高容量血液滤过对脓毒症休克犬肺TLR4的影响
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摘要
目的:探讨高容量血液滤过对脓毒症休克犬肺组织TLR4mRNA表达的影响。
方法:选择健康杂种雄性犬24条,随机分为3组,每组8条,其中正常对照组行机械通气+假治疗;对照组和治疗组均经中心静脉30min注入内毒素(LPS) 650μg/kg,诱导犬脓毒症休克模型:其中对照组行机械通气+假治疗,治疗组行机械通气+高容量血液滤过治疗。监测基础及成模(0h)时的HR、mAP、PAP、CVP、PAWP、CO值并计算PVR、SVR值;采用放射免疫法测定对照组、治疗组在治疗0h、1h、2h、4h循环血TNF-α、IL-6、IL-10的浓度;治疗4h后,开胸取其肺脏并置于液氮瓶中保存,采用半定量逆转录聚合酶联反应(RT-PCR)法测定各组TLR4mRNA表达水平。
结果:
1、静脉注入LPS后mAP、CO、HR逐步下降,而PAP、PAWP、CVP、PVR、SVR逐步上升,当mAP比基础值下降20%以上时认为模型成立。成模时各指标与基础值比较均有显著差异(P<0.01)。
2、经采用放射免疫法测定治疗组1h后循环血中TNF-α、IL-6、IL-10的浓度即有明显下降,且呈持续下降趋势(P<0.01)。而对照组各指标与治疗0h时比较差异无意义(P>0.05)。两组比较,治疗组各时点均低于对照组(P<0.01)。而TLR4mRNA在正常对照组、对照组、治疗组表达分别为0.895±0.048、0.987±0.036、0.931±0.019,对照组较正常对照组TLR4mRNA明显上调(P<0.01);治疗组较对照组TLR4mRNA表达下调(P<0.01)。相关分析显示,TLR4mRNA的表达与循环血中TNF-α、IL-6,IL-10浓度呈正相关(P<0.05)相关系数分别为:0.821、0.542,0.610。
结论:正常犬肺组织内TLR4有一定的表达;细菌内毒素LPS可上调脓毒症休克犬肺组织TLR4 mRNA的表达,促进炎症介质的释放; HVHF可下调脓毒症休克犬TLR4mRNA的表达,减轻炎症反应。其作用机制可能是通过对流、吸附等方式清除炎症介质,削弱了炎症介质对TLR4mRNA的“正反馈”调节;稳定内环境、消除应激反应,下调TLR4mRNA。高容量血液滤过对TLR4的调节可能为脓毒症休克的治疗提供一个新的理论依据。
Objective To investigate the effects of High Volume Hemofiltration (HVHF) on the expression of Toll like-receptors 4 mRNA in shock dogs induced by endotoxin (lipopolysaccharide,LPS)。
Method twenty-four healthy hybrid male dogs were selected for this study。All dogs were divided into three groups randomly,eight dogs ,one group。normal comparison did not inject LPS,only mechanic ventilation add a sham treatment; control group and treatment group were injected LPS (650μg/kg) via central vein within 30min to establish model of endotoxin shock. The dogs in treatment group were received the treatment of HVHF add mechanic ventilation, while control group was just a sham treatment add mechanic ventilation。HR、mAP、PAP、CVP、PAWP、CO were recorded at between baseline and established model after HVHF respectively and we calculated PVR and SVR。Contents of TNF-α、IL-6、IL-10 in circulation at 0h、1h、2h、4h were measured by radioimmunity.。All dogs’lung were dissected from their chest 4h after HVHF.they were reserved in liquid nitrogen cylinder。The expression levels of TLR4mRNA in all group were measured by RT-PCR。
Results 1、mAP、CO、HR decreased gradually after LPS intravenously while PAP、PAWP、CVP、PVR、SVR increased gradually。When mAP decreased to 20% baseline,the model was established successfully。All parameters were obviously significant compared to baseline (P<0.01)
2.radioimmunity showed that TNF-α、IL-6、IL-10 in therapy group decreased significantly at 1h after HVHF and presented continuous decrease trend (P<0.01) while those in control group had no change compared to baseline (P>0.05). Between two groups, TNF-α、IL-6、IL-10 in treatment group at any time point were lower than those in control group significantly(P<0.01).RT-PCR showed that mRNA expression of TLR4 in blank comparison、control group、treatment group were 0.895±0.048、0.987±0.036、0.931±0.019 respectively at 4h after HVHF,comparing with normal comparison , control group can significant up-regulate mRNA expression of TLR4(P<0.01) ; comparing with control group , HVHF treatment group can down-regulate mRNA expression of TLR4(P<0.01)。Correlation Analysis reveal:Significant correlation was found between tissue TLR4 mRNA expression and Contents of TNF-α、IL-6、IL-10 in circulation(P<0.05),Correlation coefficient between tissue TLR4 mRNA expression and Contents of TNF-α、IL-6、IL-10 in circulation were 0.821、0.542,0.610 respectively。
Conclusion There are some levers expression in normal dog’lung tissue; endotoxin(lipopolysaccharide,LPS)can up-regulate mRNA expression of TLR4,putting forward inflammatory response ; HVHF can down-regulate mRNA expression of TLR4,cutting down inflammatory response。The mechanism of HVHF to endotoxin shock were continuously to eliminate many inflammatory medators-like cytokines by Convection and adsorption,cutting-down“positive feedback Regulation”mRNA expression of TLR4;keep internal environment stable,Reduce Stress response,down-regulateing mRNA expression of TLR4。this study may offer an new theoretical basis for clinic treating septic shock。
方法:选择健康杂种雄性犬24条,随机分为3组,每组8条,其中正常对照组行机械通气+假治疗;对照组和治疗组均经中心静脉30min注入内毒素(LPS) 650μg/kg,诱导犬脓毒症休克模型:其中对照组行机械通气+假治疗,治疗组行机械通气+高容量血液滤过治疗。监测基础及成模(0h)时的HR、mAP、PAP、CVP、PAWP、CO值并计算PVR、SVR值;采用放射免疫法测定对照组、治疗组在治疗0h、1h、2h、4h循环血TNF-α、IL-6、IL-10的浓度;治疗4h后,开胸取其肺脏并置于液氮瓶中保存,采用半定量逆转录聚合酶联反应(RT-PCR)法测定各组TLR4mRNA表达水平。
结果:
1、静脉注入LPS后mAP、CO、HR逐步下降,而PAP、PAWP、CVP、PVR、SVR逐步上升,当mAP比基础值下降20%以上时认为模型成立。成模时各指标与基础值比较均有显著差异(P<0.01)。
2、经采用放射免疫法测定治疗组1h后循环血中TNF-α、IL-6、IL-10的浓度即有明显下降,且呈持续下降趋势(P<0.01)。而对照组各指标与治疗0h时比较差异无意义(P>0.05)。两组比较,治疗组各时点均低于对照组(P<0.01)。而TLR4mRNA在正常对照组、对照组、治疗组表达分别为0.895±0.048、0.987±0.036、0.931±0.019,对照组较正常对照组TLR4mRNA明显上调(P<0.01);治疗组较对照组TLR4mRNA表达下调(P<0.01)。相关分析显示,TLR4mRNA的表达与循环血中TNF-α、IL-6,IL-10浓度呈正相关(P<0.05)相关系数分别为:0.821、0.542,0.610。
结论:正常犬肺组织内TLR4有一定的表达;细菌内毒素LPS可上调脓毒症休克犬肺组织TLR4 mRNA的表达,促进炎症介质的释放; HVHF可下调脓毒症休克犬TLR4mRNA的表达,减轻炎症反应。其作用机制可能是通过对流、吸附等方式清除炎症介质,削弱了炎症介质对TLR4mRNA的“正反馈”调节;稳定内环境、消除应激反应,下调TLR4mRNA。高容量血液滤过对TLR4的调节可能为脓毒症休克的治疗提供一个新的理论依据。
Objective To investigate the effects of High Volume Hemofiltration (HVHF) on the expression of Toll like-receptors 4 mRNA in shock dogs induced by endotoxin (lipopolysaccharide,LPS)。
Method twenty-four healthy hybrid male dogs were selected for this study。All dogs were divided into three groups randomly,eight dogs ,one group。normal comparison did not inject LPS,only mechanic ventilation add a sham treatment; control group and treatment group were injected LPS (650μg/kg) via central vein within 30min to establish model of endotoxin shock. The dogs in treatment group were received the treatment of HVHF add mechanic ventilation, while control group was just a sham treatment add mechanic ventilation。HR、mAP、PAP、CVP、PAWP、CO were recorded at between baseline and established model after HVHF respectively and we calculated PVR and SVR。Contents of TNF-α、IL-6、IL-10 in circulation at 0h、1h、2h、4h were measured by radioimmunity.。All dogs’lung were dissected from their chest 4h after HVHF.they were reserved in liquid nitrogen cylinder。The expression levels of TLR4mRNA in all group were measured by RT-PCR。
Results 1、mAP、CO、HR decreased gradually after LPS intravenously while PAP、PAWP、CVP、PVR、SVR increased gradually。When mAP decreased to 20% baseline,the model was established successfully。All parameters were obviously significant compared to baseline (P<0.01)
2.radioimmunity showed that TNF-α、IL-6、IL-10 in therapy group decreased significantly at 1h after HVHF and presented continuous decrease trend (P<0.01) while those in control group had no change compared to baseline (P>0.05). Between two groups, TNF-α、IL-6、IL-10 in treatment group at any time point were lower than those in control group significantly(P<0.01).RT-PCR showed that mRNA expression of TLR4 in blank comparison、control group、treatment group were 0.895±0.048、0.987±0.036、0.931±0.019 respectively at 4h after HVHF,comparing with normal comparison , control group can significant up-regulate mRNA expression of TLR4(P<0.01) ; comparing with control group , HVHF treatment group can down-regulate mRNA expression of TLR4(P<0.01)。Correlation Analysis reveal:Significant correlation was found between tissue TLR4 mRNA expression and Contents of TNF-α、IL-6、IL-10 in circulation(P<0.05),Correlation coefficient between tissue TLR4 mRNA expression and Contents of TNF-α、IL-6、IL-10 in circulation were 0.821、0.542,0.610 respectively。
Conclusion There are some levers expression in normal dog’lung tissue; endotoxin(lipopolysaccharide,LPS)can up-regulate mRNA expression of TLR4,putting forward inflammatory response ; HVHF can down-regulate mRNA expression of TLR4,cutting down inflammatory response。The mechanism of HVHF to endotoxin shock were continuously to eliminate many inflammatory medators-like cytokines by Convection and adsorption,cutting-down“positive feedback Regulation”mRNA expression of TLR4;keep internal environment stable,Reduce Stress response,down-regulateing mRNA expression of TLR4。this study may offer an new theoretical basis for clinic treating septic shock。
引文
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[2]Miller B E,Levy J H. The inflammatory response to cardiopulmonary bypass[J]. Cardiothorac Vasc Anesth,1997,11:355
[3]Krutzik S R,Sieling P A,Modlin R L.The role of toll-like receptorsin host defense against microbial infection Currpin[J]. Immunol,2001,13:104
[4]Asea A,Rehli M,Kabingu E et al.Novel signal transduction Pathwayutilized by extracellular HSP70:role of toll like receptor(TLR)2 and TLR4[J]. Biol Chem,2002,277:15-28
[5]Holmes J H,Connolly N C,Paull D L et al.Magnitude of the inflammatory response to cardiopulmonary bypass and its relation to adverseclinical outcomes[J]. Inflamm Res,2002, 51:579
[6]Van Amersfoort E S,Van Berkel T J,Kuiper J,Receptor,medators, and mechanisms involved in bacterial sepsis and septic shock.[J]. Clin Microbiol Rev,2003,16(3):379-414.
[7] Kramer P, Wigger W, Rieger J et al. Arteriovenous hemofiltration: a new and simple method for treatment of over hydrated patient resistant to diuretics[J]. Klin Wochenschr, 1977,55:1121.
[8]罗小星,王大伟,赵永华等.开心胶囊对复苏犬心肌细胞免疫炎症因子基因表达的抑制作用[J]. 广州中医药大学学报,2004,21(5):379-381.
[9]Guest T M, Ramnanathan A V, Tuteur P G, et al.Myocardial injury in critically ill patients. A frequently unrecognized complication[J]. JAMA,1995,273(24):1945
[10] Jacques Creteur,Qinghua Sun, Omar Abid,Daniel De Backer,Philippe Van Der Linden and Jean-Louis Vincent.Normovolemic hemodilution improves oxygen extraction capabilities in endotoxic shock[J]. ApplPhysiol 91:1701-1707,2001.
[11]Mohr M,Hopken U,Oppermann M,et al.Effects of anti-C5a monoclonal antibodies on oxygen use in a porcine model of severe sepsis[J]. Eur J Clin Invest,1998,28(3):227-234.
[12]Opdenakker G.New insights in the regulation of leukocytosis and the role played by leukocytes in septic shock.[J]. Verh K Acad Geneeskd Belg,2001,63(6):531-538.
[13]Meier–Hellmann A,Sakka S G,Reinhart K.Catecholamines and splanchnic perfusion[J]. Schweiz Med Wochenschr,2000,130(50):1942-1947.
[14]Reinhart K,Sakka S G,Meier-Hellmann A.Haemodynamic management of a patient with septic shock[J]. Eur J Anaesthesiol,2000,17(1):6-17.
[15]Sharma S, Kumar A.Septic shock, multiple organ failure,and acute respiratory distress syndrome[J]. Curr Opin Pulm Med,2003,9(3):199-209.
[16] Hashimoto C,Hudson K L,Anderson K V,The Toll gene of brosophia,required for dorsalventral enbryonic polarity,appears to encode a transmembrane protein[J]. cell,1988,52(2):269-279
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