不同血液净化方式对尿毒症患者外周血单核细胞源性巨噬细胞胆固醇外流影响的研究
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摘要
目的随着血液净化技术的不断发展，维持血液透析患者的生存率较以往有了显著提高。然而，心血管疾病（Cardiovasculardisease,CVD）仍是维持透析患者（Maintenance hemodialysispatients，MHD）主要并发症和主要死亡原因。有研究表明，高通量血液透析滤过(High-flux hemodiafiltration, HDF)有助于改善透析患者的脂质代谢紊乱，减轻炎症反应，降低维持透析患者心血管疾病发生率和死亡率。然而，HDF减轻脂代谢紊乱降低患者心血管事件发生的机制尚未完全清楚。ATP结合盒受体A1(ATP-binding cassettetransporter A1,ABCA1)、ATP结合盒受体G1(ATP-binding cassettetransporter G1, ABCG1)是胆固醇逆转运中最重要的受体，在脂代谢紊乱及动脉硬化发生和发展中起着重要作用。因此，本课题以人外周血单核巨噬细胞为研究对象，观察不同血液净化方式对尿毒症患者外周血单核巨噬泡沫细胞形态以及巨噬细胞ABCA1、ABCG1mRNA及蛋白的表达情况的影响；观察不同血液净化方式尿毒症患者外周血Treg/Th17比例变化及与ABCA1、ABCG1表达的关系。以探讨不同血液透析方式对尿毒症患者动脉粥样硬化的影响及其可能的作用机制，为尿毒症患者动脉粥样硬化的临床预防和治疗寻找更合理治疗的方法。
方法选取重庆医科大学附属第一医院长期规律透析的慢性肾衰患者60例，按不同血液净化方式分为2组：血液透析(hemodialysis,HD)组、血液透析滤过(HDF)组，每组30例，同时选取健康体检者20例。均于透析前抽取空腹静脉血，密度梯度离心分离尿毒症患者外周血单个核细胞，巨噬细胞集落刺激因子诱导贴壁巨噬化，油红O染色、CD68免疫荧光鉴定巨噬细胞，酶法测定巨噬细胞内总胆固醇(TotalCholesterol, TC)、胆固醇酯(Cholesterol Ester, CE)和游离胆固醇(FreeCholesterol, FC)的水平；应用RT-PCR与Western blot方法测定巨噬细胞ABCA1、ABCG1mRNA及其蛋白表达。密度梯度离心法获得外周血单个核细胞，流式细胞技术检测不同血液净化方式患者外周血Treg、Th17细胞及Treg/Th17比例表达情况，ELISA法测定患者血清IL-6、TNF-α、IL-10水平，探讨Treg/Th17比例失衡对巨噬细胞ABCA1、ABCG1的影响，阐明两者的关系。
结果1.HD、HDF组巨噬细胞内总胆固醇、胆固醇脂均较对照组增加（P <0.01）；与对照组比较，HD、HDF组巨噬细胞游离胆固醇明显增加（P <0.05）；HDF组较HD组巨噬细胞内总胆固醇、胆固醇脂、游离胆固醇减少（P <0.05）。
2.与对照组比较，HD、HDF组巨噬细胞ABCA1mRNA、ABCG1mRNA的表达均显著降低（P<0.01，P <0.01），HDF组较HD组患者的ABCA1mRNA、ABCG1mRNA表达明显升高（P<0.01, P<0.05）。
3.与对照组比较，HD组、HDF组巨噬细胞ABCA1、ABCG1蛋白表达均明显下降（P<0.01；P <0.05），HDF组与HD组比较ABCA1、ABCG1蛋白表达均升高（P<0.05）。
4. HD、HDF组患者外周血中Treg细胞的比例明显低于对照组(P<0.05)，HDF组明显高于HD组(P<0.05)。HD、HDF组患者外周血中Thl7细胞的比例明显高于对照组(P<0.05)，HDF组明显低于HD组(P<0.05)。HD、HDF组患者Treg／Thl7的比值明显低于对照组(P <0.05)，HDF组比HD组明显升高(P <0.05)。
5.与对照组比较，HD、HDF组外周血单个核细胞Foxp3mRNA的表达显著降低（P <0.01，P<0.01）；与HD组比较，HDF组患者的Foxp3mRNA表达明显升高（P<0.05）。与对照组比较，HD、HDF组ROR-γtmRNA的表达显著升高（P <0.01，P<0.01），与HD组比较，HDF组ROR-γt mRNA表达升高（P <0.05）。
6.与对照组比较，HD、HDF组患者血清IL-6、TNF-α水平均增高（P<0.05），而IL-10水平减低（P <0.05）；HDF组患者血清IL-6、TNF-α水平均低于HD组（P<0.05）；HDF组患者血清IL-10水平高于HD组（P <0.05）。
7.尿毒症血液透析患者Treg细胞比例与ABCA1、ABCG1mRNA呈正相关（r=0.793，P<0.05；r=0.698，P <0.05）；而Th17细胞比例ABCA1、ABCG1mRNA呈负相关（r=-0.711，P <0.05；r=-0.387，P <0.05）；尿毒症血液透析患者Treg细胞比例与ABCA1、ABCG1蛋白呈正相关（r=0.791，P <0.05；r=0.761，P <0.05）；而Th17细胞比例ABCA1、ABCG1蛋白呈负相关（r=-0.577，P <0.05；r=-0.685，P <0.05）。
结论血液透析患者存在巨噬细胞内胆固醇流出受体ABCA1、ABCG1功能障碍，高通量透析滤过治疗能够改善ABCA1、ABCG1的功能障碍；ABCA1、ABCG1的功能障碍与外周血Treg/Th17细胞比例失衡有关。HDF较HD能够部分纠正透析患者Treg/Th17细胞比例失衡，导致促炎性细胞因子的释放减少，抑炎性细胞因子的释放增加，增加巨噬细胞ABCA1、ABCG1的表达，进而减少动脉粥样硬化及心血管并发症的发生。
Objective With the development of blood purification technology, thesurvival rates of hemodialysis patients have been significantly improvedcompared with the past. However, cardiovascular disease (CVD) remains themajor complications and mortality of maintenance dialysis patients(MHD).It has been shown by a large number of studies that high fluxhemodiafiltration (HDF) can improve lipid metabolism, reduceinflammation, and decrease the morbidity and the mortality of thecardiovascular diseases for the maintenance dialysis patients. But, themechanism that HDF can mitigate lipid metabolism and reducecardiovascular events in patients remains unclear. ATP-binding cassettereceptor A1（ABCA1） and ATP-binding t cassette receptor G1(ABCG1)are the most important receptors in cholesterol reverse transport（RCT）andplays important roles in both lipid metabolism and atherosclerosisdevelopment. Our objective is to examine the effects and mechanism ofdifferent dialysis on the formation of foam cells and the expression of ABCA1and ABCG1in Uremia patient's peripheral blood mononuclearmacrophages. To observe different dialysis uremic patient’s peripheralblood Treg/Th17proportional change and the relationship betweenTreg/Th17proportional change and the expression of ABCA1and ABCG1.The study may provide a new theoretical foundation for Uremic patientswith atherosclerosis，as well as offer a new pathway for clinical preventionand treatment of atherosclerosis in uremic patients.
Methods We investigated30uremia patients treated by HD,30patientstreated by HDF and20healthy volunteers. ALL patients were receivedtreatment in the department of kidney, first hospital affiliated to Chongqingmedical university. Peripheral blood mononuclear cells (PBMCs) wereisolated from venous blood before dialysis and stimulated to make themtransfer to macrophages by Macrophage colony-stimulating factor.Macrophages were identified by Oil red O dyeing and byimmunofluorescence staining of cd68. The cellular contents of totalcholesterols，Cholesterol Ester and Free Cholesterol in different groups weredetected by enzymatic colorimetry. The expression of ABCA1and ABCG1mRNA was detected by real-time fluorescent quantitative PCR, and theexpression of ABCA1and ABCG1protein was detected by Western-blot.Mononuclear cells were isolated from peripheral blood by density gradientcentrifugation，Treg and Th17cells proportion and Treg/Th17proportionwas measured by flow cytometry. The effects of Treg/Th17imbalance on the expression of ABCA1, ABCA1were investigated and to clarify therelationship between the two factors.
Results1． Compaired with control group, total cholesterol andCholesterol ester in both HD and HDF groups increased significantly（P<0.01）. Compaired with control group, free cholesterol in both HD andHDF groups increased significantly（P<0.01）, total cholesterol and Chol-esterol ester in HDF group decreased （P<0.05）.
2．Real-time fluorescent quantitative PCR results are as follows:compared with controls, the expression of ABCA1mRNA and ABCG1mRNA in both HD and HDF group were significantly lower (P<0.01,P<0.01); compared with HD group, the expression of ABCA1mRNA andABCG1mRNA in the HDF group increased significantly (P<0.01, P<0.05).
3. Compared with controls, the expression of ABCA1and ABCG1protein in both HD and HDF group was significantly lower (P<0.01,P<0.05); compared with HD group, the expression of ABCA1and ABCG1protein in the HDF group increased significantly (P<0.05, P<0.05).
4. The percent of Treg cell in peripheral blood（CD4+CD25+Foxp3+/CD4+T cells，％) in HD and HDF group patients was remarkably higherthan that in healthy controls (P<0.05)，The percent in HDF group patientswas higher than that in HD group(P<0.05)。The percent of Th17cell inperipheral blood（CD4+IL17+／CD4+T cells，％) in HD and HDF grouppatients was and remarkably higher than that in healthy controls (P<0.05)， The percent in HDF group patients was higher than that in HD group(P<0.05)。The ratio of Treg/Thl7in HDF group was obviously lower thancontrol group (P<0.05), the ratio in HDF group increased significantlycompaired with HD group (P<0.05).
5. Compared with controls, the expression of Foxp3mRNA in both HDand HDF group were significantly lower (P<0.01, P<0.01)；Compaired withHD group, the expression of Foxp3mRNA in the HDF group increasedsignificantly (P<0.05). Compared with controls, the expression of ROR-γtmRNA in both HD and HDF group were significantly higher (P<0.01,P<0.01)；Compaired with HD group, the expression of ROR-γt mRNA in theHDF group decreased significantly (P<0.05).
6. The level of IL-6TNF-αin HDF and HD groups were significantlyhigher than those in control group（P<0.05）, The level of IL-10in HDF andHD groups were lower than this in control group（P<0.05）. The level of IL-6TNF-αin HDF groups was significantly higher than those in HD group（P<0.05）, The level of IL-10in HDF groups was lower than this in HDgroup（P<0.05）.
7. The proportion of Treg cells in patients receiving hemodialysis waspositively correlated with ABCA1, ABCG1mRNA (r=0.793, P<0.05); r=0.698,P<0.05); And proportion of Th17cell with ABCA1, ABCG1mRNAshowed a negative correlation (r=-0.711, P<0.05and r=-0.387, P<0.05);Proportion of Treg cells in patients receiving hemodialysis with ABCA1, ABCG1protein was positively correlation (r=0.791, P<0.05, r=0.761,P<0.05); The proportion of Th17cell, ABCA1and ABCG1protein showeda negative correlation (r=-0.577, P<0.05and r=0.-685, P<0.05).
Conclusion Macrophage cholesterol efflux receptors ABCA1, ABCG1of maintenance dialysis patients were down-regulated， high-fluxhemodiafiltration can improve the expression of ABCA1and ABCG1.Dysfunction of ABCA1and ABCG1associated with unbalanced proportionof Treg/Th17cells and Microinflammatory. Compared with HD，HDF canimprove dialysis patients Treg/Th17cell ratio, reduced the release ofproinflam-matory cytokines, increase the release of the suppression ofinflammatory cytokines, increased expression of ABCA1and ABCG1,thereby reducing the incidence of atherosclerosis and cardiovascularcomplications.
方法选取重庆医科大学附属第一医院长期规律透析的慢性肾衰患者60例，按不同血液净化方式分为2组：血液透析(hemodialysis,HD)组、血液透析滤过(HDF)组，每组30例，同时选取健康体检者20例。均于透析前抽取空腹静脉血，密度梯度离心分离尿毒症患者外周血单个核细胞，巨噬细胞集落刺激因子诱导贴壁巨噬化，油红O染色、CD68免疫荧光鉴定巨噬细胞，酶法测定巨噬细胞内总胆固醇(TotalCholesterol, TC)、胆固醇酯(Cholesterol Ester, CE)和游离胆固醇(FreeCholesterol, FC)的水平；应用RT-PCR与Western blot方法测定巨噬细胞ABCA1、ABCG1mRNA及其蛋白表达。密度梯度离心法获得外周血单个核细胞，流式细胞技术检测不同血液净化方式患者外周血Treg、Th17细胞及Treg/Th17比例表达情况，ELISA法测定患者血清IL-6、TNF-α、IL-10水平，探讨Treg/Th17比例失衡对巨噬细胞ABCA1、ABCG1的影响，阐明两者的关系。
结果1.HD、HDF组巨噬细胞内总胆固醇、胆固醇脂均较对照组增加（P <0.01）；与对照组比较，HD、HDF组巨噬细胞游离胆固醇明显增加（P <0.05）；HDF组较HD组巨噬细胞内总胆固醇、胆固醇脂、游离胆固醇减少（P <0.05）。
2.与对照组比较，HD、HDF组巨噬细胞ABCA1mRNA、ABCG1mRNA的表达均显著降低（P<0.01，P <0.01），HDF组较HD组患者的ABCA1mRNA、ABCG1mRNA表达明显升高（P<0.01, P<0.05）。
3.与对照组比较，HD组、HDF组巨噬细胞ABCA1、ABCG1蛋白表达均明显下降（P<0.01；P <0.05），HDF组与HD组比较ABCA1、ABCG1蛋白表达均升高（P<0.05）。
4. HD、HDF组患者外周血中Treg细胞的比例明显低于对照组(P<0.05)，HDF组明显高于HD组(P<0.05)。HD、HDF组患者外周血中Thl7细胞的比例明显高于对照组(P<0.05)，HDF组明显低于HD组(P<0.05)。HD、HDF组患者Treg／Thl7的比值明显低于对照组(P <0.05)，HDF组比HD组明显升高(P <0.05)。
5.与对照组比较，HD、HDF组外周血单个核细胞Foxp3mRNA的表达显著降低（P <0.01，P<0.01）；与HD组比较，HDF组患者的Foxp3mRNA表达明显升高（P<0.05）。与对照组比较，HD、HDF组ROR-γtmRNA的表达显著升高（P <0.01，P<0.01），与HD组比较，HDF组ROR-γt mRNA表达升高（P <0.05）。
6.与对照组比较，HD、HDF组患者血清IL-6、TNF-α水平均增高（P<0.05），而IL-10水平减低（P <0.05）；HDF组患者血清IL-6、TNF-α水平均低于HD组（P<0.05）；HDF组患者血清IL-10水平高于HD组（P <0.05）。
7.尿毒症血液透析患者Treg细胞比例与ABCA1、ABCG1mRNA呈正相关（r=0.793，P<0.05；r=0.698，P <0.05）；而Th17细胞比例ABCA1、ABCG1mRNA呈负相关（r=-0.711，P <0.05；r=-0.387，P <0.05）；尿毒症血液透析患者Treg细胞比例与ABCA1、ABCG1蛋白呈正相关（r=0.791，P <0.05；r=0.761，P <0.05）；而Th17细胞比例ABCA1、ABCG1蛋白呈负相关（r=-0.577，P <0.05；r=-0.685，P <0.05）。
结论血液透析患者存在巨噬细胞内胆固醇流出受体ABCA1、ABCG1功能障碍，高通量透析滤过治疗能够改善ABCA1、ABCG1的功能障碍；ABCA1、ABCG1的功能障碍与外周血Treg/Th17细胞比例失衡有关。HDF较HD能够部分纠正透析患者Treg/Th17细胞比例失衡，导致促炎性细胞因子的释放减少，抑炎性细胞因子的释放增加，增加巨噬细胞ABCA1、ABCG1的表达，进而减少动脉粥样硬化及心血管并发症的发生。
Objective With the development of blood purification technology, thesurvival rates of hemodialysis patients have been significantly improvedcompared with the past. However, cardiovascular disease (CVD) remains themajor complications and mortality of maintenance dialysis patients(MHD).It has been shown by a large number of studies that high fluxhemodiafiltration (HDF) can improve lipid metabolism, reduceinflammation, and decrease the morbidity and the mortality of thecardiovascular diseases for the maintenance dialysis patients. But, themechanism that HDF can mitigate lipid metabolism and reducecardiovascular events in patients remains unclear. ATP-binding cassettereceptor A1（ABCA1） and ATP-binding t cassette receptor G1(ABCG1)are the most important receptors in cholesterol reverse transport（RCT）andplays important roles in both lipid metabolism and atherosclerosisdevelopment. Our objective is to examine the effects and mechanism ofdifferent dialysis on the formation of foam cells and the expression of ABCA1and ABCG1in Uremia patient's peripheral blood mononuclearmacrophages. To observe different dialysis uremic patient’s peripheralblood Treg/Th17proportional change and the relationship betweenTreg/Th17proportional change and the expression of ABCA1and ABCG1.The study may provide a new theoretical foundation for Uremic patientswith atherosclerosis，as well as offer a new pathway for clinical preventionand treatment of atherosclerosis in uremic patients.
Methods We investigated30uremia patients treated by HD,30patientstreated by HDF and20healthy volunteers. ALL patients were receivedtreatment in the department of kidney, first hospital affiliated to Chongqingmedical university. Peripheral blood mononuclear cells (PBMCs) wereisolated from venous blood before dialysis and stimulated to make themtransfer to macrophages by Macrophage colony-stimulating factor.Macrophages were identified by Oil red O dyeing and byimmunofluorescence staining of cd68. The cellular contents of totalcholesterols，Cholesterol Ester and Free Cholesterol in different groups weredetected by enzymatic colorimetry. The expression of ABCA1and ABCG1mRNA was detected by real-time fluorescent quantitative PCR, and theexpression of ABCA1and ABCG1protein was detected by Western-blot.Mononuclear cells were isolated from peripheral blood by density gradientcentrifugation，Treg and Th17cells proportion and Treg/Th17proportionwas measured by flow cytometry. The effects of Treg/Th17imbalance on the expression of ABCA1, ABCA1were investigated and to clarify therelationship between the two factors.
Results1． Compaired with control group, total cholesterol andCholesterol ester in both HD and HDF groups increased significantly（P<0.01）. Compaired with control group, free cholesterol in both HD andHDF groups increased significantly（P<0.01）, total cholesterol and Chol-esterol ester in HDF group decreased （P<0.05）.
2．Real-time fluorescent quantitative PCR results are as follows:compared with controls, the expression of ABCA1mRNA and ABCG1mRNA in both HD and HDF group were significantly lower (P<0.01,P<0.01); compared with HD group, the expression of ABCA1mRNA andABCG1mRNA in the HDF group increased significantly (P<0.01, P<0.05).
3. Compared with controls, the expression of ABCA1and ABCG1protein in both HD and HDF group was significantly lower (P<0.01,P<0.05); compared with HD group, the expression of ABCA1and ABCG1protein in the HDF group increased significantly (P<0.05, P<0.05).
4. The percent of Treg cell in peripheral blood（CD4+CD25+Foxp3+/CD4+T cells，％) in HD and HDF group patients was remarkably higherthan that in healthy controls (P<0.05)，The percent in HDF group patientswas higher than that in HD group(P<0.05)。The percent of Th17cell inperipheral blood（CD4+IL17+／CD4+T cells，％) in HD and HDF grouppatients was and remarkably higher than that in healthy controls (P<0.05)， The percent in HDF group patients was higher than that in HD group(P<0.05)。The ratio of Treg/Thl7in HDF group was obviously lower thancontrol group (P<0.05), the ratio in HDF group increased significantlycompaired with HD group (P<0.05).
5. Compared with controls, the expression of Foxp3mRNA in both HDand HDF group were significantly lower (P<0.01, P<0.01)；Compaired withHD group, the expression of Foxp3mRNA in the HDF group increasedsignificantly (P<0.05). Compared with controls, the expression of ROR-γtmRNA in both HD and HDF group were significantly higher (P<0.01,P<0.01)；Compaired with HD group, the expression of ROR-γt mRNA in theHDF group decreased significantly (P<0.05).
6. The level of IL-6TNF-αin HDF and HD groups were significantlyhigher than those in control group（P<0.05）, The level of IL-10in HDF andHD groups were lower than this in control group（P<0.05）. The level of IL-6TNF-αin HDF groups was significantly higher than those in HD group（P<0.05）, The level of IL-10in HDF groups was lower than this in HDgroup（P<0.05）.
7. The proportion of Treg cells in patients receiving hemodialysis waspositively correlated with ABCA1, ABCG1mRNA (r=0.793, P<0.05); r=0.698,P<0.05); And proportion of Th17cell with ABCA1, ABCG1mRNAshowed a negative correlation (r=-0.711, P<0.05and r=-0.387, P<0.05);Proportion of Treg cells in patients receiving hemodialysis with ABCA1, ABCG1protein was positively correlation (r=0.791, P<0.05, r=0.761,P<0.05); The proportion of Th17cell, ABCA1and ABCG1protein showeda negative correlation (r=-0.577, P<0.05and r=0.-685, P<0.05).
Conclusion Macrophage cholesterol efflux receptors ABCA1, ABCG1of maintenance dialysis patients were down-regulated， high-fluxhemodiafiltration can improve the expression of ABCA1and ABCG1.Dysfunction of ABCA1and ABCG1associated with unbalanced proportionof Treg/Th17cells and Microinflammatory. Compared with HD，HDF canimprove dialysis patients Treg/Th17cell ratio, reduced the release ofproinflam-matory cytokines, increase the release of the suppression ofinflammatory cytokines, increased expression of ABCA1and ABCG1,thereby reducing the incidence of atherosclerosis and cardiovascularcomplications.
引文
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