姜黄对大鼠肠缺血再灌注肺损伤NFκB调控作用的影响
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摘要
肠缺血再灌注损伤是严重创伤、休克等疾病治疗过程中经常发生的病理生理过程,可导致许多严重并发症,是多脏器功能衰竭(MODS)发生、发展的重要原因之一。肠缺血再灌注不仅损伤肠道本身,对远隔器官如肝、肺的功能均产生严重影响。核转录因子κB(NFκB)能调节许多炎症介质的基因转录和表达。NFκB的活化在急性肺损伤的发生发展中起重要的作用。姜黄是类姜黄素家族成员中的一员,姜黄属植物的根茎和块根中提取的黄色酚类物质,研究表明姜黄具有强大的抗氧化和抗炎作用,可以作为NFκB的阻滞剂发挥很多作用。
目的:探讨中药姜黄提取物(curcumin)对大鼠肠缺血再灌注肺损伤肺的保护作用及其机制。
方法:雄性Wistar大鼠24只随机分成对照组(control组,n=6)、模型组(IIR组,n=6)、1 mg/kg姜黄处理组(低剂量姜黄组,n=6)和5 mg/kg姜黄处理组(高剂量姜黄组,n=6)。IIR组、低剂量姜黄组和高剂量姜黄组大鼠行肠系膜上动脉夹闭1小时再灌注2小时。处理组于再灌注前10分钟分别以1 mg/kg和5 mg/kg姜黄行左股静脉注射,对照组及IIR组给予等量生理盐水。观察大鼠肠、肺组织病理学、肺泡灌洗液蛋白含量,检测血清IL-6和TNF-α水平,测定肺组织匀浆SOD、MPO水平,采用免疫组化法观察肺组织ICAM-1、NFκB表达并用Western-blot法检测其含量。
结果:肠缺血1小时再灌注2小时可导致严重的肺组织的损伤,表现为肺组织有明显的水肿、渗出和炎性细胞浸润。与对照组相比,肺泡灌洗液蛋白含量(BALF)升高(P<0.01),肺组织SOD活性降低(P<0.01),肺组织MPO活性增强(P<0.01);血清TNF-α、IL-6水平亦有显著升高(P<0.01、P<0.01);肺组织ICAM-1、NFκB表达增强。与IIR组相比,1 mg/kg姜黄处理和5 mg/kg姜黄处理组肺组织的病理表现及损伤程度明显减轻,BALF降低(P<0.01),SOD活性升高(P<0.05),血清TNF-α、IL-6水平降低(P<0.01、P<0.01),肺组织ICAM-1、NFκB表达减弱。但MPO活性仅在1 mg/kg姜黄处理组有显著降低(P<0.01)。
结论:
(1)肠缺血1小时再灌注2小时引起严重的肺损伤;
(2)肠缺血再灌注引起肺损伤的机制复杂,NFκB激活参与了这一损伤过程;
(3)姜黄可以保护肠缺血再灌注引发的肺损伤。
Intestine ischemia reperfusion (IIR) is a pathophysiologic process frequently during the therapy of many diseases such as serious trauma and shock and may result in many serious complications. The enterogenic infection is the effect induced by the impaired intestinal mucosal barrier, and it is the key cause that leads to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Intestine ischemia reperfusion not only hurts the intestines but also causes the remote organs such as lung failure. The transcription factor nuclear factor kappaB (NFκB) can regulate transcription and expression of many inflammatory mediators. The research has proved that the lung damage caused by IIR is related with NFκB, and the activation of NFκB plays an important role in the IIR. Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from powdered rhizome. Present research discovered that curcumin has powerful anti-inflammatory and antibacterial effects. As an inhibitor of NFκB, it has many effective effects.
Objective: To investigate the protection of curcumin on lung during intestinal ischemia reperfusion injury (IIR) and to examine the possible mechanism of this process.
Method: Rats were randomly divided into 4 groups: control group, IIR group, the 1 mg/kg curcumin treated (low dosage group) and the 5 mg/kg curcumin treated (high dosage group) (n=6). The IIR model was established by clamping superior mesenteric artery (SMA) for 1 hour and reperfusion for 2 hours. The 2 treated groups were administrated with femoral vein injection of 1 mg/kg and 5 mg/kg curcumin 10 min before reperfusion. Lung histology and bronchia alveolus lung fluid (BALF) protein were assayed. Serum IL-6 and TNF-α, lung superoxide dismutase (SOD) and myeloper- oxidase (MPO) as well as the expression level of NFκB and ICAM-1 were measured.
Result: Lung injury induced by intestinal IIR, was characterized by edema, hemorrhage and neutrophil infiltration as well as the significant rising of BALF protein. In model groups, compared with control group, the levels of serum IL-6, TNF-α, lung MPO increased (P<0.01, P<0.01, P<0.01) and lung SOD decreased (P<0.01) in I/R group. Strong positive expression of NFκB P65 and ICAM-1 was observed. After the administration of low and high dosage curcumin, the level of BALF protein, serum IL-6, TNF-α, decreased significantly (P<0.01, P<0.01, P<0.01) and lung SOD increased obviously (P<0.05) while lung MPO decreased (P<0.01) only in the low dosage group, the expression of NFκB P65 and ICAM-1 decreased when compared to IIR group.
Conclusion: (1) This study demonstrated that intestinal IIR may result in severe lung damage; (2) The mechanism of lung injury induced by IIR is complicated, which has relation with the activation of NFκB; (3) Curcumin can protect lung against IIR injury which may be related with inhibiting the activation of NFκB.
目的:探讨中药姜黄提取物(curcumin)对大鼠肠缺血再灌注肺损伤肺的保护作用及其机制。
方法:雄性Wistar大鼠24只随机分成对照组(control组,n=6)、模型组(IIR组,n=6)、1 mg/kg姜黄处理组(低剂量姜黄组,n=6)和5 mg/kg姜黄处理组(高剂量姜黄组,n=6)。IIR组、低剂量姜黄组和高剂量姜黄组大鼠行肠系膜上动脉夹闭1小时再灌注2小时。处理组于再灌注前10分钟分别以1 mg/kg和5 mg/kg姜黄行左股静脉注射,对照组及IIR组给予等量生理盐水。观察大鼠肠、肺组织病理学、肺泡灌洗液蛋白含量,检测血清IL-6和TNF-α水平,测定肺组织匀浆SOD、MPO水平,采用免疫组化法观察肺组织ICAM-1、NFκB表达并用Western-blot法检测其含量。
结果:肠缺血1小时再灌注2小时可导致严重的肺组织的损伤,表现为肺组织有明显的水肿、渗出和炎性细胞浸润。与对照组相比,肺泡灌洗液蛋白含量(BALF)升高(P<0.01),肺组织SOD活性降低(P<0.01),肺组织MPO活性增强(P<0.01);血清TNF-α、IL-6水平亦有显著升高(P<0.01、P<0.01);肺组织ICAM-1、NFκB表达增强。与IIR组相比,1 mg/kg姜黄处理和5 mg/kg姜黄处理组肺组织的病理表现及损伤程度明显减轻,BALF降低(P<0.01),SOD活性升高(P<0.05),血清TNF-α、IL-6水平降低(P<0.01、P<0.01),肺组织ICAM-1、NFκB表达减弱。但MPO活性仅在1 mg/kg姜黄处理组有显著降低(P<0.01)。
结论:
(1)肠缺血1小时再灌注2小时引起严重的肺损伤;
(2)肠缺血再灌注引起肺损伤的机制复杂,NFκB激活参与了这一损伤过程;
(3)姜黄可以保护肠缺血再灌注引发的肺损伤。
Intestine ischemia reperfusion (IIR) is a pathophysiologic process frequently during the therapy of many diseases such as serious trauma and shock and may result in many serious complications. The enterogenic infection is the effect induced by the impaired intestinal mucosal barrier, and it is the key cause that leads to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Intestine ischemia reperfusion not only hurts the intestines but also causes the remote organs such as lung failure. The transcription factor nuclear factor kappaB (NFκB) can regulate transcription and expression of many inflammatory mediators. The research has proved that the lung damage caused by IIR is related with NFκB, and the activation of NFκB plays an important role in the IIR. Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from powdered rhizome. Present research discovered that curcumin has powerful anti-inflammatory and antibacterial effects. As an inhibitor of NFκB, it has many effective effects.
Objective: To investigate the protection of curcumin on lung during intestinal ischemia reperfusion injury (IIR) and to examine the possible mechanism of this process.
Method: Rats were randomly divided into 4 groups: control group, IIR group, the 1 mg/kg curcumin treated (low dosage group) and the 5 mg/kg curcumin treated (high dosage group) (n=6). The IIR model was established by clamping superior mesenteric artery (SMA) for 1 hour and reperfusion for 2 hours. The 2 treated groups were administrated with femoral vein injection of 1 mg/kg and 5 mg/kg curcumin 10 min before reperfusion. Lung histology and bronchia alveolus lung fluid (BALF) protein were assayed. Serum IL-6 and TNF-α, lung superoxide dismutase (SOD) and myeloper- oxidase (MPO) as well as the expression level of NFκB and ICAM-1 were measured.
Result: Lung injury induced by intestinal IIR, was characterized by edema, hemorrhage and neutrophil infiltration as well as the significant rising of BALF protein. In model groups, compared with control group, the levels of serum IL-6, TNF-α, lung MPO increased (P<0.01, P<0.01, P<0.01) and lung SOD decreased (P<0.01) in I/R group. Strong positive expression of NFκB P65 and ICAM-1 was observed. After the administration of low and high dosage curcumin, the level of BALF protein, serum IL-6, TNF-α, decreased significantly (P<0.01, P<0.01, P<0.01) and lung SOD increased obviously (P<0.05) while lung MPO decreased (P<0.01) only in the low dosage group, the expression of NFκB P65 and ICAM-1 decreased when compared to IIR group.
Conclusion: (1) This study demonstrated that intestinal IIR may result in severe lung damage; (2) The mechanism of lung injury induced by IIR is complicated, which has relation with the activation of NFκB; (3) Curcumin can protect lung against IIR injury which may be related with inhibiting the activation of NFκB.
引文
1. Niteen Tapuria. Remote Ischemic Preconditioning: A Novel Protective Method From Ischemia Reperfusion Injury.Journal of Surgical Research 2008; 150:304–30.
2. Sen R. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. [J] Cell. 1986; 46(5):705-16.
3. Browder W. Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. [J] American Journal of Physiology. 1999; 276(2 Ptb2):H543-52.
4. Abraham E. NF-kappaB activation. [Review] Critical Care Medicine. 2000; 28(4Suppl):N100-4.
5. Michael Karin. The beginning of the end: IΚB kinase (IKK) and NFΚB activation. [J]The Journal of Biological Chemistry 1999; 274(19):27339.
6. Tian XF. Effect of nuclear factor kappa B on intercellular adhesion molecule 1 expression and neutrophil infiltration in lung injury induce by intestinal ischemia/reperfusion in rats. [J]World Gastroenterol 2006; 12(3):388.
7.罗真春.核转录因子KappaB与急性肺损伤.重庆医学2006; 35(3)277.
8. Fan CG. IκB-a and IκB-βpossess injury context specific functions that uniquely influence hepatic NFκB induction and inflammation. The Journal of Clinical Investigation 2004; 5(113):746.
9. Mosialos G. A protein kinase-A recognition sequence is structurally linked to transformation by p59v-reland cytoplasmic retention of p68 c-rel. Molecular and Cellular Biology 1991; 11(12):5867-77.
10. Hoffmann A. Transcriptional regulation via the NFκB signaling module. Oncogene 2006; (25):6706?16.
11. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. [Review] Annual Review of Immunology 1996; (14):649-83.
12. Danielle G. NFκB plays a major role during the systemic and local acute inflammatory response following intestinal reperfusion injury. British Journal of Pharmacology 2005; (145):246–54.
13. Sen R. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986; 46(5):705-16.
14. Aaron C. Ubiquitin-mediated degradation of cellular proteins in health and disease. Hepatology 2002; 35 (1): 3-6.
15. Muller S. SUMO: a regulator of gene expression and genome integrity. Oncogene2004; 23:1998-2008.
16. Zwickl P. The 20S proteasome. Current Topics Microbiology Immunology 2002; 268:23-41.
17. Keiji Tanaka. The proteasome: Overview of structure and functions. Proceedings of the Japan Academy 2009; (85):12-36.
18. Zwickl P. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annual Review of Biochemistry 1999; 68:1015-68.
19. Grzegorz Nalepa. Drug discovery in the ubiquitin–proteasome system. Nature reviews drug discovery 2006; (5):518-613.
20. Maniatis T. A ubiquitin ligase complex essential for the NF-kappa B, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev 1999; (13):505.
21. Baeruerle PA. IΚB-NFκB structures: at the interface of inflammation control. Cell 1998; (95):729-31.
22. Schmidt KN. Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-kappa B. Journal of Biological Chemistry 1995; 270(45):27136-42.
23.李军华.核因子-κB在大鼠实验性溃疡性结肠炎肠组织的表达及其意义.世界华人消化杂志2003;第11卷第02期:214-8.
24. Jiang Y. The signal transduction pathways of mitogen-activated protein kinase. J First Mil Med Univ 1999; 19 (1):59-62.
25. Zhang L. Progress of study on mitogen-activated protein kinase. Foreign Med Section Pathophysiol Clin Med 1999; 19 (2):84-7.
26. Jiang Y. P38 MAPK signal transduction pathway. Chin Bull Life 1999; 11 (3): 102-6.
27. Davis R J. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103:239-52.
28. Jin H. NPK1, an MEKK1 like mitogen activated protein kinase, regulates innate immunity and development in plants. Developmental Cell 2002; 3(2):291.
29. Widmann C. Mitogen activated protein kinase: conservation of a three kinase module from yeast to human. Physiol Rev 1999; 79(1):143-80.
30. Walter Kolch. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem 2000; (351):289-305.
31. Sundaram MV. RTK/Ras/MAPK signaling. WormBook 2006 Feb 11:1-19.
32. Alastair J. The protein kinase Pak3 positively regulates Raf-1activity through phosphorylation of serine338. Nature 1998; (396):180-3.
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37. Li Z. The primary structure of p38 gamma: a new member of p38group of MAP kinases. Biochem Biophys Res Commun 1996; (228):334-40.
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1. Jun Jiang. Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood–brain barrier damage. European Journal of Pharmacology 2007; 561: 54-62.
2. Carrico CJ. Multiple-organ-failure Syndrome. Arch Surg 1986; 121(2):196-208.
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13. Sun D. Protective effect of interleukin-1 receptorantagonist onoleic acid-induced lung injury. Chin Med J Engl. 1996; 109:5222-61.
14. Niteen Tapuria. Ischemic Preconditioning: A Novel Protective Method From Ischemia Reperfusion Injury。Journal of Surgical Research 2008; 150:304–30.
15. Giakoustidis AE.Inhibition of intestinal ischemia/repurfusion induced apoptosis and necrosis via down-regulation of the NFkB, c-Jun and caspace-3 expression by epigallocatechin-3-gallate administration. Free Radical Research 2008; 42:180-8.
16. Sen R. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986; 46(5):705-16.
17. Abraham E. NF-kappaB activation. [Review] Critical Care Medicine. 2000; 28(4): 100-4.
18. Maniatis T. A ubiquitin ligase complex essential for the NF-kappa B ,Wnt/Wingless, and Hedgehog signaling pathways . Genes Dev 1999; 13: 505.
19. Browder W. Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. American Journal of Physiology. 1999; 276(2):H543-52.
20. Baldwin Jr AS. The NF-κB and IκB proteins: new discoveries and in- sights. Annu Rev Immunol. 1996; 14:649-81.
21. Baeruerle PA. IKB-NF-κB structures: at the interface of inflammation control. Cell 1998; 95:729-31.
22. Li C. Kelley J. Browder IW. Williams DL. Early activation of IKKbeta during in vivo myocardial ischemia. American Journal of Physiology -Heart & Circulatory Physiology. 2001; 280(3):H1264-71.
23. Keiji Tanka. The proteasome: Overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci 2009; 85(1):12-36.
24. Zwickl P. The 20S proteasome. Curr Top Microbiol Immunol 2002; 268:23-41.
25. Grzegorz Nalepa. Drug discovery in the ubiquitin–proteasome system. Nature Reviews Drug Discovery 2006; (5):596-613.
26. Guang Liang. Inhibition of LPS-induced Production of Inflammatory Factors in the Macrophages by Mono-carbonyl Analogues of Curcumin. Journal of Cellular and Molecular Medicine. J Cell Mol Med 2009; Feb 20.
27. Vitaliy Poylin. The NFκB Inhibitor Curcumin Blocks Sepsis-Induced Muscle Proteolysis. Mediators of Inflammation. 2008; (2008), 13.
2. Sen R. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. [J] Cell. 1986; 46(5):705-16.
3. Browder W. Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. [J] American Journal of Physiology. 1999; 276(2 Ptb2):H543-52.
4. Abraham E. NF-kappaB activation. [Review] Critical Care Medicine. 2000; 28(4Suppl):N100-4.
5. Michael Karin. The beginning of the end: IΚB kinase (IKK) and NFΚB activation. [J]The Journal of Biological Chemistry 1999; 274(19):27339.
6. Tian XF. Effect of nuclear factor kappa B on intercellular adhesion molecule 1 expression and neutrophil infiltration in lung injury induce by intestinal ischemia/reperfusion in rats. [J]World Gastroenterol 2006; 12(3):388.
7.罗真春.核转录因子KappaB与急性肺损伤.重庆医学2006; 35(3)277.
8. Fan CG. IκB-a and IκB-βpossess injury context specific functions that uniquely influence hepatic NFκB induction and inflammation. The Journal of Clinical Investigation 2004; 5(113):746.
9. Mosialos G. A protein kinase-A recognition sequence is structurally linked to transformation by p59v-reland cytoplasmic retention of p68 c-rel. Molecular and Cellular Biology 1991; 11(12):5867-77.
10. Hoffmann A. Transcriptional regulation via the NFκB signaling module. Oncogene 2006; (25):6706?16.
11. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. [Review] Annual Review of Immunology 1996; (14):649-83.
12. Danielle G. NFκB plays a major role during the systemic and local acute inflammatory response following intestinal reperfusion injury. British Journal of Pharmacology 2005; (145):246–54.
13. Sen R. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986; 46(5):705-16.
14. Aaron C. Ubiquitin-mediated degradation of cellular proteins in health and disease. Hepatology 2002; 35 (1): 3-6.
15. Muller S. SUMO: a regulator of gene expression and genome integrity. Oncogene2004; 23:1998-2008.
16. Zwickl P. The 20S proteasome. Current Topics Microbiology Immunology 2002; 268:23-41.
17. Keiji Tanaka. The proteasome: Overview of structure and functions. Proceedings of the Japan Academy 2009; (85):12-36.
18. Zwickl P. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annual Review of Biochemistry 1999; 68:1015-68.
19. Grzegorz Nalepa. Drug discovery in the ubiquitin–proteasome system. Nature reviews drug discovery 2006; (5):518-613.
20. Maniatis T. A ubiquitin ligase complex essential for the NF-kappa B, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev 1999; (13):505.
21. Baeruerle PA. IΚB-NFκB structures: at the interface of inflammation control. Cell 1998; (95):729-31.
22. Schmidt KN. Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-kappa B. Journal of Biological Chemistry 1995; 270(45):27136-42.
23.李军华.核因子-κB在大鼠实验性溃疡性结肠炎肠组织的表达及其意义.世界华人消化杂志2003;第11卷第02期:214-8.
24. Jiang Y. The signal transduction pathways of mitogen-activated protein kinase. J First Mil Med Univ 1999; 19 (1):59-62.
25. Zhang L. Progress of study on mitogen-activated protein kinase. Foreign Med Section Pathophysiol Clin Med 1999; 19 (2):84-7.
26. Jiang Y. P38 MAPK signal transduction pathway. Chin Bull Life 1999; 11 (3): 102-6.
27. Davis R J. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103:239-52.
28. Jin H. NPK1, an MEKK1 like mitogen activated protein kinase, regulates innate immunity and development in plants. Developmental Cell 2002; 3(2):291.
29. Widmann C. Mitogen activated protein kinase: conservation of a three kinase module from yeast to human. Physiol Rev 1999; 79(1):143-80.
30. Walter Kolch. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem 2000; (351):289-305.
31. Sundaram MV. RTK/Ras/MAPK signaling. WormBook 2006 Feb 11:1-19.
32. Alastair J. The protein kinase Pak3 positively regulates Raf-1activity through phosphorylation of serine338. Nature 1998; (396):180-3.
33. Mason C S. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 1999; (18):2137-48.
34.卢建.受体、信号转导系统与疾病.第一版济南山东科学技术出版社.1999; 49-86.
35. Scott T. Rac-PAK signaling stimulates exracellular signal-regulated kinase(ERK)activation by regulating formation of MEK1-ERK complexes. Molecular and cellular biology 2002; 22(17):6023-33.
36. Jiang Y. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem 1996; (271):17920-6.
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