辛伐他汀对LPS诱导内皮祖细胞功能的影响
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摘要
研究背景：脓毒症是是目前患病率和死亡率最高的疾病之一,欧美国家脓毒症的患病率在10%以上,我国缺乏相应资料,但根据抗生素使用情况判断,其患病率远在欧美国家之上,脓毒症成为严重威胁着人类健康的最主要疾病之一；为降低脓毒症的患病率和病死率,早在2002年就由多个国家学会共同提出了"surviving sepsis campaign",并根据大量循证医学证据和广泛论证,提出了"sepsis resuscitation bundles"和‘'Sepsis management bundle",从2008年起在世界各地进行推广；经过大量的努力,同时伴随诊疗技术的不断提高,2010年数据分析显示脓毒症的病死率仍在30.8%。如何降低其发病率和病死率是当今研究的热点和难点。研究证明,毛细血管内皮细胞功能异常及结构受损,导致内皮细胞脱落变形、凝血功能异常、毛细血管渗漏等在脓毒症的病情进展中其重要作用,成年内皮细胞的自我增殖和修复能力有限,内皮祖细胞是出生后血管内皮损伤修复的重要细胞,研究表明循环内皮祖细胞数量和功能直接影响到脓毒症患者的预后。细菌脂多糖是革兰氏阴性杆菌的主要致病原,实验中经常用LPS体内注射模拟机体感染过程；3-羟-3-甲基戊二酸辅酶A(3-hydroxy-3-methylglutaryl coenzyme A,HMG-CoA)还原酶抑制剂(他汀类药物)通过抑制HMG-CoA还原酶的活性,而抑制胆固醇的生成、降低血胆固醇的水平,最近研究表明,在有效地调节血脂水平外,还具有抑制平滑肌增生和血小板聚集以及抑制炎症反应等作用,有研究证明他汀类药物还能促进血管新生和内皮损伤后的修复过程,而且已经证实EPCs在该过程中扮演了重要角色,研究证实他汀类药物有动员内皮祖细胞、提高内皮功能等作用。自2000年Ando首先报道他汀类药物可以改善大鼠脓毒症的生存率后,多个大规模临床观察显示,他汀类药物能降低脓毒症的患病率和病死率,但对于LPS对EPCs数量及功能的影响及他汀类药物对LPS作用下的内皮祖细胞作用未见相关报道。本研究共分三部分进行：1、脐静脉血EPCs分离、培养、鉴定；2、LPS与EPC共孵育后加入辛伐他汀EPC迁移、黏附、增殖情况。3、EPC与辛伐他汀共孵育后加入LPS其迁移、黏附、增殖、凋亡情况。研究目的：1、从脐静脉血获得人EPCs,鉴定并进行体外传代培养。2、将脂多糖(LPS)与人脐血EPCs共孵育,在相应时间点添加不同剂量辛伐他汀,观察LPS对人脐血EPCs增殖、迁移、黏附、凋亡的影响及辛伐他汀干预作用；3、将不同浓度辛伐他汀与人脐血EPCs共孵育,相应时间点加入LPS,观察辛伐他汀对EPCs增殖、迁移、黏附功能的影响,以及预先应用辛伐他汀后LPS对人脐血EPCs增殖、迁移、黏附的影响；通过该研究明确在细胞水平单纯LPS及辛伐他汀对内皮细胞祖的影响,及两者的相互影响,为进一步进行作用机理探讨提供基础。
方法：第一部分：采用密度梯度离心法从脐静脉血获取单个核细胞,将其接种在人纤维连接蛋白包被培养板上,诱导培养7天,收集贴壁细胞,通过细胞形态观察及DiI-acLDL、FITC-UEA-I染色激光共聚焦显微镜培养细胞。第二部分：将等量脐静脉血来源EPCs(UCBEPCs)接种到96孔培养板上,随机分为对照组：UCBEPCs与EGM-2MV标准液培养48小时；LPS组,UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养48小时;LPS+ simv0.1组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养24小时后,加入0.1μmol/L辛伐他汀培养至48小时；LPS+ simv1.0组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养24小时后,加入1.0μmol/L辛伐他汀培养至48小时；LPS+ simv10.0组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养24小时后,加入10.0μmol/L辛伐他汀培养至48小时。应用MTT比色法测定EPCs增殖功能和粘附功能,通过Transwell小室观察EPCs迁移功能。统计学处理：结果中数据以均数±标准差(x±s)表示,资料采用SPSS(16.0版)统计软件进行统计学分析,组间比较用随机取组设计的方差分析,以P<0.05为差异有显著性。第三部分：将等量EPCs接种到96孔培养板上,随机分为对照组：UCBEPCs与EGM-2MV标准液培养48小时；LPS组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养48小时；Sim0.1+LPS组：UCBEPCs与GM-2MV标准液和0.1μmol/L辛伐他汀共同孵育24小时后,加入LPS液(100ng/mL)共同培养至48小时；Siml.O+LPS组：UCBEPCs与GM-2MV标准液和1.0μmol/L辛伐他汀共同孵育24小时后,加入LPS液(100ng/mL)共同培养至48小时；Sim10.0+LPS组：UCBEPCs与GM-2MV标准液和10.0μmol/L辛伐他汀共同孵育24小时后,加入LPS液(100ng/mL)共同培养至48小时；辛伐他汀组：UCBEPCs与GM-2MV标准液和1.0μmol/L辛伐他汀共同孵育48小时。应用MTT比色法测定EPCs增殖功能和粘附功能,通过Transwell小室观察EPCs迁移功能,应用流式细胞仪检测EPCs凋亡情况,细胞凋亡率(AP)计算公式：AP=凋亡细胞数/总检测细胞数。统计学处理：结果中数据以均数±标准差(x±s)表示,资料采用SPSS(16.0版)统计软件进行统计学分析,组间比较用随机取组设计的方差分析,以P<0.05为差异有显著性
结果第一部分：经鉴定分离培养细胞为EPCs,经复苏传代见细胞生长良好。第二部分：脐静脉血来源EPCs与LPS共孵育后其增殖、迁移显著降低(P=0.009、P=0.026),黏附能力也下降,但差异无显著性(P=0.279)。脐静脉EPCs与LPS共孵育后加入不同浓度辛伐他汀,EPCs的增殖、迁移和黏附能力不同程度改善,随辛伐他汀浓度增加,该作用增强,辛伐他汀浓度为1.0μmol/L时EPCs增殖显著改善(P=0.017),浓度10.0μmol/L时EPCs增殖、黏附、迁移功能,较LPS组均显著改善(P=0.00,P=0.002,P=O.00),其中黏附和迁移功能较空白对照组显著改善(P=O.039,P=0.000)。第三部分：人EPCs与LPS共孵育后其凋亡率显著增加(12.632±0.5271 vs3.0266±0.5271, P<0.00)。辛伐他汀(1.0umol/L)与EPCs共孵育,EPCs各检测指标与对照组比较均无显著变化。UCBEPCs与不同浓度辛伐他汀孵育后再加入LPS,EPCs的增殖、迁移和黏附能力较LPS组不同程度改善,凋亡率降低,随辛伐他汀浓度增加,该作用增强,辛伐他汀浓度为0.1umol/L EPCs增殖、黏附、迁移功能较LPS组有改善,但无统计学差异(P=0.687、0.501、0.683),EPCs凋亡率显著降低(9.2750±0.5961 vs 12.632±0.5271,P=0.00),辛伐他汀浓度为10.0μmol/L时,EPCs增殖、黏附、迁移功能,较LPS组均显著改善(P=0.035,P=0.002,P=0.011),其中粘附功能较对照组也有显著改善(P=0.039),不同浓度辛伐他汀与EPCs作用24小时后再与LPS共孵育,其EPCs凋亡率较LPS组均显著改善,但仍高于对照组和辛伐他汀组。
结论自脐静脉血可成功分离内皮祖细胞,并可在体外进行传代培养。LPS与UCBEPCs共孵育,可使UCBEPCs增殖和迁移功能显著降低,黏附能力下降,凋亡率显著增加。单纯应用辛伐他汀(1.0umol/L)与UCBEPCs共孵育,对UCBEPCs的增殖、粘附、迁移功能及细胞凋亡无显著影响。辛伐他汀可以改善LPS导致的EPCs增殖、黏附、迁移功能的降低,在研究范围内改善作用随浓度增加而增强。提前应用辛伐他汀与EPCs共孵育,可以显著降低LPS导致的EPCs增殖、黏附、迁移功能的降低,在研究范围内该作用随浓度增加而增强。
Background:Sepsis continues to be a major cause of morbidity and mortality worldwide. Preclinical and clinical sepsis studies have shown that the acute systemic inflammatory and procoagulant response results in structural and functional alterations in the endothelium. The endothelial cells (ECs) play a pivotal role in the progression of sepsis; the ECs are not only the participant of inflammatory reaction, but also the first damaged target cells. The dysfunction of ECs is a critical event in the initiation of organ dysfunction caused by sepsis.Recent studies suggested that the injured ECs could be regenerated by circulating bone marrow-derived progenitor cells called endothelial progenitor cells (EPCs), which had capabilities to mobilize from bone marrow with homing to foci of injuries and to differentiate into mature ECs to ameliorate the dysfunction of ischemic organs caused by sepsis. The impairment of EPCs caused by severe inflammation may contribute to the progression of organ dysfunction. Circulating endothelial progenitor cells may be an important mechanism of vascular repair, and thus shows significant promise for prognostic and therapeutic strategies in critical illness, namely sepsis and sepsis-related organ dysfunction. Many studies have convincingly demonstrated that simvastatin benefit for sepsis,and could promote the function of EPCs.but there no evidence about the effects of simvastatin on the EPCs incubated with LPS.
Objective:1、To separate EPCs from human umbilical cord blood (HUCB).2、To investigate the variation of the proliferation、adhention、migration and apoptosis of EPCs when incubated with LPS.3、The effects of simvastatin at different concentration on the functions of EPCs when added before or after the EPCs incubated with LPS in vitro.
Methods:Total mononuclear cells(MNCs) were isolated from human umbilical cord blood by Ficoll density gradient centrifugation,and then the cells were plated on fibronectin-coated culture dishes. After 7 days culture, attached cells were isolated and assessed with a laser scanning confocal microscope. EPCs divided to different group:control group:EPCs were cultivated with standard EGM-2MW fluid for 48hr; LPS group:EPCs were cultivated with standard EGM-2MW fluid plus LPS(100 ng/Ml) for 48hr;simvastatin grup:EPCs were cultivated with standard EGM-2MW fluid add simvastatin 1.0μmol/L for 48hr;test group:first EPCs were incubated with standard EGM-2MW fluid and LPS(100 ng/ml)/simvastatin of different concentrations (simv0.1:add simvastatin 0.1μmol/L, simv1.0:add simvastatin 1.0μmol/L, simv10.0:add simvastatin 10.0μmol/L) for 24hrs then addde simvastatin of different concentrations (simv0.1:add simvastatin 0.1μmol/L, simv1.0:add simvastatin 1.0μmol/L, simv10.0:add simvastatin 10.0μmol/L)/LPS(100 ng/ml).The proliferation, adhesion and migration of EPCs were detected with MTT assay, Transwell chamber assay after 48hrs respectively.And the influences of LPS and simvastatin on EPCs'proliferation, adhesion、migration and apoptosis were evaluated.
Results:Incubated with LPS the proliferation of EPCs were decline significantly (P=0.009),the adhesion and migration of EPCs were also descended,but there was no significance (P=0.279、P=0.056),the apoptosis rate of EPCs were increased significantly.When added simvastatin the proliferation, adhesion and migration of EPCs were all improved,there are some difference for difference concentration of simvastatin.There were hardly any improvment in the proliferation, adhesion and migration of EPCs when added simvastatin of 0.1μmol/L (P=0.687、P=0.501、P=0.683 respectively), EPCs' proliferation was improve significantly when incubated with simvastatin of 1.0μmol/L compared with LPS group(P=0.017),while the adhesion and migration were also improved but there was no significance(P=0.064、P=0.069 respectively). When incubated with simvastatin at the concentration of 10.0μmol/L the the proliferation、adhesion and migration of EPCs were all improved significantly (P=0.00, P=0.002, P=0.00 respectively)compared with LPS group,and the adhesion and migration of EPCs were ameliorated significantly even compared with the EPCs cultivated with standard EGM-2MW fluid (P=0.039,P=0.000 respectivly).Incubated with simvastatin there were no significant changes on the EPCs function of proliferation, adhesion and migration. When EPCs were incubated with standard EGM-2MW fluid added simvastatin of different concentrations (simv0.1:add simvastatin 0.1μmol/L, simv1.0:add simvastatin 1.0μmol/L, simv10.0:add simvastatin 10.0μmol/L) for 24hrs then addde LPS(100 ng/ml).The proliferation, adhesion and migration of EPCs all improved compare with the LPS group,but lower than the control group;the apoptosis were all decreased compare with the LPS group,but higher than control group and simvastatin group still.
Conclusion:LPS could cut down the proliferation of EPCs sharply while the adhesion and migration were decline in some degree when incubated with EPCs.Simvastatin could improve the declined proliferation, adhesion and migration of EPCs which incubated with LPS first.When incubated with simvastatin first there were some profect function on the effect of LPS on EPCs
方法：第一部分：采用密度梯度离心法从脐静脉血获取单个核细胞,将其接种在人纤维连接蛋白包被培养板上,诱导培养7天,收集贴壁细胞,通过细胞形态观察及DiI-acLDL、FITC-UEA-I染色激光共聚焦显微镜培养细胞。第二部分：将等量脐静脉血来源EPCs(UCBEPCs)接种到96孔培养板上,随机分为对照组：UCBEPCs与EGM-2MV标准液培养48小时；LPS组,UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养48小时;LPS+ simv0.1组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养24小时后,加入0.1μmol/L辛伐他汀培养至48小时；LPS+ simv1.0组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养24小时后,加入1.0μmol/L辛伐他汀培养至48小时；LPS+ simv10.0组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养24小时后,加入10.0μmol/L辛伐他汀培养至48小时。应用MTT比色法测定EPCs增殖功能和粘附功能,通过Transwell小室观察EPCs迁移功能。统计学处理：结果中数据以均数±标准差(x±s)表示,资料采用SPSS(16.0版)统计软件进行统计学分析,组间比较用随机取组设计的方差分析,以P<0.05为差异有显著性。第三部分：将等量EPCs接种到96孔培养板上,随机分为对照组：UCBEPCs与EGM-2MV标准液培养48小时；LPS组：UCBEPCs与GM-2MV标准液和LPS液(100ng/mL)共同培养48小时；Sim0.1+LPS组：UCBEPCs与GM-2MV标准液和0.1μmol/L辛伐他汀共同孵育24小时后,加入LPS液(100ng/mL)共同培养至48小时；Siml.O+LPS组：UCBEPCs与GM-2MV标准液和1.0μmol/L辛伐他汀共同孵育24小时后,加入LPS液(100ng/mL)共同培养至48小时；Sim10.0+LPS组：UCBEPCs与GM-2MV标准液和10.0μmol/L辛伐他汀共同孵育24小时后,加入LPS液(100ng/mL)共同培养至48小时；辛伐他汀组：UCBEPCs与GM-2MV标准液和1.0μmol/L辛伐他汀共同孵育48小时。应用MTT比色法测定EPCs增殖功能和粘附功能,通过Transwell小室观察EPCs迁移功能,应用流式细胞仪检测EPCs凋亡情况,细胞凋亡率(AP)计算公式：AP=凋亡细胞数/总检测细胞数。统计学处理：结果中数据以均数±标准差(x±s)表示,资料采用SPSS(16.0版)统计软件进行统计学分析,组间比较用随机取组设计的方差分析,以P<0.05为差异有显著性
结果第一部分：经鉴定分离培养细胞为EPCs,经复苏传代见细胞生长良好。第二部分：脐静脉血来源EPCs与LPS共孵育后其增殖、迁移显著降低(P=0.009、P=0.026),黏附能力也下降,但差异无显著性(P=0.279)。脐静脉EPCs与LPS共孵育后加入不同浓度辛伐他汀,EPCs的增殖、迁移和黏附能力不同程度改善,随辛伐他汀浓度增加,该作用增强,辛伐他汀浓度为1.0μmol/L时EPCs增殖显著改善(P=0.017),浓度10.0μmol/L时EPCs增殖、黏附、迁移功能,较LPS组均显著改善(P=0.00,P=0.002,P=O.00),其中黏附和迁移功能较空白对照组显著改善(P=O.039,P=0.000)。第三部分：人EPCs与LPS共孵育后其凋亡率显著增加(12.632±0.5271 vs3.0266±0.5271, P<0.00)。辛伐他汀(1.0umol/L)与EPCs共孵育,EPCs各检测指标与对照组比较均无显著变化。UCBEPCs与不同浓度辛伐他汀孵育后再加入LPS,EPCs的增殖、迁移和黏附能力较LPS组不同程度改善,凋亡率降低,随辛伐他汀浓度增加,该作用增强,辛伐他汀浓度为0.1umol/L EPCs增殖、黏附、迁移功能较LPS组有改善,但无统计学差异(P=0.687、0.501、0.683),EPCs凋亡率显著降低(9.2750±0.5961 vs 12.632±0.5271,P=0.00),辛伐他汀浓度为10.0μmol/L时,EPCs增殖、黏附、迁移功能,较LPS组均显著改善(P=0.035,P=0.002,P=0.011),其中粘附功能较对照组也有显著改善(P=0.039),不同浓度辛伐他汀与EPCs作用24小时后再与LPS共孵育,其EPCs凋亡率较LPS组均显著改善,但仍高于对照组和辛伐他汀组。
结论自脐静脉血可成功分离内皮祖细胞,并可在体外进行传代培养。LPS与UCBEPCs共孵育,可使UCBEPCs增殖和迁移功能显著降低,黏附能力下降,凋亡率显著增加。单纯应用辛伐他汀(1.0umol/L)与UCBEPCs共孵育,对UCBEPCs的增殖、粘附、迁移功能及细胞凋亡无显著影响。辛伐他汀可以改善LPS导致的EPCs增殖、黏附、迁移功能的降低,在研究范围内改善作用随浓度增加而增强。提前应用辛伐他汀与EPCs共孵育,可以显著降低LPS导致的EPCs增殖、黏附、迁移功能的降低,在研究范围内该作用随浓度增加而增强。
Background:Sepsis continues to be a major cause of morbidity and mortality worldwide. Preclinical and clinical sepsis studies have shown that the acute systemic inflammatory and procoagulant response results in structural and functional alterations in the endothelium. The endothelial cells (ECs) play a pivotal role in the progression of sepsis; the ECs are not only the participant of inflammatory reaction, but also the first damaged target cells. The dysfunction of ECs is a critical event in the initiation of organ dysfunction caused by sepsis.Recent studies suggested that the injured ECs could be regenerated by circulating bone marrow-derived progenitor cells called endothelial progenitor cells (EPCs), which had capabilities to mobilize from bone marrow with homing to foci of injuries and to differentiate into mature ECs to ameliorate the dysfunction of ischemic organs caused by sepsis. The impairment of EPCs caused by severe inflammation may contribute to the progression of organ dysfunction. Circulating endothelial progenitor cells may be an important mechanism of vascular repair, and thus shows significant promise for prognostic and therapeutic strategies in critical illness, namely sepsis and sepsis-related organ dysfunction. Many studies have convincingly demonstrated that simvastatin benefit for sepsis,and could promote the function of EPCs.but there no evidence about the effects of simvastatin on the EPCs incubated with LPS.
Objective:1、To separate EPCs from human umbilical cord blood (HUCB).2、To investigate the variation of the proliferation、adhention、migration and apoptosis of EPCs when incubated with LPS.3、The effects of simvastatin at different concentration on the functions of EPCs when added before or after the EPCs incubated with LPS in vitro.
Methods:Total mononuclear cells(MNCs) were isolated from human umbilical cord blood by Ficoll density gradient centrifugation,and then the cells were plated on fibronectin-coated culture dishes. After 7 days culture, attached cells were isolated and assessed with a laser scanning confocal microscope. EPCs divided to different group:control group:EPCs were cultivated with standard EGM-2MW fluid for 48hr; LPS group:EPCs were cultivated with standard EGM-2MW fluid plus LPS(100 ng/Ml) for 48hr;simvastatin grup:EPCs were cultivated with standard EGM-2MW fluid add simvastatin 1.0μmol/L for 48hr;test group:first EPCs were incubated with standard EGM-2MW fluid and LPS(100 ng/ml)/simvastatin of different concentrations (simv0.1:add simvastatin 0.1μmol/L, simv1.0:add simvastatin 1.0μmol/L, simv10.0:add simvastatin 10.0μmol/L) for 24hrs then addde simvastatin of different concentrations (simv0.1:add simvastatin 0.1μmol/L, simv1.0:add simvastatin 1.0μmol/L, simv10.0:add simvastatin 10.0μmol/L)/LPS(100 ng/ml).The proliferation, adhesion and migration of EPCs were detected with MTT assay, Transwell chamber assay after 48hrs respectively.And the influences of LPS and simvastatin on EPCs'proliferation, adhesion、migration and apoptosis were evaluated.
Results:Incubated with LPS the proliferation of EPCs were decline significantly (P=0.009),the adhesion and migration of EPCs were also descended,but there was no significance (P=0.279、P=0.056),the apoptosis rate of EPCs were increased significantly.When added simvastatin the proliferation, adhesion and migration of EPCs were all improved,there are some difference for difference concentration of simvastatin.There were hardly any improvment in the proliferation, adhesion and migration of EPCs when added simvastatin of 0.1μmol/L (P=0.687、P=0.501、P=0.683 respectively), EPCs' proliferation was improve significantly when incubated with simvastatin of 1.0μmol/L compared with LPS group(P=0.017),while the adhesion and migration were also improved but there was no significance(P=0.064、P=0.069 respectively). When incubated with simvastatin at the concentration of 10.0μmol/L the the proliferation、adhesion and migration of EPCs were all improved significantly (P=0.00, P=0.002, P=0.00 respectively)compared with LPS group,and the adhesion and migration of EPCs were ameliorated significantly even compared with the EPCs cultivated with standard EGM-2MW fluid (P=0.039,P=0.000 respectivly).Incubated with simvastatin there were no significant changes on the EPCs function of proliferation, adhesion and migration. When EPCs were incubated with standard EGM-2MW fluid added simvastatin of different concentrations (simv0.1:add simvastatin 0.1μmol/L, simv1.0:add simvastatin 1.0μmol/L, simv10.0:add simvastatin 10.0μmol/L) for 24hrs then addde LPS(100 ng/ml).The proliferation, adhesion and migration of EPCs all improved compare with the LPS group,but lower than the control group;the apoptosis were all decreased compare with the LPS group,but higher than control group and simvastatin group still.
Conclusion:LPS could cut down the proliferation of EPCs sharply while the adhesion and migration were decline in some degree when incubated with EPCs.Simvastatin could improve the declined proliferation, adhesion and migration of EPCs which incubated with LPS first.When incubated with simvastatin first there were some profect function on the effect of LPS on EPCs
引文
1、Levy MM, Dellinger RP, Townsend SR, et al; Surviving Sepsis Campaign:The Surviving Sepsis Campaign:results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010,38:367-74.
2、Asahara T, Murohara T, Sullivan A,et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science.1997;275(5302):964-7.
3、Chapel A, Bertho JM, Bensidhoum M,et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome.J Gene Med.2003;5(12):1028-38.
4、纪巧丽,林蓉,袁秉祥血管内皮祖细胞与炎性因子相关性的研究进展.生理科学进展2009：40(3)；264-267。
5、Rafat N,Hanusch C,Brinkkoetter PT,et al.Increased circulating endothelial progenitor cells in septic patients:correlation with survival (J). Crit Care Med, 2007,35(7):1677-1684。
6、F.B. Mayr, A.O. Spiel, J.M. Leitner,et al. Effects of low dose endotoxemia on endothelial progenitor cells in humans (J). Atherosclerosis,2007,195 (1):e202-e206。
7.付文政,毛岸荣,罗天恩等。内皮祖细胞在创伤后多器官功能障碍中的变化及意义。中国危重病急救医学2010,22(6)；356-350
8. Dimmeler S, AicherA, VasaM, et al. HMG - CoA reductase inhibitors (statins) increase endothelial p rogenitor cells via the P I3- kinase/Akt pathway [J]. J Clin Invest, 2001,108 (3):391-397.
9. WalterDH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization:a novel effect involving mobilization and incorporation of bone marrow-derived endothelial p rogenitor cells[J]. Circulation,2002,105 (25):3017-3024.
10. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitormobilizes bone marrow--derived endothelial p rogenitor cells [J]. J Clin Invest, 2001,108 (3):399-405
11.Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide—induced sepsis. J Pharmacol Exp Ther.2000.294:1043—1046.
12. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis.2001 Oct 15;33(8):1352-7. Epub 2001 Sep 20.
13. Schmidt H, Hennen R, Keller A, et al. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med.2006 Aug;32(8):1248-51. Epub 2006 Jun 21.
14. Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases.Crit Care Med.2007 Feb;35(2):372-8.
15. Mortensen EM, Restrepo MI, Copeland LA, et al. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy.2007 Dec;27(12):1619-26.
16. Gupta R, Plantinga LC, Fink NE, et al. tatin use and sepsis events in patients with chronic kidney disease.JAMA.2007 Apr 4;297(13):1455-64.
17.Thomsen RW, Riis A, Kornum JB, Christensen S, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients. Arch Intern Med.2008 Oct 27;168(19):2081-7.
18. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia:a population-based cohort study.Crit Care Med.2006 Apr;34(4):1080-6.
19. Botelho-Nevers E, Rolain JM, Espinosa L, Raoult D. Statins limit Rickettsia conorii infection in cells. Int J Antimicrob Agents.2008 Oct;32(4):344-8. Epub 2008 Aug 13.
20. Buerke U, Carter JM, Schlitt A, et al. Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. Shock.2008 Apr;29(4):497-503.
21、Dimmeler S,Aicher A,Vasa M, et al. HMG2CoA reductase inhibitors(statins) increase endothelial progenitor cells via the PI 32kinase/Aktpathway. J Clin Invest,2001,108:3912397.
22、Werner N,Priller J,Laufs U, et al. Bone marrow2derived progenitor cells modulate vascular reendothelialization and neointimal formation:effect of 32hydroxy232methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol,2002,22:156721572.
23、Llevadot J,Murasawa S,Kureishi Y, et al. HMG2CoA reductase inhibitor mobilizes bone marrow2derived endothelial progenitor cells.J Clin Invest,2001,108:3992405.
24、Landmesser U, Engberding N,Bahlmann FH,et al. Statin2inducedimprovement of endothelial progenitor cell mobilization, myocardialneovascularization,left ventricular function,and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. irculation,2004,110:193321939.
25、Vasa M,Fichtlscherer S,Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation,2001,103:288522890.
26、Assmus B,Urbich C,Aicher A, et al. HMG2CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res,2003,92:104921055.
27、Urbich C,Dernbach E, Zeiher AM, et al. Double2edged role of statins in angiogenesis signaling. Circ Res,2002,90:7372744.
28、Walter DH,Rittig K,Bahlmann FH, et al. Statin therapy accelerates reendothelialization:a novel effect involving mobilization and incorporation of bone marrow2derived endothelial progenitor cells. Circulation,2002,105:301723024.
1、Asahara T,Murohara T,Sullivan A,et al.Isolation of putative progenitor endothelial cells for angiogenesis.Science,1997,275(5302):964-967.
2、Fan C L, Li Y, Gao P J, et al. Differentiation of endothelial progenitor cells from human umbilical cord blood CD 34+cells in vitro.Acta Pharmacol Sin, 2003, 24(3):212-218.
3、Urbich C, Dimmeler S. Endothelial progenitor cells:characterization and role in vascular biology. Circ Res.2004;95(4):343-353.
4、Hill JM,Zalos G,Halcox JP,et al.Circulating endothelial progenitor cells,vascular function,and cardiovascular risk.N Engl J Med,2003,348(7):593-600.
5、Bonello L,Basire A,Sabatier F,et al.Endothelial injury induced by coronary angioplasty triggers mobilization of endothelial progenitor cells in patients with stable coronary artery disease.J Thromb Haemost,2006,4(5):979—981.
6、Peichev M,Naiyer AJ,Pereira D,et al.Experession of VEGFR-2 and AC133 by circulating human CD34(+)cells identifies a population of functional endothelial precursors.Blood,2000,95(3):952-958.
7、Eggermann J,Kliche S,Jarmy G,et al.Endothelial progenitor cell culture and differentiation in vitro:a methodological comparison using human umbilical cord blood.Cardiovascular Research,2003,58(2):478-486.
8、Murohara T, Ikeda H, Duan J, et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest,2000,105(11):1527-1536.
9、Hill J M, Zalos G, Halcox J P, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med,2003,348 (7): 593-600.
10、Ergun S, Gehling UM. Nonbone marrow-derived endothelial progenitor cells: what is their exact location? Circ Res.2007; 101(3):e31.
11、Aicher A, Rentsch M, Sasaki K, et al. Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res.2007; 100(4):581-589.
12、Kallka C,Masuda H, Takahashi T, et al. Transplantation of Ex Vivo Expanded Endothelial Progenitor Cells for Therapeutic Neovascularization. Proc Natl Acad Sci USA,2000,97:3422-3427.
13、Timmermans F, Plum J, Yoder MC, et al. Endothelial progenitor cells: identity defined? J Cell Mol Med.2009; 13(1):87-102.
14、Brown MA, Wallace CS, Angelos M, et al. Characterization of umbilical cord blood-derived late outgrowth endothelial progenitor cells exposed to laminar shear stress. Tissue Eng Part A.2009;15(11):3575-3587.
15、Bahlmann FH, de Groot K, Mueller 0, et al. Stimulation of endothelial progenitor cells:a new putative therapeutic effect of angiotensin Ⅱ receptor antagonists. Hypertension,2005,45(4):526-529.
16、Bellik L, Ledda F, Parenti A. Morphological and phenotypical characterization of human endothelial progenitor cells in an early stage of differentiation. FEBS Lett,2005,579(12):2731-2736.
1. Peters K, Unger RE, Brunner J, et al:Molecular basis of endothelial dysfunction in sepsis (J). Cardiovasc Res,2003,15(1):49-573.
2、Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis (J). Science,1997,275(5302):964-7.
3、杨乃全,张馥敏*,胡政力等辛伐他汀对内皮祖细胞增殖、迁移及凋亡影响的研究(J).南京医科大学学报(自然科学版),2007,27(9)：952-955.
4.Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases (J),Crit Care Med,2007,35(2):372-378.
5.Thomsen RW, Riis A, Kornum JB, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients (J).Arch Intern Med,2008,168(19):2081-2087.
6. Mutunga M,Fulton B,Bullock R,et al. Circulating endothelial cells in patients with septic shock (J). Am J Respir Crit Care Med,2001,163(1):195-200.
7、Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome (J).J Gene Med, 2003,5 (12).-1028-38.
8、Sushma K. Cribbs, Greg S. Martin, Mauricio Rojas. Monitoring of endothelial dysfunction in critically ill patients:the role of endothelial progenitor cells (J). Curr Opin Crit Care,2008,14 (3):354-360。
9、Rafat N, Hanusch C, Brinkkoetter PT, et al. Increased circulating endothelial progenitor cells in septic patients:correlation with survival (J). Crit Care Med,2007,35(7):1677-1684。
10. F. B. Mayr, A.O. Spiel, J. M. Leitner, et al. Effects of low dose endotoxemia on endothelial progenitor cells in humans (J). Atherosclerosis,2007,195 (1):e202-e206。
11. Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide induced sepsis (J). Pharmacol Exp Ther,2000,294 (3):1043-1046.
12. Waldow T,Witt W, Weber E, et al. Nit ric oxide donorinduced persistent inhibition of cell adhesion protein expression and NF-kappaB activation in endothelial cells (J). Nitric Oxide,2006,15(1):103-113.
13. Mastuda N, Hayashi Y, Takahashi Y, et al. Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway: reversal effect of fluvastatin therapy. (J). Pharmacol Exp Ther,2006,319 (3):1348-1354.
14、Burnham EL, Taylor WR, Quyyumi AA, et al. Increased circulating endothelial progenitor cells are associated with survival in acute lung injury (J). Am J Respir Crit Care Med,2005,172(7):854-860
15、Yamada M, Kubo H, Ishizawa K, et al:Increased circulating endothelial progenitor cells in patients with bacterial pneumonia:Evidence that bone marrow derived cells contribute to lung repair (J). Thorax,2005,60(5):410-413.
16. Luo TH, Wang Y, Lu ZM,et al.The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes (J).Critical Care,2009:13 (4) R118。
17. Burnham EL, Taylor WR, Quyyumi AA, et al. Increased circulating endothelial progenitor cells are associated with survival in acute lung injury (J). Am J Respir Crit Care Med,2005,172(7):854-860.
18. Mutunga M, Fulton B, Bullock R, et al:Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 2001; 163:195-200
19. Goon PK, Boos CJ, Lip GY:Circulating endothelial cells:Markers of vascular dysfunction. Clin Lab 2005; 51:531-538。
20. Mayr FB, Spiel AO, Leitner JM, et al:Effects of low dose endotoxemia on endothelial progenitor cells in humans. Atherosclerosis 2007, 195:e202-e206.
21.Tian Hang Luo, Yao Wang, Zheng Mao Lu, et al.The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes.Critical Care 2009:13 (4) R118。
22. Rafat N, Hanusch C, Brinkkoetter PT,et al. Increased circulating endothelial progenitor cells in septic patients:correlation with survival. Crit Care Med.2007 Jul;35(7):1677-84.
23. Sakr Y, Dubois MJ, De Backer D, et al:Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004:32:1825-1831
1、Zheng X, Li W, Song Y, et al. Nonhematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 2007; 5:1394-1400.
2、Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004; 32:1825-1831.
3、SK. Cribbs, GS. MM. Rojas Monitoring of endothelial dysfunction in critically ill patients:therole of endothelial progenitor cells. Current Opinion in Critical Care 2008,14:354-360)
4. Peters K, Unger RE, Brunner J, et al:Molecular basis of endothelial dysfunction in sepsis. Cardiovasc Res 2003; 15:49-573.
5. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science.1997;275(5302):964-7.
6. R Lavi, XY Zhu, A R, et al. Simvastatin Decreases Endothelial Progenitor Cell Apoptosis in the Kidney of Hypertensive Hypercholesterolemic Pigs. Chade (Arterioscler Thromb Vasc Biol.2010;30 (5):976-983.
7. XM Bao, CF Wu, GP Lu. Atorvastatin inhibits homocysteine-induceddysfunction and apoptosis in endothelial progenitor cells Acta Pharmacologica Sinica 2010; 31 (3):476-484)
8. Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases[J].Crit Care Med,2007 Feb,35(2):372-378.
9. Thomsen RW, Riis A, Kornum JB, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients[J]. Arch Intern Med,2008 Oct 27,168(19):2081-2087.
10. Mutunga M, Fulton B,Bullock R,et al. Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 2001; 163:195-200.
11、Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5(12):1028-38.
12、Burnham EL, Taylor WR, Quyyumi AA, et al:Increased circulating endothelial progenitor cells are associated with survival in acute lung injury. Am J Respir Crit Care Med 2005; 172:854-860
13、Yamada M, Kubo H, Ishizawa K, et al:Increased circulating endothelial progenitor cells in patients with bacterial pneumonia:Evidence that bone marrow derived cells contribute to lung repair. Thorax 2005; 60:410-413
14. Tian Hang Luo, Yao Wang, Zheng Mao Lu, et al.The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes. Critical Care 2009:13 (4) R118。
15. Rafat N, Hanusch C, Brinkkoetter PT,et al. Increased circulating endothelial progenitor cells in septic patients:correlation with survival. Crit Care Med 2007; 35:1677-1684.
16. Mayr FB, Spiel AO, Leitner JM, et al. Effects of low dose endotoxemia on endothelial progenitor cells in humans. Atherosclerosis.2007 Nov;195(1):e202-6.
17. Spiel A0, Mayr FB, Leitner JM,et al. Simvastatin and rosuvastatin mobilize Endothelial Progenitor Cells but do not prevent their acute decrease during systemic inflammation. Thromb Res.2008;123(1):108-13.
18. Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide induced sepsis. Pharmacol Exp Ther,2000,294:1043 1046.
19. Gupta R, Plantinga LC, Fink NE, et al. tatin use and sepsis events in patients with chronic kidney disease. JAMA.2007;297(13):1455-64.
20. Thomsen RW, Riis A, Kornum JB, Christensen S, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients. Arch Intern Med.2008;168(19):2081-7.
21. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia:a population-based cohort study. Crit Care Med.2006; 34 (4):1080-6.
22. Waldow T,Witt W, Weber E, et al. Nit ric oxide donorinduced persistent inhibition of cell adhesion protein expression and NF-kappaB activation in endothelial cells. Nitric Oxide.2006;15(1):103-113.
23. Mast uda N, Hayashi Y, Takahashi Y, et al. Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric ateries from septic rabbits depending on the altered phosphati-dylinositol 32kinase/Akt pat hway reversal effect of fluvastatin therapy. Pharmacol Exp Ther.2006;319:1348-1354.
24. Urbich C, Knau A, Fichtlscherer S, et al. FOXO-dependent expression of the proapoptotic protein Bim:pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 2005;19(8)):974-6.
25. XM Bao, CF Wu, GP Lu Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK。 Atherosclerosis 2010; 210:114-121
26、杨乃全,张馥敏*,胡政力等。辛伐他汀对内皮祖细胞增殖、迁移及凋亡影响的研究南京医科大学学报(自然科学版).2007；27(9)：952-955。
27、Henrich D, Seebach C, Wilhelm K, et al. High dosage of simvastatin reduces TNF2induced apop tosis of endothelial p rogenitor cells but fails to p revent apop tosis induced by IL21 in vitro. Surg Res,2007,142 (1):13-19
1.Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide—induced sepsis. J Pharmacol Exp Ther.2000.294: 1043—104 6.
2. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis.2001 Oct 15;33(8):1352-7. Epub 2001 Sep 20.
3. Schmidt H, Hennen R, Keller A, et al. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med.2006 Aug;32(8):1248-51. Epub 2006 Jun 21.
4. Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases. Crit Care Med.2007 Feb;35(2):372-8.
5. Mortensen EM, Restrepo MI, Copeland LA, et al. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy.2007 Dec;27(12):1619-26.
6. Gupta R, Plantinga LC, Fink NE, et al. tatin use and sepsis events in patients with chronic kidney disease. JAMA.2007 Apr 4;297(13):1455-64.
7. Thomsen RW, Ri is A, Kornum JB, Christensen S, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients. Arch Intern Med.2008 Oct 27; 168(19):2081-7.
8. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia:a population-based cohort study. Crit Care Med. 2006 Apr;34(4):1080-6.
9. Botelho-Nevers E, Rolain JM, Espinosa L, Raoult D. Statins limit Rickettsia conorii infection in cells. Int J Antimicrob Agents.2008 Oct;32(4):344-8. Epub 2008 Aug 13.
10. Buerke U, Carter JM, Schlitt A, et al. Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. Shock.2008 Apr;29(4):497-503.
11. Berbee JF,Havekes LM,Rensen PC. Apolipoprotiens modulate the inflammatory response to lipoplysaceharide[J]. J Endotoxin Res,2005.11(2):97—103.
12. Chien JY, Jemg JS, Yu CJ, et al. Low serom level of hiish—density lipoprotein cholesterol is a poor prognostic factor for severe sepsis [J]. Crit Care Med,2005,33(8):1688—1693.
13. Ascan Warnholtz, Sabine Genth-Zotz, Thomas Munzel. Should Treatment of Sepsis Include Statins? [J]. Circulation,2005,111:1735-1737.
14.周爱儒,查锡良,等.生物化学(第五版).人民卫生出版社,2000,134-141.
15. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002:40:2125-34.
16. Bays HE, Ose L, Fraser N, et al. Ezetimibe Study Group. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004:26:1758-73.
17. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 1993:72:1031-7.
18. Guerin M, Lassel TS, Le Goff W, Farnier M, Chapman MJ. Action of atorvastatin in combined hyperlipidemia:preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles. Arterioscler Thromb Vasc Biol 2000:20:189-97.
19. Stein EA, Strutt K, Southworth H, Diggle PJ, Miller E. HeFH Study Group. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2003:92:1287-93.
20.Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997;79:38-42.
21.KUREISHI Y, LUO Z, SHIOJIMA I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals[J]. Nat Med,2000,6:1004—1010
22.Llevadot J, Murasawa S, Kureishi Y, et al. HMG—CoA reductase inhibitor mobilizes bone—nl/IITOW derived endothelial progenitor cels. J Clin Invest.2001,108:399-405.
23. Dimmeler S。Aicher A, Vasa M, et al. HMG—GoA—eductase inhibitors (statins) increase endothelial progenitor cells via the PI3 kinase /Akt pathway. J Clin Invest,2001,108:391—397.
24. Assmus B, Urbich C, Aicher A, et al. HMG—CoA reductase inhlbitors reduce senescence an d increase proliferation of endothelial progenitor cels via regulation of cel cycle regulatory genes. Circ Res.20o3。92:lo49—1055.)
25. Assmus B, Urbich C, Aicher A, et al. HMG—CoA reductase inhlbitors reduce senescence an d increase proliferation of endothelial progenitor cels via regulation of cel cycle regulatory genes. Circ Res.20o3。92:lo49—1055.
26. Walter DH, Rittig K, Bahlmann FH, et al, Statin therapy accelerates reendOthelializatiOn:a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells[J]. Circulation,2002,105(25):3017-3024.
27. Kurzen H, Manns S, Dandekar G, Schmidt T, Pratzel S, Kraling BM. (2002) Tightening of endothelial cell contacts:a physiologic response to cocultures with smooth-muscle-like 10T1/2 cells. J Invest Dermatol 119:143-53.
28. Luo Y and Radice GL. (2003) Cadherin-mediated adhesion is essential for myofibril continuity across the plasma membrane but not for assembly of the contractile apparatus. J Cell Sci 116:1471-9.
29. Gonzalez D, Herrera B, Otero BK, Quintero G, Rojas A. (2003) Nitric oxide disrupts VE-cadherin complex in murine microvascular endothelial cells. Biochem Biophys Res Commun 304:113-8.
30. Angelini DJ, Hyun SW, Grigoryev DN, et al. (2006) TNF{α} increases tyrosine phosphorylation of vascular endothelial-cadherin opens the paracellular pathway through fyn activation in human lung endothelia. Am J Physiol Lung Cell Mol Physiol 291:L1232-45.
31. De Maio A, Gingalewski C, Theodorakis NG, Clemens MG. (2000) Interruption of hepatic gap junctional communication in the rat during inflammation induced by bacterial lipopolysaccharide. Shock 14:53-9.
32. Rignault S, Haefliger J, Gasser D, et al. (2005) Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium. Crit Care Med 33:1302-10.
33. Simon AM, McWhorter AR, Chen H, Jackson CL, Ouellette Y. (2004) Decreased intercellular communication and connexin expression in mouse aortic endothelium during lipopolysaccharide-induced inflammation. J Vasc Res 41:323-33.
34. Jacobson J, Barnard J, Grigoryev D, Ma S, Tuder R, Garcia J. (2005) Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 288:L1026-32.
35. van Nieuw Amerongen GP, Vermeer MA, Negre-Aminou P, Lankelma J, Emeis JJ, van Hinsbergh VW. (2000) Simvastatin improves disturbed endothelial barrier function. Circulation 102:2803-9.
36. Scalia R and Stalker TJ. (2002) Microcirculation as a target for the anti-inflammatory properties of statins. Microcirculation 9:431-442.
37. Fukuhra S, Sakurai A, Yamagishi A, Sako K, Mochizuki N. (2006) Vascular endothelial cadherin-mediated cell-cell adhesion regulated by a small GTPase, Rapl. J Biochem Mol Biol 39:132-9.
38. van Griensven M, Probst C, Muller K, Hoevel P, Pape HC. (2006) Leukocyte-endothelial interactions via ICAM-1 are detrimental in polymicrobial sepsis. Shock 25:254-9.
39.Cernuda-Morollon E and Ridley AJ. (2006) Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ Res 98:757-67.
40. Rasmussen LM, Hansen PR, Nabipour MT, Olesen P, Kristiansen MT, Ledet T. (2001) Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells. Biochem J 360:363-70.
41. Takeuchi S, Kawashima S, Rikitake Y, et al. (2000) Cerivastatin suppresses lipopolysaccharide-induced ICAM-1 expression through inhibition of Rho GTPase in BAEC. Biochem Biophys Res Commun 269:97-102. [
42. Zapolska-Downar D, Siennicka A, Kaczmarczyk M, Kolodziej B, Naruszewicz M. (2004) Simvastatin modulates TNFα-induced adhesion molecules expression in human endothelial cells. Life Sci 75:1287-302.
43. Pozo M, de Nicolas R, Egido J, Gonzalez-Cabrero J. (2006) Simvastatin inhibits the migration and adhesion of monocytic cells and disorganizes the cytoskeleton of activated endothelial cells. Eur J Pharmacol 548:53-63.
44. Croner RS, Kulu Y, Hoerer E, et al. (2005) Intravenous glycine after cecal ligation and puncture has no effect on impaired hepatic microperfusion, leukocyte adhesion, and mortality in septic rats. Microvasc Res 69:71-8.
45.刘德培,查锡良,药立波等.医学分子生物学.北京：人民卫生出版社,2006.375-448.
46. Sealia R, Stalker TJ. Mieroeirculation as a target for the antiinflammatoryproperties of statins[J]. Mieroeirculation,2002,9:431-442.
47. Giuti Paiva A, Martinez MR, Felix JV, et al. Simvastatine decreases nitric oxide overproduction and reverts the impaired vascular responsiveness indued by endotoxic shock in rats[J]. Shock,2004,21:271—275.
48. Stalker TJ, Lefer AM, Scalia R. (2001) A new HMG-CoA reductase inhibitor rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium:the role of mevalonic acid. Br J Pharmacol 133:406-412.
49. Naoyuki Matsuda, Yukio Hayashi, Yoshika Takahashi,et al. (2006)Phosphorylation of Endothelial Nitric-Oxide Synthase Is Diminished in Mesenteric Arteries from Septic Rabbits Depending on the Altered Phosphatidylinositol 3-Kinase/Akt Pathway:Reversal Effect of Fluvastatin Therapy. CARDIOVASCULAR,319:1348-1354.
50. Waldow T, Witt W, Weber E, et al. Nitric oxide donorindueed persistent inh ibition of cell adhesion protein expression and NFkappaB activation in endothelial cells[J]. Nitric Oxide,2006,15:103—113.
51. Alvarez de Sotomayor M, Vega S, Mingorance C, et al. Effects of HMG-CoA reductase inhibition by simvastatin on vascular dysfunction induced by lipopolysaccharide in rats. Pharmacology.2008;82(2):89-96. Epub 2008 May 29.
52. Matsuda N, Hayashi Y, Takahashi Y, et al. J Pharmacol Exp Ther. Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway:reversal effect of fluvastatin therapy.2006 Dec;319(3):1348-54. Epub 2006 Sep 26.
53. Frey T, De Maio A. Increased expression of CD14 in macrophages after inhibition of the cholesterol biosynthetic pathway by lovastatin. Mol Med. 2007 Nov-Dec;13(11-12):592-604.
54. Chen CH, Lee RP, Wu WT, et al. Fluvastatin ameliorates endotoxin induced multiple organ failure in conscious rats. Resuscitation.2007 Jul;74(1):166-74. Epub 2007 Mar 13.
55. Novack V, Eisinger M, Frenkel A, et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections:a randomized double-blind placebo controlled clinical trial. Intensive Care Med.2009 Feb 11. [Epub ahead of print]
56. Niessner A, Steiner S, Speidl WS, et al. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis.2006 Dec;189(2):408-13. Epub 2006 Jan 26.
57. Ebdrup L, Krog J, Granfeldt A, et al. APMIS. Leukocyte, plasma, and organ-associated cytokine profiles in an animal model of acute inflammation.2008 May;116(5):352-60.
58. Chaudhry MZ, Wang JH, Blankson S, et al. Surg Infect (Larchmt). Statin (cerivastatin) protects mice against sepsis-related death via reduced proinflammatory cytokines and enhanced bacterial clearance.2008 Apr; 9 (2):183-94.
59. Yasuda H, Yuen PS, Hu X, Kidney Int, et al. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. 2006 May;69(9):1535-42.
60. Rotundo RF, Curtis TM, Shah MD, et al. (2002) TNF-α disruption of lung endothelial integrity:reduced integrin mediated adhesion to fibronectin. Am J Physiol Lung Cell Mol Physiol 282:L316-329.
61. Redl H, Schlag G, Lamche H. (1990) TNF- and LPS-induced changes of lung vascular permeability:studies in unanesthetised sheep. Circ Shock 31:183-92.
62. Tracey KJ, Fong Y, Hesse D, et al. (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662-4.
63. Sutton ET, Norman JG, Newton CA, Hellermann GR, Richards IS. (1997) Endothelial structural integrity is maintained during endotoxic shock in an interleukin-1 type 1 receptor knockout mouse. Shock 7:105-10.
64. Wang Q, Fang CH, Hasselgran P0. (2001) Intestinal permeability is reduced and IL-10 levels are increased in septic IL-6 knockout mice. Am J Physiol Regul Integr Comp Physiol 281:R1013-23.
65. Berg DJ, Kuhn R, Rajewsky K, et al. (1995) Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock the Shwartzman reaction but not endotoxin tolerance. J Clin Invest 96:2339-47.
66. Howard M, Muchamuel T, Andrade S, Menon S. (1993) Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 177:1205-8.
67. Zelvyte I, Dominaitiene R, Crisby M, et al. Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res. 2002:45:147-154.
68. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure:role of xanthine—oxidase and extracellular superoxide dismutase. Circulation, 2002,106(24):3073—3078
69. Wassmann S, Laufs U, Muller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol.2002:22:300-305.
70. Wagner AH, Kohler T, Ruckschloss U, et al. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol.2000:20:61-69.
71. Luigina Guastil, Franca Marinol, Marco Cosentinol, et al.Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin Ⅱ type 1 receptor expression:1-year follow-up. European Heart Journal 2008; 29:1118-1126.
72. Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation.2004:110:3349-3354.
73. Durant R, Klouche K, Delbosc S, et al. Superoxide anion overproduction in sepsis:effects of vitamin e and simvastatin. Shock.2004 Jul;22(1):34-9.
74. Shishehbor MH, Aviles RJ, Brennan ML, Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF Jr, Penn MS, Sprecher DL, Vita JA, Hazen SL. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA.2003; 289:1675-1680.
75. Fukai T, Siegfried MR, Ushio—Fukai M, et al. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest,2000,105(11):1631—1639.
76. UIf L, Ferdinand B, Maja M, et al. Simvastatin versus ezetimibe pleiotropic and lipid—lowering effects on endothelial function in humans. Circulation.2005,111(18):2356—2363.
77. Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation.2004 Nov 23;110(21):3349-54. Epub 2004 Nov 1.
78. Martin CP, Talbert RL, Burgess DS, et al. Effectiveness of statins in reducing the rate of severe sepsis:a retrospective evaluation. Pharmacotherapy.2007 Jan;27(1):20-6.
79. Horn MP, Knecht SM, Rushing FL, et al. Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates.J Pharmacol Exp Ther.2008 Jul;326(1):135-43.
80. Zager RA, Johnson A. Renal cortical cholesterol accumulation is an integral component of the systemic stress response. Kidney Int.2001 Dec; 60 (6):2299-310.
81. Zager RA, Johnson AC, Hanson SY. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter. Kidney Int.2003 Jan;63(1):123-33.
82. Majumdar SR, McAlister FA, Eurich DT, et al. Statins and outcomes in patients admitted to hospital with community acquired pneumonia:population based prospective cohort study. BMJ.2006;333(7576):999.
83. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001; 33:1352-1357.
2、Asahara T, Murohara T, Sullivan A,et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science.1997;275(5302):964-7.
3、Chapel A, Bertho JM, Bensidhoum M,et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome.J Gene Med.2003;5(12):1028-38.
4、纪巧丽,林蓉,袁秉祥血管内皮祖细胞与炎性因子相关性的研究进展.生理科学进展2009：40(3)；264-267。
5、Rafat N,Hanusch C,Brinkkoetter PT,et al.Increased circulating endothelial progenitor cells in septic patients:correlation with survival (J). Crit Care Med, 2007,35(7):1677-1684。
6、F.B. Mayr, A.O. Spiel, J.M. Leitner,et al. Effects of low dose endotoxemia on endothelial progenitor cells in humans (J). Atherosclerosis,2007,195 (1):e202-e206。
7.付文政,毛岸荣,罗天恩等。内皮祖细胞在创伤后多器官功能障碍中的变化及意义。中国危重病急救医学2010,22(6)；356-350
8. Dimmeler S, AicherA, VasaM, et al. HMG - CoA reductase inhibitors (statins) increase endothelial p rogenitor cells via the P I3- kinase/Akt pathway [J]. J Clin Invest, 2001,108 (3):391-397.
9. WalterDH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization:a novel effect involving mobilization and incorporation of bone marrow-derived endothelial p rogenitor cells[J]. Circulation,2002,105 (25):3017-3024.
10. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitormobilizes bone marrow--derived endothelial p rogenitor cells [J]. J Clin Invest, 2001,108 (3):399-405
11.Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide—induced sepsis. J Pharmacol Exp Ther.2000.294:1043—1046.
12. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis.2001 Oct 15;33(8):1352-7. Epub 2001 Sep 20.
13. Schmidt H, Hennen R, Keller A, et al. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med.2006 Aug;32(8):1248-51. Epub 2006 Jun 21.
14. Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases.Crit Care Med.2007 Feb;35(2):372-8.
15. Mortensen EM, Restrepo MI, Copeland LA, et al. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy.2007 Dec;27(12):1619-26.
16. Gupta R, Plantinga LC, Fink NE, et al. tatin use and sepsis events in patients with chronic kidney disease.JAMA.2007 Apr 4;297(13):1455-64.
17.Thomsen RW, Riis A, Kornum JB, Christensen S, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients. Arch Intern Med.2008 Oct 27;168(19):2081-7.
18. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia:a population-based cohort study.Crit Care Med.2006 Apr;34(4):1080-6.
19. Botelho-Nevers E, Rolain JM, Espinosa L, Raoult D. Statins limit Rickettsia conorii infection in cells. Int J Antimicrob Agents.2008 Oct;32(4):344-8. Epub 2008 Aug 13.
20. Buerke U, Carter JM, Schlitt A, et al. Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. Shock.2008 Apr;29(4):497-503.
21、Dimmeler S,Aicher A,Vasa M, et al. HMG2CoA reductase inhibitors(statins) increase endothelial progenitor cells via the PI 32kinase/Aktpathway. J Clin Invest,2001,108:3912397.
22、Werner N,Priller J,Laufs U, et al. Bone marrow2derived progenitor cells modulate vascular reendothelialization and neointimal formation:effect of 32hydroxy232methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol,2002,22:156721572.
23、Llevadot J,Murasawa S,Kureishi Y, et al. HMG2CoA reductase inhibitor mobilizes bone marrow2derived endothelial progenitor cells.J Clin Invest,2001,108:3992405.
24、Landmesser U, Engberding N,Bahlmann FH,et al. Statin2inducedimprovement of endothelial progenitor cell mobilization, myocardialneovascularization,left ventricular function,and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. irculation,2004,110:193321939.
25、Vasa M,Fichtlscherer S,Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation,2001,103:288522890.
26、Assmus B,Urbich C,Aicher A, et al. HMG2CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res,2003,92:104921055.
27、Urbich C,Dernbach E, Zeiher AM, et al. Double2edged role of statins in angiogenesis signaling. Circ Res,2002,90:7372744.
28、Walter DH,Rittig K,Bahlmann FH, et al. Statin therapy accelerates reendothelialization:a novel effect involving mobilization and incorporation of bone marrow2derived endothelial progenitor cells. Circulation,2002,105:301723024.
1、Asahara T,Murohara T,Sullivan A,et al.Isolation of putative progenitor endothelial cells for angiogenesis.Science,1997,275(5302):964-967.
2、Fan C L, Li Y, Gao P J, et al. Differentiation of endothelial progenitor cells from human umbilical cord blood CD 34+cells in vitro.Acta Pharmacol Sin, 2003, 24(3):212-218.
3、Urbich C, Dimmeler S. Endothelial progenitor cells:characterization and role in vascular biology. Circ Res.2004;95(4):343-353.
4、Hill JM,Zalos G,Halcox JP,et al.Circulating endothelial progenitor cells,vascular function,and cardiovascular risk.N Engl J Med,2003,348(7):593-600.
5、Bonello L,Basire A,Sabatier F,et al.Endothelial injury induced by coronary angioplasty triggers mobilization of endothelial progenitor cells in patients with stable coronary artery disease.J Thromb Haemost,2006,4(5):979—981.
6、Peichev M,Naiyer AJ,Pereira D,et al.Experession of VEGFR-2 and AC133 by circulating human CD34(+)cells identifies a population of functional endothelial precursors.Blood,2000,95(3):952-958.
7、Eggermann J,Kliche S,Jarmy G,et al.Endothelial progenitor cell culture and differentiation in vitro:a methodological comparison using human umbilical cord blood.Cardiovascular Research,2003,58(2):478-486.
8、Murohara T, Ikeda H, Duan J, et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest,2000,105(11):1527-1536.
9、Hill J M, Zalos G, Halcox J P, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med,2003,348 (7): 593-600.
10、Ergun S, Gehling UM. Nonbone marrow-derived endothelial progenitor cells: what is their exact location? Circ Res.2007; 101(3):e31.
11、Aicher A, Rentsch M, Sasaki K, et al. Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res.2007; 100(4):581-589.
12、Kallka C,Masuda H, Takahashi T, et al. Transplantation of Ex Vivo Expanded Endothelial Progenitor Cells for Therapeutic Neovascularization. Proc Natl Acad Sci USA,2000,97:3422-3427.
13、Timmermans F, Plum J, Yoder MC, et al. Endothelial progenitor cells: identity defined? J Cell Mol Med.2009; 13(1):87-102.
14、Brown MA, Wallace CS, Angelos M, et al. Characterization of umbilical cord blood-derived late outgrowth endothelial progenitor cells exposed to laminar shear stress. Tissue Eng Part A.2009;15(11):3575-3587.
15、Bahlmann FH, de Groot K, Mueller 0, et al. Stimulation of endothelial progenitor cells:a new putative therapeutic effect of angiotensin Ⅱ receptor antagonists. Hypertension,2005,45(4):526-529.
16、Bellik L, Ledda F, Parenti A. Morphological and phenotypical characterization of human endothelial progenitor cells in an early stage of differentiation. FEBS Lett,2005,579(12):2731-2736.
1. Peters K, Unger RE, Brunner J, et al:Molecular basis of endothelial dysfunction in sepsis (J). Cardiovasc Res,2003,15(1):49-573.
2、Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis (J). Science,1997,275(5302):964-7.
3、杨乃全,张馥敏*,胡政力等辛伐他汀对内皮祖细胞增殖、迁移及凋亡影响的研究(J).南京医科大学学报(自然科学版),2007,27(9)：952-955.
4.Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases (J),Crit Care Med,2007,35(2):372-378.
5.Thomsen RW, Riis A, Kornum JB, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients (J).Arch Intern Med,2008,168(19):2081-2087.
6. Mutunga M,Fulton B,Bullock R,et al. Circulating endothelial cells in patients with septic shock (J). Am J Respir Crit Care Med,2001,163(1):195-200.
7、Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome (J).J Gene Med, 2003,5 (12).-1028-38.
8、Sushma K. Cribbs, Greg S. Martin, Mauricio Rojas. Monitoring of endothelial dysfunction in critically ill patients:the role of endothelial progenitor cells (J). Curr Opin Crit Care,2008,14 (3):354-360。
9、Rafat N, Hanusch C, Brinkkoetter PT, et al. Increased circulating endothelial progenitor cells in septic patients:correlation with survival (J). Crit Care Med,2007,35(7):1677-1684。
10. F. B. Mayr, A.O. Spiel, J. M. Leitner, et al. Effects of low dose endotoxemia on endothelial progenitor cells in humans (J). Atherosclerosis,2007,195 (1):e202-e206。
11. Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide induced sepsis (J). Pharmacol Exp Ther,2000,294 (3):1043-1046.
12. Waldow T,Witt W, Weber E, et al. Nit ric oxide donorinduced persistent inhibition of cell adhesion protein expression and NF-kappaB activation in endothelial cells (J). Nitric Oxide,2006,15(1):103-113.
13. Mastuda N, Hayashi Y, Takahashi Y, et al. Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway: reversal effect of fluvastatin therapy. (J). Pharmacol Exp Ther,2006,319 (3):1348-1354.
14、Burnham EL, Taylor WR, Quyyumi AA, et al. Increased circulating endothelial progenitor cells are associated with survival in acute lung injury (J). Am J Respir Crit Care Med,2005,172(7):854-860
15、Yamada M, Kubo H, Ishizawa K, et al:Increased circulating endothelial progenitor cells in patients with bacterial pneumonia:Evidence that bone marrow derived cells contribute to lung repair (J). Thorax,2005,60(5):410-413.
16. Luo TH, Wang Y, Lu ZM,et al.The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes (J).Critical Care,2009:13 (4) R118。
17. Burnham EL, Taylor WR, Quyyumi AA, et al. Increased circulating endothelial progenitor cells are associated with survival in acute lung injury (J). Am J Respir Crit Care Med,2005,172(7):854-860.
18. Mutunga M, Fulton B, Bullock R, et al:Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 2001; 163:195-200
19. Goon PK, Boos CJ, Lip GY:Circulating endothelial cells:Markers of vascular dysfunction. Clin Lab 2005; 51:531-538。
20. Mayr FB, Spiel AO, Leitner JM, et al:Effects of low dose endotoxemia on endothelial progenitor cells in humans. Atherosclerosis 2007, 195:e202-e206.
21.Tian Hang Luo, Yao Wang, Zheng Mao Lu, et al.The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes.Critical Care 2009:13 (4) R118。
22. Rafat N, Hanusch C, Brinkkoetter PT,et al. Increased circulating endothelial progenitor cells in septic patients:correlation with survival. Crit Care Med.2007 Jul;35(7):1677-84.
23. Sakr Y, Dubois MJ, De Backer D, et al:Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004:32:1825-1831
1、Zheng X, Li W, Song Y, et al. Nonhematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 2007; 5:1394-1400.
2、Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004; 32:1825-1831.
3、SK. Cribbs, GS. MM. Rojas Monitoring of endothelial dysfunction in critically ill patients:therole of endothelial progenitor cells. Current Opinion in Critical Care 2008,14:354-360)
4. Peters K, Unger RE, Brunner J, et al:Molecular basis of endothelial dysfunction in sepsis. Cardiovasc Res 2003; 15:49-573.
5. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science.1997;275(5302):964-7.
6. R Lavi, XY Zhu, A R, et al. Simvastatin Decreases Endothelial Progenitor Cell Apoptosis in the Kidney of Hypertensive Hypercholesterolemic Pigs. Chade (Arterioscler Thromb Vasc Biol.2010;30 (5):976-983.
7. XM Bao, CF Wu, GP Lu. Atorvastatin inhibits homocysteine-induceddysfunction and apoptosis in endothelial progenitor cells Acta Pharmacologica Sinica 2010; 31 (3):476-484)
8. Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases[J].Crit Care Med,2007 Feb,35(2):372-378.
9. Thomsen RW, Riis A, Kornum JB, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients[J]. Arch Intern Med,2008 Oct 27,168(19):2081-2087.
10. Mutunga M, Fulton B,Bullock R,et al. Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 2001; 163:195-200.
11、Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5(12):1028-38.
12、Burnham EL, Taylor WR, Quyyumi AA, et al:Increased circulating endothelial progenitor cells are associated with survival in acute lung injury. Am J Respir Crit Care Med 2005; 172:854-860
13、Yamada M, Kubo H, Ishizawa K, et al:Increased circulating endothelial progenitor cells in patients with bacterial pneumonia:Evidence that bone marrow derived cells contribute to lung repair. Thorax 2005; 60:410-413
14. Tian Hang Luo, Yao Wang, Zheng Mao Lu, et al.The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes. Critical Care 2009:13 (4) R118。
15. Rafat N, Hanusch C, Brinkkoetter PT,et al. Increased circulating endothelial progenitor cells in septic patients:correlation with survival. Crit Care Med 2007; 35:1677-1684.
16. Mayr FB, Spiel AO, Leitner JM, et al. Effects of low dose endotoxemia on endothelial progenitor cells in humans. Atherosclerosis.2007 Nov;195(1):e202-6.
17. Spiel A0, Mayr FB, Leitner JM,et al. Simvastatin and rosuvastatin mobilize Endothelial Progenitor Cells but do not prevent their acute decrease during systemic inflammation. Thromb Res.2008;123(1):108-13.
18. Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide induced sepsis. Pharmacol Exp Ther,2000,294:1043 1046.
19. Gupta R, Plantinga LC, Fink NE, et al. tatin use and sepsis events in patients with chronic kidney disease. JAMA.2007;297(13):1455-64.
20. Thomsen RW, Riis A, Kornum JB, Christensen S, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients. Arch Intern Med.2008;168(19):2081-7.
21. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia:a population-based cohort study. Crit Care Med.2006; 34 (4):1080-6.
22. Waldow T,Witt W, Weber E, et al. Nit ric oxide donorinduced persistent inhibition of cell adhesion protein expression and NF-kappaB activation in endothelial cells. Nitric Oxide.2006;15(1):103-113.
23. Mast uda N, Hayashi Y, Takahashi Y, et al. Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric ateries from septic rabbits depending on the altered phosphati-dylinositol 32kinase/Akt pat hway reversal effect of fluvastatin therapy. Pharmacol Exp Ther.2006;319:1348-1354.
24. Urbich C, Knau A, Fichtlscherer S, et al. FOXO-dependent expression of the proapoptotic protein Bim:pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 2005;19(8)):974-6.
25. XM Bao, CF Wu, GP Lu Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK。 Atherosclerosis 2010; 210:114-121
26、杨乃全,张馥敏*,胡政力等。辛伐他汀对内皮祖细胞增殖、迁移及凋亡影响的研究南京医科大学学报(自然科学版).2007；27(9)：952-955。
27、Henrich D, Seebach C, Wilhelm K, et al. High dosage of simvastatin reduces TNF2induced apop tosis of endothelial p rogenitor cells but fails to p revent apop tosis induced by IL21 in vitro. Surg Res,2007,142 (1):13-19
1.Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide—induced sepsis. J Pharmacol Exp Ther.2000.294: 1043—104 6.
2. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis.2001 Oct 15;33(8):1352-7. Epub 2001 Sep 20.
3. Schmidt H, Hennen R, Keller A, et al. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med.2006 Aug;32(8):1248-51. Epub 2006 Jun 21.
4. Almog Y, Novack V, Eisinger M, et al. The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases. Crit Care Med.2007 Feb;35(2):372-8.
5. Mortensen EM, Restrepo MI, Copeland LA, et al. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy.2007 Dec;27(12):1619-26.
6. Gupta R, Plantinga LC, Fink NE, et al. tatin use and sepsis events in patients with chronic kidney disease. JAMA.2007 Apr 4;297(13):1455-64.
7. Thomsen RW, Ri is A, Kornum JB, Christensen S, et al. Preadmission use of statins and outcomes after hospitalization with pneumonia:population-based cohort study of 29,900 patients. Arch Intern Med.2008 Oct 27; 168(19):2081-7.
8. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia:a population-based cohort study. Crit Care Med. 2006 Apr;34(4):1080-6.
9. Botelho-Nevers E, Rolain JM, Espinosa L, Raoult D. Statins limit Rickettsia conorii infection in cells. Int J Antimicrob Agents.2008 Oct;32(4):344-8. Epub 2008 Aug 13.
10. Buerke U, Carter JM, Schlitt A, et al. Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. Shock.2008 Apr;29(4):497-503.
11. Berbee JF,Havekes LM,Rensen PC. Apolipoprotiens modulate the inflammatory response to lipoplysaceharide[J]. J Endotoxin Res,2005.11(2):97—103.
12. Chien JY, Jemg JS, Yu CJ, et al. Low serom level of hiish—density lipoprotein cholesterol is a poor prognostic factor for severe sepsis [J]. Crit Care Med,2005,33(8):1688—1693.
13. Ascan Warnholtz, Sabine Genth-Zotz, Thomas Munzel. Should Treatment of Sepsis Include Statins? [J]. Circulation,2005,111:1735-1737.
14.周爱儒,查锡良,等.生物化学(第五版).人民卫生出版社,2000,134-141.
15. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002:40:2125-34.
16. Bays HE, Ose L, Fraser N, et al. Ezetimibe Study Group. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004:26:1758-73.
17. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 1993:72:1031-7.
18. Guerin M, Lassel TS, Le Goff W, Farnier M, Chapman MJ. Action of atorvastatin in combined hyperlipidemia:preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles. Arterioscler Thromb Vasc Biol 2000:20:189-97.
19. Stein EA, Strutt K, Southworth H, Diggle PJ, Miller E. HeFH Study Group. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2003:92:1287-93.
20.Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997;79:38-42.
21.KUREISHI Y, LUO Z, SHIOJIMA I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals[J]. Nat Med,2000,6:1004—1010
22.Llevadot J, Murasawa S, Kureishi Y, et al. HMG—CoA reductase inhibitor mobilizes bone—nl/IITOW derived endothelial progenitor cels. J Clin Invest.2001,108:399-405.
23. Dimmeler S。Aicher A, Vasa M, et al. HMG—GoA—eductase inhibitors (statins) increase endothelial progenitor cells via the PI3 kinase /Akt pathway. J Clin Invest,2001,108:391—397.
24. Assmus B, Urbich C, Aicher A, et al. HMG—CoA reductase inhlbitors reduce senescence an d increase proliferation of endothelial progenitor cels via regulation of cel cycle regulatory genes. Circ Res.20o3。92:lo49—1055.)
25. Assmus B, Urbich C, Aicher A, et al. HMG—CoA reductase inhlbitors reduce senescence an d increase proliferation of endothelial progenitor cels via regulation of cel cycle regulatory genes. Circ Res.20o3。92:lo49—1055.
26. Walter DH, Rittig K, Bahlmann FH, et al, Statin therapy accelerates reendOthelializatiOn:a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells[J]. Circulation,2002,105(25):3017-3024.
27. Kurzen H, Manns S, Dandekar G, Schmidt T, Pratzel S, Kraling BM. (2002) Tightening of endothelial cell contacts:a physiologic response to cocultures with smooth-muscle-like 10T1/2 cells. J Invest Dermatol 119:143-53.
28. Luo Y and Radice GL. (2003) Cadherin-mediated adhesion is essential for myofibril continuity across the plasma membrane but not for assembly of the contractile apparatus. J Cell Sci 116:1471-9.
29. Gonzalez D, Herrera B, Otero BK, Quintero G, Rojas A. (2003) Nitric oxide disrupts VE-cadherin complex in murine microvascular endothelial cells. Biochem Biophys Res Commun 304:113-8.
30. Angelini DJ, Hyun SW, Grigoryev DN, et al. (2006) TNF{α} increases tyrosine phosphorylation of vascular endothelial-cadherin opens the paracellular pathway through fyn activation in human lung endothelia. Am J Physiol Lung Cell Mol Physiol 291:L1232-45.
31. De Maio A, Gingalewski C, Theodorakis NG, Clemens MG. (2000) Interruption of hepatic gap junctional communication in the rat during inflammation induced by bacterial lipopolysaccharide. Shock 14:53-9.
32. Rignault S, Haefliger J, Gasser D, et al. (2005) Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium. Crit Care Med 33:1302-10.
33. Simon AM, McWhorter AR, Chen H, Jackson CL, Ouellette Y. (2004) Decreased intercellular communication and connexin expression in mouse aortic endothelium during lipopolysaccharide-induced inflammation. J Vasc Res 41:323-33.
34. Jacobson J, Barnard J, Grigoryev D, Ma S, Tuder R, Garcia J. (2005) Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 288:L1026-32.
35. van Nieuw Amerongen GP, Vermeer MA, Negre-Aminou P, Lankelma J, Emeis JJ, van Hinsbergh VW. (2000) Simvastatin improves disturbed endothelial barrier function. Circulation 102:2803-9.
36. Scalia R and Stalker TJ. (2002) Microcirculation as a target for the anti-inflammatory properties of statins. Microcirculation 9:431-442.
37. Fukuhra S, Sakurai A, Yamagishi A, Sako K, Mochizuki N. (2006) Vascular endothelial cadherin-mediated cell-cell adhesion regulated by a small GTPase, Rapl. J Biochem Mol Biol 39:132-9.
38. van Griensven M, Probst C, Muller K, Hoevel P, Pape HC. (2006) Leukocyte-endothelial interactions via ICAM-1 are detrimental in polymicrobial sepsis. Shock 25:254-9.
39.Cernuda-Morollon E and Ridley AJ. (2006) Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ Res 98:757-67.
40. Rasmussen LM, Hansen PR, Nabipour MT, Olesen P, Kristiansen MT, Ledet T. (2001) Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells. Biochem J 360:363-70.
41. Takeuchi S, Kawashima S, Rikitake Y, et al. (2000) Cerivastatin suppresses lipopolysaccharide-induced ICAM-1 expression through inhibition of Rho GTPase in BAEC. Biochem Biophys Res Commun 269:97-102. [
42. Zapolska-Downar D, Siennicka A, Kaczmarczyk M, Kolodziej B, Naruszewicz M. (2004) Simvastatin modulates TNFα-induced adhesion molecules expression in human endothelial cells. Life Sci 75:1287-302.
43. Pozo M, de Nicolas R, Egido J, Gonzalez-Cabrero J. (2006) Simvastatin inhibits the migration and adhesion of monocytic cells and disorganizes the cytoskeleton of activated endothelial cells. Eur J Pharmacol 548:53-63.
44. Croner RS, Kulu Y, Hoerer E, et al. (2005) Intravenous glycine after cecal ligation and puncture has no effect on impaired hepatic microperfusion, leukocyte adhesion, and mortality in septic rats. Microvasc Res 69:71-8.
45.刘德培,查锡良,药立波等.医学分子生物学.北京：人民卫生出版社,2006.375-448.
46. Sealia R, Stalker TJ. Mieroeirculation as a target for the antiinflammatoryproperties of statins[J]. Mieroeirculation,2002,9:431-442.
47. Giuti Paiva A, Martinez MR, Felix JV, et al. Simvastatine decreases nitric oxide overproduction and reverts the impaired vascular responsiveness indued by endotoxic shock in rats[J]. Shock,2004,21:271—275.
48. Stalker TJ, Lefer AM, Scalia R. (2001) A new HMG-CoA reductase inhibitor rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium:the role of mevalonic acid. Br J Pharmacol 133:406-412.
49. Naoyuki Matsuda, Yukio Hayashi, Yoshika Takahashi,et al. (2006)Phosphorylation of Endothelial Nitric-Oxide Synthase Is Diminished in Mesenteric Arteries from Septic Rabbits Depending on the Altered Phosphatidylinositol 3-Kinase/Akt Pathway:Reversal Effect of Fluvastatin Therapy. CARDIOVASCULAR,319:1348-1354.
50. Waldow T, Witt W, Weber E, et al. Nitric oxide donorindueed persistent inh ibition of cell adhesion protein expression and NFkappaB activation in endothelial cells[J]. Nitric Oxide,2006,15:103—113.
51. Alvarez de Sotomayor M, Vega S, Mingorance C, et al. Effects of HMG-CoA reductase inhibition by simvastatin on vascular dysfunction induced by lipopolysaccharide in rats. Pharmacology.2008;82(2):89-96. Epub 2008 May 29.
52. Matsuda N, Hayashi Y, Takahashi Y, et al. J Pharmacol Exp Ther. Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway:reversal effect of fluvastatin therapy.2006 Dec;319(3):1348-54. Epub 2006 Sep 26.
53. Frey T, De Maio A. Increased expression of CD14 in macrophages after inhibition of the cholesterol biosynthetic pathway by lovastatin. Mol Med. 2007 Nov-Dec;13(11-12):592-604.
54. Chen CH, Lee RP, Wu WT, et al. Fluvastatin ameliorates endotoxin induced multiple organ failure in conscious rats. Resuscitation.2007 Jul;74(1):166-74. Epub 2007 Mar 13.
55. Novack V, Eisinger M, Frenkel A, et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections:a randomized double-blind placebo controlled clinical trial. Intensive Care Med.2009 Feb 11. [Epub ahead of print]
56. Niessner A, Steiner S, Speidl WS, et al. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis.2006 Dec;189(2):408-13. Epub 2006 Jan 26.
57. Ebdrup L, Krog J, Granfeldt A, et al. APMIS. Leukocyte, plasma, and organ-associated cytokine profiles in an animal model of acute inflammation.2008 May;116(5):352-60.
58. Chaudhry MZ, Wang JH, Blankson S, et al. Surg Infect (Larchmt). Statin (cerivastatin) protects mice against sepsis-related death via reduced proinflammatory cytokines and enhanced bacterial clearance.2008 Apr; 9 (2):183-94.
59. Yasuda H, Yuen PS, Hu X, Kidney Int, et al. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. 2006 May;69(9):1535-42.
60. Rotundo RF, Curtis TM, Shah MD, et al. (2002) TNF-α disruption of lung endothelial integrity:reduced integrin mediated adhesion to fibronectin. Am J Physiol Lung Cell Mol Physiol 282:L316-329.
61. Redl H, Schlag G, Lamche H. (1990) TNF- and LPS-induced changes of lung vascular permeability:studies in unanesthetised sheep. Circ Shock 31:183-92.
62. Tracey KJ, Fong Y, Hesse D, et al. (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662-4.
63. Sutton ET, Norman JG, Newton CA, Hellermann GR, Richards IS. (1997) Endothelial structural integrity is maintained during endotoxic shock in an interleukin-1 type 1 receptor knockout mouse. Shock 7:105-10.
64. Wang Q, Fang CH, Hasselgran P0. (2001) Intestinal permeability is reduced and IL-10 levels are increased in septic IL-6 knockout mice. Am J Physiol Regul Integr Comp Physiol 281:R1013-23.
65. Berg DJ, Kuhn R, Rajewsky K, et al. (1995) Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock the Shwartzman reaction but not endotoxin tolerance. J Clin Invest 96:2339-47.
66. Howard M, Muchamuel T, Andrade S, Menon S. (1993) Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 177:1205-8.
67. Zelvyte I, Dominaitiene R, Crisby M, et al. Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res. 2002:45:147-154.
68. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure:role of xanthine—oxidase and extracellular superoxide dismutase. Circulation, 2002,106(24):3073—3078
69. Wassmann S, Laufs U, Muller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol.2002:22:300-305.
70. Wagner AH, Kohler T, Ruckschloss U, et al. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol.2000:20:61-69.
71. Luigina Guastil, Franca Marinol, Marco Cosentinol, et al.Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin Ⅱ type 1 receptor expression:1-year follow-up. European Heart Journal 2008; 29:1118-1126.
72. Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation.2004:110:3349-3354.
73. Durant R, Klouche K, Delbosc S, et al. Superoxide anion overproduction in sepsis:effects of vitamin e and simvastatin. Shock.2004 Jul;22(1):34-9.
74. Shishehbor MH, Aviles RJ, Brennan ML, Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF Jr, Penn MS, Sprecher DL, Vita JA, Hazen SL. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA.2003; 289:1675-1680.
75. Fukai T, Siegfried MR, Ushio—Fukai M, et al. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest,2000,105(11):1631—1639.
76. UIf L, Ferdinand B, Maja M, et al. Simvastatin versus ezetimibe pleiotropic and lipid—lowering effects on endothelial function in humans. Circulation.2005,111(18):2356—2363.
77. Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation.2004 Nov 23;110(21):3349-54. Epub 2004 Nov 1.
78. Martin CP, Talbert RL, Burgess DS, et al. Effectiveness of statins in reducing the rate of severe sepsis:a retrospective evaluation. Pharmacotherapy.2007 Jan;27(1):20-6.
79. Horn MP, Knecht SM, Rushing FL, et al. Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates.J Pharmacol Exp Ther.2008 Jul;326(1):135-43.
80. Zager RA, Johnson A. Renal cortical cholesterol accumulation is an integral component of the systemic stress response. Kidney Int.2001 Dec; 60 (6):2299-310.
81. Zager RA, Johnson AC, Hanson SY. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter. Kidney Int.2003 Jan;63(1):123-33.
82. Majumdar SR, McAlister FA, Eurich DT, et al. Statins and outcomes in patients admitted to hospital with community acquired pneumonia:population based prospective cohort study. BMJ.2006;333(7576):999.
83. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001; 33:1352-1357.