外源性一氧化碳释放分子（CORM-2）对脓毒症早期肝脏炎症反应和JAK分子磷酸化的抑制作用及分子机制
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摘要
背景与目的
脓毒症(Spesis)是指由感染引起的全身性炎症反应综合征(SystemicInflammatory Response Syndrome,SIRS),是当前创伤、烧伤外科以及ICU所面临的棘手难题,其进一步发展所导致的脓毒性休克(septic shock,SS)、急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)以及多脏器功能不全综合征(multiple organ dysfunction syndrome,MODS),已成为临床主要死亡原因之一。尽管现代外科监护技术和抗生素治疗有了很大进展,但脓毒症的死亡率仍然居高不下,因此脓毒症及其并发症尤其是MODS的防治,仍然是当代外科学领域的难题之一。
肝脏作为机体的一个重要器官,在脓毒症的发生发展过程中起着至关重要的作用。有证据表明:肝脏拥有全身最多数量的巨噬细胞,负责清除来自肠道、脾脏的细菌和内毒素,肝巨噬细胞(Kuffer细胞)在脓毒症时合成和释放的多种急性时相蛋白和细胞因子,能使多种信号通路活化(包括januskinase/signal transducer andactivator of transcription-JAK/STAT通路)释放炎症介质且不断循环形成“瀑布样”级联反应,在脓毒症发生发展中起重要的作用。
本研究即采用LPS刺激单核巨噬细胞细胞和小鼠盲肠结扎和穿孔(cecalligation and puncture,CLP)脓毒症模型,以外源性CO释放分子CORM-2进行早期干预,观察它对JAKs分子磷酸化的抑制作用,旨在研究其对脓毒症JAK/STAT通路的活化是否具有调节作用,并探讨可能的分子机制。
方法
研究分为2部分,第一部分,利用LPS刺激单核巨噬细胞(RAW264.7),建立细胞脓毒症模型作为脓毒症小鼠的肝脏离体模型,在离体方面研究炎症反应的机制以及外源性一氧化碳释放分子(CORM-2)所释放的CO对该模型的干预作用;第二部分,应用盲肠结扎穿孔(CLP)的C57BL/6小鼠复制脓毒症的在体模型,将小鼠随机分为4组(具体例数根据检测指标而定):假手术组(sham)、CLP组、CLP+iCORM组、CLP+CORM-2组,以肝脏的形态学、功能、细胞因子以及JAK/STAT表达水平为指标探讨CLP小鼠早期肝脏炎症反应的部分分子机制,评价了外源性一氧化碳释放分子(CORM-2)所释放的CO对CLP小鼠早期肝脏炎症反应的抑制作用。
结果及结论
1.单核巨噬细胞炎症模型:LPS刺激后细胞损伤明显,活性下降;炎症因子IL-1β、TNF-α相关炎性蛋白表达明显增加,JAK/STAT活性也显著增高。外源性CO的干预组炎症的反应较对照组明显减轻,说明外源性CO能在一定程度抑制小鼠脓毒症离体模型的炎症反应。
2.CLP小鼠脓毒症模型:术后24h小鼠肝脏炎症细胞浸润明显,血浆中IL-1β、TNF-α等指标明显上升,ICAM-1、JAK/STAT蛋白表达明显增加。外源性CO的直接干预可以明显改善肝脏组织肿胀程度,减少验证细胞的浸润,抑制炎性反应,有效维护细胞功能。
以上结果表明,外源性外源性一氧化碳释放分子能明显抑制JAKs分子磷酸化,继而抑制了JAK/STAT信号通路的活化,减少下游相关细胞因子的表达,有效防止严重感染时炎症反应的级联反应。证实了外源性一氧化碳的干预在一定程度上抑制了脓毒症早期肝脏炎症反应的发展。
Background and objective:
Sepsis refers to infections caused by SIRS and is confirmed the existence of bacteria or highly suspicious of infection.Sepsis is the difficult problem faced by trauma,burns surgical and ICU and its further development due to septic shock (septic shock,SS),acute respiratory distress syndrome(acute respiratory distress syndrome,ARDS),as well as integrated multi-organ dysfunction syndrome (multiple organ dysfunction syndrome,MODS),has become a leading cause of death in septic patients.Despite modern surgical techniques,care and antibiotic treatment has made great progress,the mortality rate of sepsis is still high, therefore,the prevention and treatment of sepsis and its complications in particular MODS is still one of the problems among contemporary science. Intestine is an important organ of body and its important physiological functions can not be ignored.
As an important organ,the Liver plays a vital role in the occurrence and development of sepsis and its important physiological functions can not be ignored,the acute-phase proteins and cytokines released by liver cell and kuffer cell play an important role in sepsis.The liver has the largest number of full-body macrophages,responsible for eliminating from the intestinal LPS and bacteria,so it plays an important role in the SIRS
In this study,the CO-releasing molecule(CORM-2) was used as an exogenous source of CO.Through in vitro and in vivo experiments we studied whether the exogenous CO could inhibit the inflammatory response of the Liver of early sepsis and explored its mechanism.
Method:
The research is divided into 2 parts.In the first part,Monocyte-derived macrophages was stimulated LPS to establish cells sepsis model as a sepsis model of the Liver in vitro.The cells were used to study the mechanism of inflammatory response in vitro,as well as the intervention effect of the CO released by the CORM-2 on the role model.In the second part,use the C57BL/6 mice dealed with cecal ligation and puncture(CLP) as the in vivo model of sepsis.Mice were randomly divided into 4 groups(the number of specific cases may be based on the detection of targets):Sham-operated group,CLP group, CLP+iCORM group,CLP+CORM-2 group,the Liver morphology,function,and inflammatory cells in CLP mice was used as an index to explore the molecular mechanisms on early inflammatory responses in sepsis.The inhibition effect of exogenous carbon monoxide released by CORM-2 on the CLP mice's early liver inflammatory response was evaluated.
Results and conclusions:
1.Monocyte-derived macrophages Sepsis model:The phosphorylation levels of and the IL-1β,TNF-αlevel in the culture media in LPS-stimulated Monocyte-derived macrophages increased significantly.ICAM-1,JAK1/JAK3 protein expression was significantly increased.Inflammatory response in the exogenous CO intervention group was significantly reduced than in the control group and thus to some extent,exogenous CO can inhibit the inflammatory response in RAW264.7 model as in vitro model of the Liver sepsis.
2.Sepsis model in CLP mice:24h after operation,the inflammatory cell infiltration of liver is obvious,plasma indicators increased significantly,ICAM-1, JAK1/JAK3 protein expression significantly increased.The direct intervention of exogenous CO can significantly improve the degree of liver tissue swelling, enhance peristaltic function,inhibit inflammatory response and protect cells. These results show that the cell and animal models of sepsis demonstrated that the intervention of exogenous carbon monoxide somewhat inhibited the development of inflammatory response of early sepsis in the the small intestine.
脓毒症(Spesis)是指由感染引起的全身性炎症反应综合征(SystemicInflammatory Response Syndrome,SIRS),是当前创伤、烧伤外科以及ICU所面临的棘手难题,其进一步发展所导致的脓毒性休克(septic shock,SS)、急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)以及多脏器功能不全综合征(multiple organ dysfunction syndrome,MODS),已成为临床主要死亡原因之一。尽管现代外科监护技术和抗生素治疗有了很大进展,但脓毒症的死亡率仍然居高不下,因此脓毒症及其并发症尤其是MODS的防治,仍然是当代外科学领域的难题之一。
肝脏作为机体的一个重要器官,在脓毒症的发生发展过程中起着至关重要的作用。有证据表明:肝脏拥有全身最多数量的巨噬细胞,负责清除来自肠道、脾脏的细菌和内毒素,肝巨噬细胞(Kuffer细胞)在脓毒症时合成和释放的多种急性时相蛋白和细胞因子,能使多种信号通路活化(包括januskinase/signal transducer andactivator of transcription-JAK/STAT通路)释放炎症介质且不断循环形成“瀑布样”级联反应,在脓毒症发生发展中起重要的作用。
本研究即采用LPS刺激单核巨噬细胞细胞和小鼠盲肠结扎和穿孔(cecalligation and puncture,CLP)脓毒症模型,以外源性CO释放分子CORM-2进行早期干预,观察它对JAKs分子磷酸化的抑制作用,旨在研究其对脓毒症JAK/STAT通路的活化是否具有调节作用,并探讨可能的分子机制。
方法
研究分为2部分,第一部分,利用LPS刺激单核巨噬细胞(RAW264.7),建立细胞脓毒症模型作为脓毒症小鼠的肝脏离体模型,在离体方面研究炎症反应的机制以及外源性一氧化碳释放分子(CORM-2)所释放的CO对该模型的干预作用;第二部分,应用盲肠结扎穿孔(CLP)的C57BL/6小鼠复制脓毒症的在体模型,将小鼠随机分为4组(具体例数根据检测指标而定):假手术组(sham)、CLP组、CLP+iCORM组、CLP+CORM-2组,以肝脏的形态学、功能、细胞因子以及JAK/STAT表达水平为指标探讨CLP小鼠早期肝脏炎症反应的部分分子机制,评价了外源性一氧化碳释放分子(CORM-2)所释放的CO对CLP小鼠早期肝脏炎症反应的抑制作用。
结果及结论
1.单核巨噬细胞炎症模型:LPS刺激后细胞损伤明显,活性下降;炎症因子IL-1β、TNF-α相关炎性蛋白表达明显增加,JAK/STAT活性也显著增高。外源性CO的干预组炎症的反应较对照组明显减轻,说明外源性CO能在一定程度抑制小鼠脓毒症离体模型的炎症反应。
2.CLP小鼠脓毒症模型:术后24h小鼠肝脏炎症细胞浸润明显,血浆中IL-1β、TNF-α等指标明显上升,ICAM-1、JAK/STAT蛋白表达明显增加。外源性CO的直接干预可以明显改善肝脏组织肿胀程度,减少验证细胞的浸润,抑制炎性反应,有效维护细胞功能。
以上结果表明,外源性外源性一氧化碳释放分子能明显抑制JAKs分子磷酸化,继而抑制了JAK/STAT信号通路的活化,减少下游相关细胞因子的表达,有效防止严重感染时炎症反应的级联反应。证实了外源性一氧化碳的干预在一定程度上抑制了脓毒症早期肝脏炎症反应的发展。
Background and objective:
Sepsis refers to infections caused by SIRS and is confirmed the existence of bacteria or highly suspicious of infection.Sepsis is the difficult problem faced by trauma,burns surgical and ICU and its further development due to septic shock (septic shock,SS),acute respiratory distress syndrome(acute respiratory distress syndrome,ARDS),as well as integrated multi-organ dysfunction syndrome (multiple organ dysfunction syndrome,MODS),has become a leading cause of death in septic patients.Despite modern surgical techniques,care and antibiotic treatment has made great progress,the mortality rate of sepsis is still high, therefore,the prevention and treatment of sepsis and its complications in particular MODS is still one of the problems among contemporary science. Intestine is an important organ of body and its important physiological functions can not be ignored.
As an important organ,the Liver plays a vital role in the occurrence and development of sepsis and its important physiological functions can not be ignored,the acute-phase proteins and cytokines released by liver cell and kuffer cell play an important role in sepsis.The liver has the largest number of full-body macrophages,responsible for eliminating from the intestinal LPS and bacteria,so it plays an important role in the SIRS
In this study,the CO-releasing molecule(CORM-2) was used as an exogenous source of CO.Through in vitro and in vivo experiments we studied whether the exogenous CO could inhibit the inflammatory response of the Liver of early sepsis and explored its mechanism.
Method:
The research is divided into 2 parts.In the first part,Monocyte-derived macrophages was stimulated LPS to establish cells sepsis model as a sepsis model of the Liver in vitro.The cells were used to study the mechanism of inflammatory response in vitro,as well as the intervention effect of the CO released by the CORM-2 on the role model.In the second part,use the C57BL/6 mice dealed with cecal ligation and puncture(CLP) as the in vivo model of sepsis.Mice were randomly divided into 4 groups(the number of specific cases may be based on the detection of targets):Sham-operated group,CLP group, CLP+iCORM group,CLP+CORM-2 group,the Liver morphology,function,and inflammatory cells in CLP mice was used as an index to explore the molecular mechanisms on early inflammatory responses in sepsis.The inhibition effect of exogenous carbon monoxide released by CORM-2 on the CLP mice's early liver inflammatory response was evaluated.
Results and conclusions:
1.Monocyte-derived macrophages Sepsis model:The phosphorylation levels of and the IL-1β,TNF-αlevel in the culture media in LPS-stimulated Monocyte-derived macrophages increased significantly.ICAM-1,JAK1/JAK3 protein expression was significantly increased.Inflammatory response in the exogenous CO intervention group was significantly reduced than in the control group and thus to some extent,exogenous CO can inhibit the inflammatory response in RAW264.7 model as in vitro model of the Liver sepsis.
2.Sepsis model in CLP mice:24h after operation,the inflammatory cell infiltration of liver is obvious,plasma indicators increased significantly,ICAM-1, JAK1/JAK3 protein expression significantly increased.The direct intervention of exogenous CO can significantly improve the degree of liver tissue swelling, enhance peristaltic function,inhibit inflammatory response and protect cells. These results show that the cell and animal models of sepsis demonstrated that the intervention of exogenous carbon monoxide somewhat inhibited the development of inflammatory response of early sepsis in the the small intestine.
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60. LU Y, ZHOU J , XU C, et all JAK/STAT and P I3K/AKT pathways form a mutual transactivation loop and afford resistance to oxidative stress-induced apop tosis incardiomyocytes [ J ]. Cell Physiol Biochem, 2008, 21(4): 305-314.
61. MART1NEZ-CHANTAR M L, VAZQUEZ-CHANTADAM, ARIZU, et al. Loss of the glycine N2methyltrans-ferase gene leads to steatosis and hepatocellular carcinoma in mice [ J ]. Hepatology, 2008, 47 (4 ) : 1191-1199.
62. BAUTISTA D, BERMU' DEZ2SILVA F J , LASARTE J J,et al. Liver expression of p roteins controlling interferon-mediated signalling as p redictive factors in the response to therapy in patients with hepatitis C virus infection [ J ]. J Pathol, 2007, 213 (3): 347-355.
63. CAO Q, MAK KM, L IEBER C S.Leptin represses matrix metallop roteinase-1 gene expression in LX2 human hepatic stellate cells [ J ]. J Hepatol, 2007, 46 ( 1) :124-133.
64. WENG H, MERTENS P R, GRESSNER A M, et al. IFN-gamma abrogates p rofibrogenic TGF-beta signaling in liver by targeting exp ression of inhibitory and receptor Smads[ J ].J Hepatol, 2007, 46 (2 ): 295-303.
65. CH IEN C M, YANG S H, L IN K L, et al.Novel indoloquinoline derivative, IQDMA, suppresses STAT5 phosphorylation and induces apop tosis in HL-60 cells[ J ]. Chem Biol Interact, 2008, 176 (1) : 40-47.
66. ANTAO-MENEZES A, TURP IN E A, Bost P C, et al.STAT-1 signaling in human lung fibroblasts is induced by vanadium pentoxide through an IFN2beta autocrine loop [ J ] . J Immunol, 2008, 180 ( 6 ) : 4200-4207.
67. WANG G, Q IAN P, JACKSON F R, et al. Sequential activation of JAKs, STATs and xanthine dehydrogenase /oxidase by hypoxia in lung microvascular endothelial cells[ J ] . Int J Biochem Cell Biol, 2008, 40 ( 3 ) :461-470.
68. AUJLA S J , DUB IN P J , KOLLS J K Th17 cells and mucosal host defense [ J ] . Semin Immunol, 2007,19(6): 377-382.
69. KIMURA A, NAKA T, NOHARA K, et all Aryl hydro-carbon recep tor regulates Statl activation and participates in the development of Th17 cells [ J ] . Proc Natl Acad Sci USA, 2008,105 (28): 9721-9726.
70. GAGNON J , RAMANATHAN S, LEBLANC C, et al. IL-6, in synergy with IL-7 or IL-15, stimulates TCR-independent proliferation and functional differentiation of CD8 + T lymphocytes [ J ]. J Immunol, 2008,180(12): 7958-7968.
71. OWAKI T, ASAKAWA M, MOR ISH IMA N, et al.STAT3 is indispensable to IL2272mediated cell p roliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production[ J ].J Immunol, 2008, 180 (5) : 2903-2911.
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[1]D.G.McCormack,S.Mehta,K.Tyml,et al.Pulmonary Microvascular Changes during Sepsis:Evaluation Using Intravital Videomicroscopy.[J].Microvascular Research 2000,60:131-140
[2]郭志良.气体信使分子—氧化亚氮与一氧化碳在生物医学中的研究现状[J].实用心脑肺血管病杂志,2000,8(2):118-121.
[3]Bing-Wei Sun,Qin Jin,Yan Sun,etal.Carbon liberated from CO-releasing molecules attenuates leukocyte infiltration in the small intestine of thermally injured mice.[J].World J Gastroenterol 2007 December 14;13(46):6183-6190
[4]Sun,B.,et al.,Preconditioning of carbon monoxide releasing molecule-derived CO attenuates LPS-induced activation of HUVEC.Int J Biol Sci,2008.4(5):p.270-278.
[5]PrabhakarNR,Dinerman JL,Agani FH,et al.Carbon monoxide:a role in carotid body chemoreception[J].Proc NatlAcad SciUSA,1995,92:1994-1997.
[6]STEFFEL J,LESCHER TF,TANNEr FC.Tissue factor in cardiovascular diseases: Molecular mechanisms and clinical implications[J].Circulation,2006,113:722-731.
[7]Sun,B.W.,et al.,CO liberated from CORM-2 modulates the inflammatory response in the liver of thermally injured mice.World J Gastroenterol,2008.14(4):p.547-553.
[8]Canbay A,Feldstein AE,Higuchi H,Wemeburg N,Grambihler A,BronkSF,Gores GJ.Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression[J].Hepatology.2003 Nov;38(5):1188-1198.
[9]姚胜,姚永明,梁华平.脓毒症时JAK/STAT通路活化及意义.中国危重病急救医学2001;13(9):559-562
[10]Sun BW,Chen ZY,Chen X,et al.Attenuation of leukocytes sequestration by carbon monoxide-releasing molecules:liberated carbon monoxide in the liver of thermally injured mice[J].J Bum Care Res,2007,28(1):173-181.
[11]Diamond P,Doran P,Brady H R et al.Suppressors of cytokine signaling(SOCS):putative modulators of cytokine bioactivity in health and disease.J Nephrol,2000;13:9
[12]Naka T,Narazaki M,Hirata M,et al.Structure and function of a new STAT2induced STAT inhibitor[J].Nature,1997,387(6636):9242929.
[13]Bingwei S,Hui S,Chang L,etal.Role of CO-Releasing Molecules Liberated CO in Attenuating Leukocytes Sequestration and Inflammatory Responses in the Lung of Thermally Injured Mice[J].Journal of Surgical Res,2007,139:128-135
[14]尹文,杨剑虹,虎晓岷等,急性肺损伤肺泡巨噬细胞NF-κB激活通路的实验研究.中国急救医学2003年5月第23卷第5期2003,5(23):281-283
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