辛伐他汀对脓毒症肝功能的影响
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摘要
目的:脓毒症(Sepsis)是由感染引起的炎症反应综合症,最终导致器官功能障碍。严重脓毒症在ICU及其他危重病人中很常见,每年临床大量病人因脓毒症而死亡。最近十多年尽管新的抗生素不断问世,重症护理也不断改进,但脓毒症的死亡率仍居高不下。从20世纪70年代开始,对脓毒症的主流观念认为其是失控的炎症级联反应,最终导致器官衰竭及死亡,而随后的研究主要集中在炎症的目标上。最近,可通过抑制HMG-CoA还原酶达到降脂目的的他汀类药物因为他的免疫调节效应以及抗炎作用受到了关注。本研究应用盲肠结扎及穿孔(CLP)方法制作大鼠脓毒症模型,进而观察辛伐他汀在脓毒症治疗方面的有效性的情况,以期对临床诊断和治疗提供帮助。
方法:清洁级健康雌性wistar大鼠80只,体重200-250g(河北医科大学实验动物中心,合格证编号:909043)。随机分为4组,I组:正常对照组(8只);II组:假手术组(24只);III组:脓毒症模型组(24只);IV组:辛伐他汀干预后造模组(24只)。除正常组外各实验组按处死大鼠留取标本时间点(6小时、24小时和48小时),分为3组,每组8只。本实验采用应用盲肠结扎及穿孔(CLP)方法制作大鼠脓毒症模型,以大鼠出现精神倦怠、躁动、寒战、腹胀、眼角分泌物增多、竖毛等表现,直肠温度较造模前升高或降低1℃视为造模成功的标志。给药方法如下:I组:正常对照组(经大鼠灌胃针饲入1ml生理盐水);II组:假手术组(1ml生理盐水);III组:脓毒症模型组(1ml生理盐水);IV组:辛伐他汀干预后造模组(辛伐他汀20mg/kg/d)。给药时间为14天。正常对照组大鼠给药14天后即留取血液标本。脓毒症模型组、假手术组及辛伐他汀干预后造模组大鼠分别在制模及手术成功后6h、24h、48h留取血液标本。应用酶联免疫吸附试验(ELISA)的方法检测血液标本中谷胱甘肽硫转移酶(GST)及谷氨酸脱氢酶(GLDH)水平。
结果:
1大鼠一般表现:
脓毒症模型组及辛伐他汀干预后造模组在手术后2~3h后大鼠可自由饮水,6~8h出现精神倦怠、躁动、寒战、腹胀、眼角分泌物增多、竖毛等表现,用电子体温计测直肠温度较造模前升高或降低1℃。假手术组在手术后2~3h后可自由饮水及活动,未再表现出任何异常状态。
2谷胱甘肽硫转移酶(GST):
造模后III组及IV组GST均进行性升高;造模后按6h、24h、48h各时间段进行各组间比较,I组与II组差别不显著(P>0.05);III组较I组GST显著升高(P<0.05),差别有统计学意义;III组较II组GST显著升高(P<0.05),差别有统计学意义;IV组较I组GST显著升高(P<0.05),差别有统计学意义;IV组较II组GST显著升高(P<0.05),差别有统计学意义;IV组较III组GST降低(P<0.05),差别有统计学意义。
3谷氨酸脱氢酶(GLDH):
造模后III组及IV组GLDH均进行性升高;造模后按6h、24h、48h各时间段进行各组间比较,I组与II组差别不显著(P>0.05);III组较I组GLDH显著升高(P<0.05),差别有统计学意义;III组较II组GLDH显著升高(P<0.05),差别有统计学意义;IV组较I组GLDH显著升高(P<0.05),差别有统计学意义;IV组较II组GLDH显著升高(P<0.05),差别有统计学意义;IV组较III组GLDH降低(P<0.05),差别有统计学意义。
结论:
1应用盲肠结扎及穿孔的方法可制造出大鼠脓毒症的模型。
2脓毒症大鼠血清谷氨酸脱氢酶及谷胱甘肽硫转移酶水平均明显升高,提示脓毒症导致肝脏微循环灌注不足,引起肝细胞的缺血、缺氧而发生肝细胞及线粒体损伤。
3辛伐他汀可降低脓毒症时血清谷氨酸脱氢酶及谷胱甘肽硫转移酶水平。进而我们可以认为辛伐他汀可改善脓毒症时肝脏微循环灌注情况。但其并不能从根本上对脓毒症起到治疗的作用。
Objectives: Sepsis is an infection-induced inflammatory syndrome that ultimately leads to organ dysfunction. Severe sepsis is very common in ICU and other critically ill patients, a large number of clinical patients die each year from sepsis. In recent ten years despite new antibiotics continuously appear, intensive care continuous improve, sepsis is still high mortality. From the 1970s, Most investigators would agree that severe sepsis is accompanied by the inability to regulate the inflammatory response, eventually leads to organ failure and death. Recently, statins, inhibit HMG-CoA oxidoreductase reaches the objective of cholesterol- lowering, have also been characterized by their immunomodulatory effects, as well as anti-inflammatory properties. In our tests, simvastatin is pretreated on the rat septic model which is made by caecum ligated and punctur(CLP), in order to observe simvastatin’curative effect in sepsis,then provide help for clinical diagnosis and treatment.
Methods:Eighty clean and healthy female Wistar rats weight 200-250g, (supplied by the experimental animal center of Hebei medical university) were randomly divided into 4 groups. Group I: healthy control group(8 rats); group II: sham operation group(24 rats); group III: model group(24 rats); groupⅣ: model group pre-treated by simvastin(24 rats). Except healthy control group,other groups were divided into three subgroups according to the time of drawing blood(6h, 24h and 48h), the number of each subgroup is 8. The septic models were made by caecum ligation and puncture after treatment for 2 weeks. Rats appeared mental burnout, the abdominal distension, restlessness, shiver, canthal secretion increased, hairs in disorder, rectal temperature raise or lower 1℃as the symbol of success. The rats in groupⅣwere administrated with simvastatin (20mg/kg.day)by continuously, once a day. The other three groups were given normal saline of the same volume via gastric tube for 2 weeks. The blood speciemens of group I were taken after simvastain for 2 weeks. The blood speciemens of group II, group III and groupⅣwere taken after operation for 6h,24h,48h respectively. The values of GST and GLDH in the blood speciemen were measured by means of enzyme-linked immuno sorbent assay (ELISA).
Results:
1 The general performance of rats: The rats of group III and groupⅣcould drink water freely after operation for 2~3h, rats appeared mental burnout, the abdominal distension, restlessness, shiver, canthal secretion increased, hairs in disorder for 6~8h, Measuring rectal temperature by electronic thermometer, these were risen or reduced 1℃. The rats of group II could drink water freely after sham operation for 2~3h, without any abnormal condition.
2 GST:Both of the values of GST in group III and groupⅣprogressively increased significantly after CLP; Comparison of each group by the time of drawing blood, the difference between group I and group II was not significant. GST in group III was higher than group I (P<0.05), the difference was significant; group III was higher than group II (P<0.05), the difference was significant; group IV was higher than group I (P<0.05), the difference was significant; group IV was higher than group II (P<0.05), the difference was significant; group III was higher than group IV (P<0.05), the difference was significant.
3 GLDH: Both of the values of GLDH in group III and groupⅣprogressively increased significantly after CLP; Comparison of each group by the time of drawing blood, the difference between group I and group II was not significant. GLDH in group III was higher than group I (P<0.05), the difference was significant; group III was higher than group II (P<0.05), the difference was significant; group IV was higher than group I (P<0.05), the difference was significant; group IV was higher than group II (P<0.05), the difference was significant; group III was higher than group IV (P<0.05), the difference was significant.
Conclusions:
1 The septic rat model could be made successfully by CLP.
2 The values of GST and GLDH of the septic rats in serum increase significantly. It pointe that sepsis causes liver microcirculation perfusion inadequacy, causes liver cell ischemia and hypoxia, eventually damages liver cell and mitochondria.
3 Simvastatin could lower the values of serum GST and GLDH of septic rats. Then we can presume that simvastatin can improve the septic liver microcirculation perfusion. But it cannot completely treatment of sepsis.
方法:清洁级健康雌性wistar大鼠80只,体重200-250g(河北医科大学实验动物中心,合格证编号:909043)。随机分为4组,I组:正常对照组(8只);II组:假手术组(24只);III组:脓毒症模型组(24只);IV组:辛伐他汀干预后造模组(24只)。除正常组外各实验组按处死大鼠留取标本时间点(6小时、24小时和48小时),分为3组,每组8只。本实验采用应用盲肠结扎及穿孔(CLP)方法制作大鼠脓毒症模型,以大鼠出现精神倦怠、躁动、寒战、腹胀、眼角分泌物增多、竖毛等表现,直肠温度较造模前升高或降低1℃视为造模成功的标志。给药方法如下:I组:正常对照组(经大鼠灌胃针饲入1ml生理盐水);II组:假手术组(1ml生理盐水);III组:脓毒症模型组(1ml生理盐水);IV组:辛伐他汀干预后造模组(辛伐他汀20mg/kg/d)。给药时间为14天。正常对照组大鼠给药14天后即留取血液标本。脓毒症模型组、假手术组及辛伐他汀干预后造模组大鼠分别在制模及手术成功后6h、24h、48h留取血液标本。应用酶联免疫吸附试验(ELISA)的方法检测血液标本中谷胱甘肽硫转移酶(GST)及谷氨酸脱氢酶(GLDH)水平。
结果:
1大鼠一般表现:
脓毒症模型组及辛伐他汀干预后造模组在手术后2~3h后大鼠可自由饮水,6~8h出现精神倦怠、躁动、寒战、腹胀、眼角分泌物增多、竖毛等表现,用电子体温计测直肠温度较造模前升高或降低1℃。假手术组在手术后2~3h后可自由饮水及活动,未再表现出任何异常状态。
2谷胱甘肽硫转移酶(GST):
造模后III组及IV组GST均进行性升高;造模后按6h、24h、48h各时间段进行各组间比较,I组与II组差别不显著(P>0.05);III组较I组GST显著升高(P<0.05),差别有统计学意义;III组较II组GST显著升高(P<0.05),差别有统计学意义;IV组较I组GST显著升高(P<0.05),差别有统计学意义;IV组较II组GST显著升高(P<0.05),差别有统计学意义;IV组较III组GST降低(P<0.05),差别有统计学意义。
3谷氨酸脱氢酶(GLDH):
造模后III组及IV组GLDH均进行性升高;造模后按6h、24h、48h各时间段进行各组间比较,I组与II组差别不显著(P>0.05);III组较I组GLDH显著升高(P<0.05),差别有统计学意义;III组较II组GLDH显著升高(P<0.05),差别有统计学意义;IV组较I组GLDH显著升高(P<0.05),差别有统计学意义;IV组较II组GLDH显著升高(P<0.05),差别有统计学意义;IV组较III组GLDH降低(P<0.05),差别有统计学意义。
结论:
1应用盲肠结扎及穿孔的方法可制造出大鼠脓毒症的模型。
2脓毒症大鼠血清谷氨酸脱氢酶及谷胱甘肽硫转移酶水平均明显升高,提示脓毒症导致肝脏微循环灌注不足,引起肝细胞的缺血、缺氧而发生肝细胞及线粒体损伤。
3辛伐他汀可降低脓毒症时血清谷氨酸脱氢酶及谷胱甘肽硫转移酶水平。进而我们可以认为辛伐他汀可改善脓毒症时肝脏微循环灌注情况。但其并不能从根本上对脓毒症起到治疗的作用。
Objectives: Sepsis is an infection-induced inflammatory syndrome that ultimately leads to organ dysfunction. Severe sepsis is very common in ICU and other critically ill patients, a large number of clinical patients die each year from sepsis. In recent ten years despite new antibiotics continuously appear, intensive care continuous improve, sepsis is still high mortality. From the 1970s, Most investigators would agree that severe sepsis is accompanied by the inability to regulate the inflammatory response, eventually leads to organ failure and death. Recently, statins, inhibit HMG-CoA oxidoreductase reaches the objective of cholesterol- lowering, have also been characterized by their immunomodulatory effects, as well as anti-inflammatory properties. In our tests, simvastatin is pretreated on the rat septic model which is made by caecum ligated and punctur(CLP), in order to observe simvastatin’curative effect in sepsis,then provide help for clinical diagnosis and treatment.
Methods:Eighty clean and healthy female Wistar rats weight 200-250g, (supplied by the experimental animal center of Hebei medical university) were randomly divided into 4 groups. Group I: healthy control group(8 rats); group II: sham operation group(24 rats); group III: model group(24 rats); groupⅣ: model group pre-treated by simvastin(24 rats). Except healthy control group,other groups were divided into three subgroups according to the time of drawing blood(6h, 24h and 48h), the number of each subgroup is 8. The septic models were made by caecum ligation and puncture after treatment for 2 weeks. Rats appeared mental burnout, the abdominal distension, restlessness, shiver, canthal secretion increased, hairs in disorder, rectal temperature raise or lower 1℃as the symbol of success. The rats in groupⅣwere administrated with simvastatin (20mg/kg.day)by continuously, once a day. The other three groups were given normal saline of the same volume via gastric tube for 2 weeks. The blood speciemens of group I were taken after simvastain for 2 weeks. The blood speciemens of group II, group III and groupⅣwere taken after operation for 6h,24h,48h respectively. The values of GST and GLDH in the blood speciemen were measured by means of enzyme-linked immuno sorbent assay (ELISA).
Results:
1 The general performance of rats: The rats of group III and groupⅣcould drink water freely after operation for 2~3h, rats appeared mental burnout, the abdominal distension, restlessness, shiver, canthal secretion increased, hairs in disorder for 6~8h, Measuring rectal temperature by electronic thermometer, these were risen or reduced 1℃. The rats of group II could drink water freely after sham operation for 2~3h, without any abnormal condition.
2 GST:Both of the values of GST in group III and groupⅣprogressively increased significantly after CLP; Comparison of each group by the time of drawing blood, the difference between group I and group II was not significant. GST in group III was higher than group I (P<0.05), the difference was significant; group III was higher than group II (P<0.05), the difference was significant; group IV was higher than group I (P<0.05), the difference was significant; group IV was higher than group II (P<0.05), the difference was significant; group III was higher than group IV (P<0.05), the difference was significant.
3 GLDH: Both of the values of GLDH in group III and groupⅣprogressively increased significantly after CLP; Comparison of each group by the time of drawing blood, the difference between group I and group II was not significant. GLDH in group III was higher than group I (P<0.05), the difference was significant; group III was higher than group II (P<0.05), the difference was significant; group IV was higher than group I (P<0.05), the difference was significant; group IV was higher than group II (P<0.05), the difference was significant; group III was higher than group IV (P<0.05), the difference was significant.
Conclusions:
1 The septic rat model could be made successfully by CLP.
2 The values of GST and GLDH of the septic rats in serum increase significantly. It pointe that sepsis causes liver microcirculation perfusion inadequacy, causes liver cell ischemia and hypoxia, eventually damages liver cell and mitochondria.
3 Simvastatin could lower the values of serum GST and GLDH of septic rats. Then we can presume that simvastatin can improve the septic liver microcirculation perfusion. But it cannot completely treatment of sepsis.
引文
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1 Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit are Med, 2001 ,29(7):1303-10
2 Vo PA, Lad B, Tomlinson JA, et al.Autoregulatory role of endothelium-derived nitric oxide (NO) on lipopolysaccharide-induced vascular inducible NO synthase expression and function. J Biol Chem, 2005, 280(8): 7236–43
3 Giusti-Paiva A, Martinez MR, Cestari Felix JV, et al. Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats. Shock ,2004, 21(3): 271–5
4 Yamashita T, Kawashima S, Ohashi Y, et al. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation, 2000, 101(8): 931–7
5 Leaver SK, Finney SJ, Burke-Gaffney A, et al. Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities. Crit Care Med, 2007, 35(5): 1404–10
6 Andrews P, Azoulay E, Antonelli M, et al. Year in review in intensive care medicine, 2006. II Infections and sepsis, haemodynamics,elderly, invasive and noninvasive mechanical ventilation,weaning, ARDS. Intensive Care Med, 2007, 33(2):214–29
7 Marshall JC. Such stuff as dreams are made on: mediatordirected therapy in sepsis. Nat Rev Drug Discov, 2003, 2(5):391–405
8 Pleiner JM, Schaller GM, Mittermayer FM, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation, 2004, 110(21): 3349–54
9 Scalia R, Stalker TJ. Microcirculation as a target for the anti-inflammatory properties of statins. Microcirculation, 2002, 9(6):431–442
10 Chello M, Patti G, Candura D, et al. Effects of atorvastatin on systemicinflammatory response after coronary bypass surgery. Crit Care Med, 2006, 34(3): 660–7
11 McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet, 2004, 363(9426): 2015–21
12 Arnaud C, Burger F, Steffens S, et al. Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.Arterioscler Thromb Vasc Biol, 2005, 25(6): 1231–6
13 Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation, 2004,110(21): 3349-3354
14 Inoue K, Takano H, Yanagisawa R, et al.Statin, inflammation,and sepsis. Chest, 2004,125(6):2365
15 Delbosc S, Morena M, Djouad F, et al. Statins, 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes. J Cardiovasc Pharmacol, 2002,40:611-617
16 Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med, 2001,345(8):588-595
17 Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol, 2006, 6(5): 358–70
18 Ishii K,Ito Y,Katagiri H, et al.Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice. Shock,2002, 18(2):163-168
19 Arai M,Mochida S,Ohno A, et al.Blood coagulation equilibrium in rat liver microcirculation as evaluated by endothelial cell thrombmomdulin and macrophage tissue factor. ThrombRes,1995,80(2):113-123
20 Vollmar B,Siegmund S,Menger MD.An intravital fluorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in rats. Hepatology, 1998,27(6):1544-53
21严律南.现代肝脏移植学.北京:人民军医出版社,2004,43
22 Jungermann K , Kietzmann T.Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr,1996,16:179-203
23 Yachida S,Kokudo Y,Wakabayashi H, et al.Morphological and functional alterations to sinusoidal endothelial cells in early phase of endotoxin-induced liver failure after partial hepatectomy in rats.Virchows Arch,1998,433(2):173-181
24 Yokomori H,Oda M,Ogi M,et al.Hepatic sinusoidal endothelial fenestrae express plasma membrane Ca2+pump and Ca2+ Mg2+-ATPase.Liver,2000,20(6):458-464
25 Hansen B,Longati P,Elvevold K.Stabilin-1 and stabilin-2 are both directed into the early endocytic pathway in hepatic sinusoidal endothelium via interactions with clathrin/AP-2,independent of ligand binding.Exp Cell Res,2005,303(1):160-173
26 Rothkopf C,Fahr A,Fricker G.Uptake of phosphatidyl- serinecontaining liposomes by liver sinusoidal endothelial cells in the serum-free perfused rat liver. Biochim Biophys Acta,2005, 1668(1):10-6
27 Chouker A,Martignoni A, Schauer RJ, et al. Alpha- gluthathione Stransferase as an early marker of hepatic ischemia/reperfusion injury after liver resection. World J Surg , 2005,29(4):528-34
28 O'Brien PJ, Slaughter MR, Polley SR, et al. Advantagesof glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. Lab Anim,2002,36(3):313-321
29 Difraia R,Wilquet V,Ciardiello MA,et al NADP+ dependent glutamate dehydrogenase in the antarctic psychrotolerant bacterium psychrobactersp TAD1. Charaterization, protein and DNA sequence, and relationship to other glutamate dehydrogenases J. Eur J Bioche, 2000, 267(1): 121- 131
30 Kopke-Aguiar CA, Martins JR, Passerotti CC.Serum Hyaluronil acid as a comprehensive marker to assess severity of liver disease in schistosomiasis.Acta Trop ,2002,84(2):11-26
31 Romano M, Diomede L, Sironi M, et al. Inhibition of monocytechemotactic protein-1 synthesis by statins. Lab Invest, 2000, 80(7):1095–100
32 Pruefer D, Makowski J, Schnell M, et al. Simvastatin inhibits inflammatory properties of taphylococcus aureus alpha-toxin. Circulation, 2002, 106(16): 2104–10
33 Sniderman AD.Is there value in liver function test and creatine phosphokinase monitoring with statin use ?Am J Cardiol, 2004,94(9):30– 34
34 Farmer JA, Torre - Amione G.Comparative tolerability of the HMG - CoA reductase inhibitors.Drug Saf ,2000,23(9):197– 213
35 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology, 2005, 41(4): 690-695
36 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med, 2002,346(16): 1221–31
37 Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol,2006,97(8):77-81
2 Leaver SK, Finney SJ, Burke-Gaffney A, et al. Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities. Crit Care Med, 2007, 35(5): 1404-10
3 Vollmar B, Siegmund S, Menger MD. An intravital fluorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in rats.Hepatology, 1998,27(6):1544-53
4严律南.现代肝脏移植学.北京:人民军医出版社,2004,43
5 Jungermann K , Kietzmann T.Zonation of parenchymal and nonparenchymal metabolism in liver.Annu Rev Nutr,1996,16:179-203
6 Copeland S,Warren HS,Lowry SF.Acute inflammatory response to endotoxin in minc and humans.Clin Diagn Lab Immunol,2005,12(1):60-67
7 Lekkou A , Karakantza M , Mouzaki A ,et al. Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin Diagn Lab Immunol, 2004, 11(1):161-167
8 Deitch EA. Animal models of sepsis and shock: a review and lessons learned. Shock, 1998,9(1):1-11
9 Rothkopf C,Fahr A,Fricker G.Uptake of phosphatidyl- serinecontaining liposomes by liver sinusoidal endothelial cells in the serum-free perfused rat liver.Biochim Biophys Acta,2005, 1668(1):10-6
10 Chouker A,Martignoni A,Schauer RJ,et al. Alphaglutha- thione Stransferase as an early marker of hepatic ischemia/reperfusion injury after liver resection.World J Surg , 2005,29(4):528-34
11 O'Brien PJ, Slaughter MR, Polley SR, et al. Advantagesof glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. Lab Anim,2002,36(3):313-321
12 Difraia R,Wilquet V,Ciardiello MA,et al NADP+ dependent glutamate dehydrogenase in the antarctic psychrotolerant bacterium psychrobactersp TAD1. Charaterization, protein and DNA sequence, and relationship to other glutamate dehydrogenases J. Eur J Bioche, 2000, 267(1): 121- 131
13宋林萍,张星火,李莉,等.脓毒症患者血流动力学数值与动脉压力波形关系的探讨.中国危重病急救医学, 2002, 14:457-460
14 Remick DG, Newcomb DE, Bolgos G, et al. Comparison of the mortality and inflammatory response of two models of sepsis: lipopo lysaccharide vs cecal ligation and puncture. Shock, 2000, 13(2): 110-116
15 Andrews P, Azoulay E, Antonelli M, et al. Year in review in intensive care medicine, 2006. II Infections and sepsis, haemodynamics,elderly, invasive and noninvasive mechanical ventilation,weaning, ARDS. Intensive Care Med, 2007, 33(2):214–29
16 Ishii K, Ito Y, Katagiri H, et al.Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice.Shock,2002, 18(2):163-168
17 Arai M, Mochida S, Ohno A, et al.Blood coagulation equilibrium in rat liver microcirculation as evaluated by endothelial cell thrombmomdulin and macrophage tissue factor.ThrombRes,1995,80(2):113-123
18 Marshall JC. Such stuff as dreams are made on: mediatordirected therapy in sepsis. Nat Rev Drug Discov, 2003, 2(5):391–405
19 Vo PA, Lad B, Tomlinson JA, et al.Autoregulatory role of endothelium-derived nitric oxide (NO) on lipopolysaccharide-induced vascular inducible NO synthase expression and function. J Biol Chem, 2005, 280(8): 7236–43
20 Pleiner JM, Schaller GM, Mittermayer FM, et al. Simvastatin prevents vascular hyporeactivity during inflammation.Circulation, 2004, 110(21): 3349–54
21 Yamashita T, Kawashima S, Ohashi Y, et al. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation, 2000, 101(8): 931–7
22 Giusti-Paiva A, Martinez MR, Cestari Felix JV, et al. Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats. Shock ,2004, 21(3): 271–5
23 Chello M, Patti G, Candura D, et al. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med, 2006, 34(3): 660–7
24 McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet, 2004, 363(9426): 2015–21
25 Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation, 2004, 110(21):3349-54
26 Arnaud C, Burger F, Steffens S, et al. Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.Arterioscler Thromb Vasc Biol, 2005, 25(6): 1231–6
27 Delbosc S, Morena M, Djouad F, et al. Statins, 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes. J Cardiovasc Pharmacol, 2002,40:611-617
28 Inoue K, Takano H, Yanagisawa R, et al. Statin, inflammation,and sepsis. Chest, 2004,125(6):2365
29 Landry DW, Oliver JA. The pathogenesis of vasodilatory shock.N Engl J Med, 2001,345(8):588-595
30 Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation.Nat Rev Immunol, 2006, 6(5): 358–70
31 Crouse E,Exline M,Knoell D,et al.Sepsis:links between pathogen sensing and organ damage.Curr Pharm Des,2008,14(19):1840-1852
32 Schenkman KA,Arakaki LS,Ciesielski WA,et al.Optical sepctroscopy demonstrates elevated intracelluar oxygenation in an endotoxic model of sepsis in the perfused heart.Shock,2007,27(6):695-700
33 Barsante MM, RoffêE, Yokoro CM, et al. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. Eur J Pharmacol, 2005,516(3):282-9
34 Romano M, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 2000, 80(7):1095–100
35 Pruefer D, Makowski J, Schnell M, et al. Simvastatin inhibits inflammatory properties of taphylococcus aureus alpha-toxin.Circulation, 2002, 106(16): 2104–10
36 Sims NR, Anderson MF. Mitochondrial contributions to tissue damange in stroke.Neurochem Int, 2002, 40(6):511-526
37 Boya P, Roques B, Kroemer G. New EMBO members’review: viral and bacterial proteins regulating apoptosis at the mitochondrial level. EMBO J ,2001,20 (16) :4325-4331
1 Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit are Med, 2001 ,29(7):1303-10
2 Vo PA, Lad B, Tomlinson JA, et al.Autoregulatory role of endothelium-derived nitric oxide (NO) on lipopolysaccharide-induced vascular inducible NO synthase expression and function. J Biol Chem, 2005, 280(8): 7236–43
3 Giusti-Paiva A, Martinez MR, Cestari Felix JV, et al. Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats. Shock ,2004, 21(3): 271–5
4 Yamashita T, Kawashima S, Ohashi Y, et al. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation, 2000, 101(8): 931–7
5 Leaver SK, Finney SJ, Burke-Gaffney A, et al. Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities. Crit Care Med, 2007, 35(5): 1404–10
6 Andrews P, Azoulay E, Antonelli M, et al. Year in review in intensive care medicine, 2006. II Infections and sepsis, haemodynamics,elderly, invasive and noninvasive mechanical ventilation,weaning, ARDS. Intensive Care Med, 2007, 33(2):214–29
7 Marshall JC. Such stuff as dreams are made on: mediatordirected therapy in sepsis. Nat Rev Drug Discov, 2003, 2(5):391–405
8 Pleiner JM, Schaller GM, Mittermayer FM, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation, 2004, 110(21): 3349–54
9 Scalia R, Stalker TJ. Microcirculation as a target for the anti-inflammatory properties of statins. Microcirculation, 2002, 9(6):431–442
10 Chello M, Patti G, Candura D, et al. Effects of atorvastatin on systemicinflammatory response after coronary bypass surgery. Crit Care Med, 2006, 34(3): 660–7
11 McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet, 2004, 363(9426): 2015–21
12 Arnaud C, Burger F, Steffens S, et al. Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.Arterioscler Thromb Vasc Biol, 2005, 25(6): 1231–6
13 Pleiner J, Schaller G, Mittermayer F, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation, 2004,110(21): 3349-3354
14 Inoue K, Takano H, Yanagisawa R, et al.Statin, inflammation,and sepsis. Chest, 2004,125(6):2365
15 Delbosc S, Morena M, Djouad F, et al. Statins, 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes. J Cardiovasc Pharmacol, 2002,40:611-617
16 Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med, 2001,345(8):588-595
17 Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol, 2006, 6(5): 358–70
18 Ishii K,Ito Y,Katagiri H, et al.Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice. Shock,2002, 18(2):163-168
19 Arai M,Mochida S,Ohno A, et al.Blood coagulation equilibrium in rat liver microcirculation as evaluated by endothelial cell thrombmomdulin and macrophage tissue factor. ThrombRes,1995,80(2):113-123
20 Vollmar B,Siegmund S,Menger MD.An intravital fluorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in rats. Hepatology, 1998,27(6):1544-53
21严律南.现代肝脏移植学.北京:人民军医出版社,2004,43
22 Jungermann K , Kietzmann T.Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr,1996,16:179-203
23 Yachida S,Kokudo Y,Wakabayashi H, et al.Morphological and functional alterations to sinusoidal endothelial cells in early phase of endotoxin-induced liver failure after partial hepatectomy in rats.Virchows Arch,1998,433(2):173-181
24 Yokomori H,Oda M,Ogi M,et al.Hepatic sinusoidal endothelial fenestrae express plasma membrane Ca2+pump and Ca2+ Mg2+-ATPase.Liver,2000,20(6):458-464
25 Hansen B,Longati P,Elvevold K.Stabilin-1 and stabilin-2 are both directed into the early endocytic pathway in hepatic sinusoidal endothelium via interactions with clathrin/AP-2,independent of ligand binding.Exp Cell Res,2005,303(1):160-173
26 Rothkopf C,Fahr A,Fricker G.Uptake of phosphatidyl- serinecontaining liposomes by liver sinusoidal endothelial cells in the serum-free perfused rat liver. Biochim Biophys Acta,2005, 1668(1):10-6
27 Chouker A,Martignoni A, Schauer RJ, et al. Alpha- gluthathione Stransferase as an early marker of hepatic ischemia/reperfusion injury after liver resection. World J Surg , 2005,29(4):528-34
28 O'Brien PJ, Slaughter MR, Polley SR, et al. Advantagesof glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. Lab Anim,2002,36(3):313-321
29 Difraia R,Wilquet V,Ciardiello MA,et al NADP+ dependent glutamate dehydrogenase in the antarctic psychrotolerant bacterium psychrobactersp TAD1. Charaterization, protein and DNA sequence, and relationship to other glutamate dehydrogenases J. Eur J Bioche, 2000, 267(1): 121- 131
30 Kopke-Aguiar CA, Martins JR, Passerotti CC.Serum Hyaluronil acid as a comprehensive marker to assess severity of liver disease in schistosomiasis.Acta Trop ,2002,84(2):11-26
31 Romano M, Diomede L, Sironi M, et al. Inhibition of monocytechemotactic protein-1 synthesis by statins. Lab Invest, 2000, 80(7):1095–100
32 Pruefer D, Makowski J, Schnell M, et al. Simvastatin inhibits inflammatory properties of taphylococcus aureus alpha-toxin. Circulation, 2002, 106(16): 2104–10
33 Sniderman AD.Is there value in liver function test and creatine phosphokinase monitoring with statin use ?Am J Cardiol, 2004,94(9):30– 34
34 Farmer JA, Torre - Amione G.Comparative tolerability of the HMG - CoA reductase inhibitors.Drug Saf ,2000,23(9):197– 213
35 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology, 2005, 41(4): 690-695
36 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med, 2002,346(16): 1221–31
37 Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol,2006,97(8):77-81