是导致急性肾损伤的一个重要因素。
2.PGE1可显著降低TNF-α的表达、促进IL-10的表达,减轻炎症的发生与发展;PGE1抑制血小板释放TM,降低血小板聚集,改善血液流变学状态,促进内皮细胞保护。
3.LMWH可减少致炎细胞因子如TNF-α、IFN-γ的分泌,增加抗炎细胞因子如IL-4、IL-10的分泌,下调NF-κB水平,抑制MCP-1和ICAM-1的表达,从而减轻炎症的发生与发展,对于保护肾功能具有积极的意义。改善毛细血管血流紊乱状态和内皮细胞功能,重建机体免疫系统内稳状态。
OBJECTIVE:To approach the immuno-protection and their possible mechanisms of prostaglandin E1(PGE1) and low molecular weight heparins(LMWH) against the experimental renal ischemia reperfusion injury(IRI) in rat model.IRI model was establis hed and treated with PGE1 and LMWH respectively.The expression of proinflammatory cytokines(TNF-aαIFN-γ) and anti-inflammatory cytokines(IL-4,IL-10) as well as polymorphonuclear neutrophils-derived intercellular adhesion molecular-1(ICAM-1), kidney injury molecule 1(KIM-1),angiotensinⅡ(ANGⅡ),angiotensinⅡreceptorⅠ(ATⅠR),thrombomodulin(TM),monocyte chemoattractant protein-1(MCP-1) and nuclear factor-κB(NF-κB) were estimated either in protein or mRNA level.
METHODS:In part 1,45 healthy 8-weeks-old Wistar rats were divided into 3 groups according to defferent intervention methods(Sham-operated control,IRI control and PGE1 treated).Meanwhile,3 groups were stratified further according to the postoperative observation periods(1 h,3 h,6 h and 24 h).The right kidney was removed, the renal artery of left kidney in IRI control group and PGE1 treated group were occluded with a vascular clamp for 60 minutes.PGE1 treatedgroup received a PGE1 injection at the dose of 25 ng/kg after the left renal artery was occluded for 5 min.Other groups were treated with equal doses of normal saline.Blood and tissue specimen were collected at 1,3, 6 and 24 h respectively.Levels of serum creatinine(Scr) and blood urea nitrogen(BUN) were analysed.TNF-α,IFN-γ,,IL-4 and IL-10 were detected by ELISA in each group. Expressions in mRNA level of TNF-α,IL-10,MCP-1,NF-κB,KIM-1,ANGⅡ,ATⅠR, ICAM-1 were measured by real time PCR(RT-PCR).Flow cytometry was used to examine the expression of ICAM-1.Immunohistochemisal method was also applied for observation the expression of MCP-1,NF-κB and TM in renal tissue specimen.
In part 2,65 healthy 8-weeks-old Wistar rats were also divided randomly into following groups:Sham-operated control group,IRI control group and LMWH treatment group.Meanwhile,3 groups were stratified further according to the postoperative observation periods(1 h,3 h,6 h,24 h,48 h and 72 h).Right kidney removed,the renal artery of left kidney in IRI control group and LMWH treatment group were occluded with a vascular clamp for 60 minutes.Instead of PGE1,we injected LMWH(500 U/kg) in rats' inferior vena at 30 minutes before reperfusion.Other groups treated with equal doses of normal saline.Blood and tissue specimen were collected at 1,3,6,24,48 and 72 h respectively.Levels of serum Scr and blood BUN were analysed.TNF-α,IFN-γ,,IL-4 and IL-10 were detected by ELISA in each group.Expressions in mRNA level of TNF-α, IL-10,MCP-1,NF-κB,KIM-1,ANGⅡ,ATⅠR,ICAM-1 were measured by RT-PCR. Flow cytometry was used to examine the expression of ICAM-1.Immuno histochemisal method was also applied for obvervation of the expression of MCP-1,NF-κB and TM in renal tissue specimen.
RESULTS:1.PGE1 treatment made TNF-αat the point of 3 h and 6 h,IL-10, MCP-1 at 1 h and 3 h,statistical significant increased compared to AKI group.While there were no statistically significance at 3 h and 6 h within AKI group.
2.Compared to AKI group,PGE1 treated group shows much slight appearances in renal tubular epithelial cell intumesce and protein cast formation.Glomerulum ectasia and hyperemia,renal tubular epithelial intumesces,matrix angiectasia and cellular cast could be seen in the IRI 24 h group.Immunohistochemistry shows that the level of MCP-1 and AngⅡwere declined obviously in PGE1 treated group(P＜0.01).
3.24 h after reperfusion,the levels of serum Cr and BUN in IRI group and LMWH treatment group were higher than the Sham operated group(P＜0.01).Yet there was no significance in IRI group and LMWH treatment group(P＞0.05).
4.After LMWH treatment,The expression of ICAM-1 in PMNs reduced 72.2%,48.3 %and 61.4%at IR 6,24 and 48 h(P＜0.01)
5.24 h after reperfusion,serum TNF-αsecreted by mononuclear macrophages and IFN-γby Th1 cell in LMWH treatment group were lower than in IRI group(P＜0.01), Meanwhile,the levels of serum IL-4 and IL-10 secreted by Th2 cell in LMWH treatment group were higher than IRI group(P＜0.01).
6.The renal damage of LMWH treated group was much less marked compared to that of IRI group as observed under the light microscope.
7.Compared to IRI group,The expression of MCP-1 was significantly decreased at IR 6 h,24 h in LMWH treated group(P＜0.01).LMWH treatment reduced the expression of NF-κB significantly in glomcrulus of IRI group from 24.45%to 12.23%at IR 6 h after injury(P＜0.01).Meanwhile,the level of NF-κB in renal tubule decreased from 45.20%to 20.00%.While the expression of ATⅠR were increased.
CONCLUSIONS:1.We establis hed the rat ischemia acute renal failure model successfully by the right kidney removement and the left renal artery occluded with a vascular clamp for 60 minutes.IRI may elevate the expression of proinflammatory cytokines in rat plasma,activates ICAM-1 to promote immunoreaction between leucocyte and renal tubular epithelial cell,and lead to AKI.
2.PGE1 exhibits the inhibition to the secretion of the proinflammatory cytokines TNF-α,IFN-γ,and elevates the level of anti-inflammatory cytokines IL-4 and IL-10, leading to the depression of the over-inmmuoreaction.PGE1 could prevent platelets from releasing TM,and it was benefit to reduce platelet aggregation and to protect endothelial cell function.
3.LMWH also inhibits the secretion of the proinflammatory cytokines TNF-α,IFN-γand elevates the level of anti-inflammatory cytokines IL-4 and IL-10.It also down-regulates the expression of NF-κB,MCP-1 and ICAM-1 which are benefit for rebuilding the steady state of immune responses and to protect the renal function.
通过建立大鼠肾缺血再灌注损伤(ischemia reperfusion injury,IRI)造成的缺血性急性肾衰竭(ischemia acute renal failure,iARF)模型,观察iARF不同阶段血清致炎(TNF-α、IFN-γ)和抗炎细胞因子(IL-4、IL-10)的表达水平变化,以及对中性粒细胞细胞间黏附分子-1(intercellular adhesion molecular-1,ICAM-1)、单核细胞趋化蛋白-1(MCP-1)、核因子-κB(NF-κB)、肾损伤分子-1(Kidney injury molecule 1,KIM-1)、血管紧张素Ⅱ(AngiotensinⅡ,ANGⅡ)、血管紧张素Ⅱ1型受体(AngiotensinⅡreceptorⅠ,AT I R)、血栓调节蛋白(Thrombomodulin,TM)表达的影响,以探讨前列腺素E1(Prostaglandin E1,PGE1)及低分子量肝素(low molecularweight heparin,LMWH)在改善iARF时肾脏免疫反应紊乱、肾脏病理损伤中的作用。
[方法]
第一部分:45只健康Wistar大鼠(8周龄)随机分为假手术对照组(Sham)、模型组(IRI)和PGE1治疗组。假手术对照组只行麻醉、开腹、不阻断肾动脉;模型组与治疗组均行右侧肾切除,在夹闭左肾动脉5 min后经下腔静脉给PGE1治疗组的大鼠注射PGE1(5 ng/kg),模型组则注射等剂量的生理盐水。按不同再灌注时间(1、3、6、24 h)再分为4组,并于相应时间点采集标本。RT-PCR法检测TNF-α、IL-10、ICAM-1、KIM-1、ANGⅡ、AT I R、MCP-1、NF-κB的mRNA水平变化。测定血清Cr、BUN,ELISA法检测各组血清TNF-α及IL-10的含量。免疫组织化学方法检测肾脏组织MCP-1、NF-κB、TM的表达。光学显微镜同步观察肾脏病理改变。
第二部分:65只健康Wistar大鼠(8周龄)按照相同的方法分组,除假手术组外其他两组均切除右肾,左侧肾动脉夹闭60 min肾缺血后再灌注制备动物模型;LMWH治疗组于再灌注前30 min经下腔静脉注射低分子肝素500 U/kg进行干预治疗,模型组和正常对照组给予等量生理盐水注射。各组按不同再灌注时间(1、3、6、24、48、72 h)再分为6组,并于相应时间点处死大鼠。采血测定血肌酐(Cr)、尿素氮(BUN),应用酶联免疫吸附试验(ELISA)方法检测各组血清TNF-α、IFN-γ、IL-4及IL-10含量。RT-PCR法检测TNF-α、IL-10、ICAM-1、KIM-1、ANGⅡ、AT I R、MCP-1、NF-κB的mRNA水平。用流式细胞仪(flow cytometry)测定ICAM-1的表达。免疫组织化学方法检测肾脏组织MCP-1、NF-κB、TM的表达。光学显微镜同步观察肾脏病理改变。
[结果]
1.建模后5 min进行PGE1的注射干预,结果显示TNF-α在3 h和6 h;IL-10、MCP-1在1 h和3 h同非治疗组差异有统计学意义,而治疗组内3 h和6 h差异无统计学意义。
2.与模型组形态学比较,PGE1治疗组小管上皮肿胀较轻,蛋白管型较少;再灌注24 h模型组可见小球扩张充血,小管上皮肿胀,间质血管扩张充血及细胞管型。免疫组织化学方法显示PGE1治疗组MCP-1表达较模型组明显减少,差异有统计学意义(P＜0.01)。
3.缺血再灌注24 h时模型组和治疗组的血Cr、BUN水平明显升高,与假手术组相比,差异有统计学意义(P＜0.01),而治疗组和模型组之间差异无统计学意义(P＞0.05)。
4.LMWH治疗组ICAM-1的表达较模型组在缺血再灌注6 h、24 h降低了72.2%、48.3%,差异有统计学意义(P＜0.01),治疗组48 h较模型组降低61.4%。
5.模型组单核巨噬细胞分泌的血清致炎细胞因子(TNF-α、IFN-γ)浓度较假手术组增加,血清抗炎性细胞因子(IL-4、IL-10)浓度降低;经LMWH治疗后总体变化趋势是:TNF-α、IFN-γ浓度较模型组降低,IL-4、IL-10浓度升高。
6.缺血再灌注早期,光镜下可见模型组肾小管上皮细胞肿胀,空泡样变性,出现不同程度变性和坏死。缺血再灌注24 h时,模型组可见肾髓质高度充血,细胞核固缩、溶解、消失,肾外髓质大部分肾小管上皮细胞坏死脱落,远端肾小管及集合管内可见细胞管型。LMWH治疗后肾脏组织损伤明显减轻。
7.免疫组织化学方法显示,模型组中MCP-1蛋白主要分布在外髓质带的近端肾小管上皮细胞内和肾间质中,肾小球系膜区及毛细血管有少量表达,其中以肾小管上皮细胞中表达为主;肾组织NF-KB表达在缺血再灌注3 h表达增加,缺血再灌注24 h达最高峰,主要在肾小球及肾小管及肾间质中,LMWH治疗组MCP-1、NF-KB表达均较模型组明显减少,差异有统计学意义(P＜0.01),AT I R则表达显著增高。
[结论]
1.本研究在成功地建立大鼠缺血性急性肾衰竭模型的基础上,证明缺血再灌注引起的炎症级联反应是导致急性肾损伤的一个重要因素。
2.PGE1可显著降低TNF-α的表达、促进IL-10的表达,减轻炎症的发生与发展;PGE1抑制血小板释放TM,降低血小板聚集,改善血液流变学状态,促进内皮细胞保护。
3.LMWH可减少致炎细胞因子如TNF-α、IFN-γ的分泌,增加抗炎细胞因子如IL-4、IL-10的分泌,下调NF-κB水平,抑制MCP-1和ICAM-1的表达,从而减轻炎症的发生与发展,对于保护肾功能具有积极的意义。改善毛细血管血流紊乱状态和内皮细胞功能,重建机体免疫系统内稳状态。
OBJECTIVE:To approach the immuno-protection and their possible mechanisms of prostaglandin E1(PGE1) and low molecular weight heparins(LMWH) against the experimental renal ischemia reperfusion injury(IRI) in rat model.IRI model was establis hed and treated with PGE1 and LMWH respectively.The expression of proinflammatory cytokines(TNF-aαIFN-γ) and anti-inflammatory cytokines(IL-4,IL-10) as well as polymorphonuclear neutrophils-derived intercellular adhesion molecular-1(ICAM-1), kidney injury molecule 1(KIM-1),angiotensinⅡ(ANGⅡ),angiotensinⅡreceptorⅠ(ATⅠR),thrombomodulin(TM),monocyte chemoattractant protein-1(MCP-1) and nuclear factor-κB(NF-κB) were estimated either in protein or mRNA level.
METHODS:In part 1,45 healthy 8-weeks-old Wistar rats were divided into 3 groups according to defferent intervention methods(Sham-operated control,IRI control and PGE1 treated).Meanwhile,3 groups were stratified further according to the postoperative observation periods(1 h,3 h,6 h and 24 h).The right kidney was removed, the renal artery of left kidney in IRI control group and PGE1 treated group were occluded with a vascular clamp for 60 minutes.PGE1 treatedgroup received a PGE1 injection at the dose of 25 ng/kg after the left renal artery was occluded for 5 min.Other groups were treated with equal doses of normal saline.Blood and tissue specimen were collected at 1,3, 6 and 24 h respectively.Levels of serum creatinine(Scr) and blood urea nitrogen(BUN) were analysed.TNF-α,IFN-γ,,IL-4 and IL-10 were detected by ELISA in each group. Expressions in mRNA level of TNF-α,IL-10,MCP-1,NF-κB,KIM-1,ANGⅡ,ATⅠR, ICAM-1 were measured by real time PCR(RT-PCR).Flow cytometry was used to examine the expression of ICAM-1.Immunohistochemisal method was also applied for observation the expression of MCP-1,NF-κB and TM in renal tissue specimen.
In part 2,65 healthy 8-weeks-old Wistar rats were also divided randomly into following groups:Sham-operated control group,IRI control group and LMWH treatment group.Meanwhile,3 groups were stratified further according to the postoperative observation periods(1 h,3 h,6 h,24 h,48 h and 72 h).Right kidney removed,the renal artery of left kidney in IRI control group and LMWH treatment group were occluded with a vascular clamp for 60 minutes.Instead of PGE1,we injected LMWH(500 U/kg) in rats' inferior vena at 30 minutes before reperfusion.Other groups treated with equal doses of normal saline.Blood and tissue specimen were collected at 1,3,6,24,48 and 72 h respectively.Levels of serum Scr and blood BUN were analysed.TNF-α,IFN-γ,,IL-4 and IL-10 were detected by ELISA in each group.Expressions in mRNA level of TNF-α, IL-10,MCP-1,NF-κB,KIM-1,ANGⅡ,ATⅠR,ICAM-1 were measured by RT-PCR. Flow cytometry was used to examine the expression of ICAM-1.Immuno histochemisal method was also applied for obvervation of the expression of MCP-1,NF-κB and TM in renal tissue specimen.
RESULTS:1.PGE1 treatment made TNF-αat the point of 3 h and 6 h,IL-10, MCP-1 at 1 h and 3 h,statistical significant increased compared to AKI group.While there were no statistically significance at 3 h and 6 h within AKI group.
2.Compared to AKI group,PGE1 treated group shows much slight appearances in renal tubular epithelial cell intumesce and protein cast formation.Glomerulum ectasia and hyperemia,renal tubular epithelial intumesces,matrix angiectasia and cellular cast could be seen in the IRI 24 h group.Immunohistochemistry shows that the level of MCP-1 and AngⅡwere declined obviously in PGE1 treated group(P＜0.01).
3.24 h after reperfusion,the levels of serum Cr and BUN in IRI group and LMWH treatment group were higher than the Sham operated group(P＜0.01).Yet there was no significance in IRI group and LMWH treatment group(P＞0.05).
4.After LMWH treatment,The expression of ICAM-1 in PMNs reduced 72.2%,48.3 %and 61.4%at IR 6,24 and 48 h(P＜0.01)
5.24 h after reperfusion,serum TNF-αsecreted by mononuclear macrophages and IFN-γby Th1 cell in LMWH treatment group were lower than in IRI group(P＜0.01), Meanwhile,the levels of serum IL-4 and IL-10 secreted by Th2 cell in LMWH treatment group were higher than IRI group(P＜0.01).
6.The renal damage of LMWH treated group was much less marked compared to that of IRI group as observed under the light microscope.
7.Compared to IRI group,The expression of MCP-1 was significantly decreased at IR 6 h,24 h in LMWH treated group(P＜0.01).LMWH treatment reduced the expression of NF-κB significantly in glomcrulus of IRI group from 24.45%to 12.23%at IR 6 h after injury(P＜0.01).Meanwhile,the level of NF-κB in renal tubule decreased from 45.20%to 20.00%.While the expression of ATⅠR were increased.
CONCLUSIONS:1.We establis hed the rat ischemia acute renal failure model successfully by the right kidney removement and the left renal artery occluded with a vascular clamp for 60 minutes.IRI may elevate the expression of proinflammatory cytokines in rat plasma,activates ICAM-1 to promote immunoreaction between leucocyte and renal tubular epithelial cell,and lead to AKI.
2.PGE1 exhibits the inhibition to the secretion of the proinflammatory cytokines TNF-α,IFN-γ,and elevates the level of anti-inflammatory cytokines IL-4 and IL-10, leading to the depression of the over-inmmuoreaction.PGE1 could prevent platelets from releasing TM,and it was benefit to reduce platelet aggregation and to protect endothelial cell function.
3.LMWH also inhibits the secretion of the proinflammatory cytokines TNF-α,IFN-γand elevates the level of anti-inflammatory cytokines IL-4 and IL-10.It also down-regulates the expression of NF-κB,MCP-1 and ICAM-1 which are benefit for rebuilding the steady state of immune responses and to protect the renal function.
引文
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