缺血后处理和ATP后处理对心肌缺血再灌注损伤的保护作用
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摘要
目的观察缺血后处理(IPO)、三磷酸腺苷(ATP)和腺苷受体激动剂CGS-21680、阻断剂SCH58261药物后处理对心肌缺血再灌注损伤(MIRI)的影响,并探讨其机制。
方法60只健康新西兰大白兔随机分成5组,即缺血再灌注组(I/R组)、IPO组、ATP后处理组、CGS-21680后处理组、SCH58261+IPO组(即SCH58261组),每组12只。建立兔心肌I/R模型,于再灌注末,由颈静脉取血用硫代巴比妥酸法测定丙二醛(MDA)的活性及黄嘌呤氧化酶法测定超氧化物歧化酶(SOD)的活力。采用伊文思蓝和NBT染色方法计算各组兔的心肌梗死面积。用HE染色法观察心肌组织病理形态变化。以末端脱氧核苷酸转移酶介导的dUTP末端缺口标记(TUNEL)法检测心肌细胞凋亡指数。用实时荧光定量反转录聚合酶链反应(RT-PCR)法检测各组心肌组织中凋亡基因caspase-3 mRNA和Bcl-2 mRNA的表达。
结果①与I/R组和SCH58261组比较,IPO组、ATP组和CGS21680组血清MDA水平及心肌梗死面积显著降低(P＜0.05),而血清SOD的活力明显升高(P<0.01)。②TUNEL法检测结果显示,IPO组、ATP组和CGS-21680组的细胞凋亡指数,与I/R组和SCH58261组相比明显降低,心肌组织的损伤显著减轻(P＜0.01)。③与I/R组和SCH58261组比较,IPO组、ATP组和CGS-21680组caspase-3 mRNA的表达明显下调(P<0.01), Bcl-2 mRNA的表达显著上调(P<0.01)。以上检测指标,I/R组和SCH58261组2组间比较,IPO组、ATP组和CGS-21680组3组间比较差异均无统计学意义(P＞0.05)
结论缺血后处理与ATP后处理均可减轻MIRI发挥保护作用。二者的保护作用与腺苷A2a受体的激活有关,其机制可能与上调Bcl-2基因和下调caspase-3基因的表达,抑制氧自由基的氧化应激损伤,减少细胞的凋亡有关。
Objective To investigate the effects of ischemic postconditioning (IPO), adenosine triphosphate (ATP) and adenosine receptor agonist CGS-21680 and antagonist SCH58261 pharmacological postconditioning on myocardial ischemia reperfusion injury (MIRI), and to explore the mechanism.
Methods Sixty New Zealand white rabbits were randomly divided into five groups (n=12 each):I/R group, IPO group, ATP group, CGS-21680 group and SCH58261+IPO group (SCH58261 group).The model of myocardial I/R was established. Malondialdaldehyde (MDA) and superoxide dismutase (SOD) in the five groups were evaluated at the end of 3h reperfusion. Ischemic and infarct areas were measured by Evans blue and NBT staining. The light microscope was used to observe the tissue changes of myocardium. Apoptosis was identified and quantified as apoptosis index (AI) using TUNEL method. The mRNA expression of caspase-3 and Bcl-2 in myocardial tissue was determined by real-time quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR).
Results Compared with those in I/R group and SCH58261 group, myocardial infarct size and the level of MDA markedly decreased in IPO group, in ATP group and CGS-21680 group (P<0.05). The levels of SOD increased significantly (P<0.01). TUNEL method showed that AI significantly decreased and the histopathological changes of the myocardium were relieved obviously in IPO group, in ATP group and CGS-21680 group compared with those in IR group and SCH58261 group (P<0.01). The results of real-time RT-PCR showed that the mRNA expression of caspase-3 was down-regulated, while Bcl-2 was up-regulated in IPO group, in ATP and CGS-21680 group (P<0.01).No significant difference was observed between I/R group and SCH58261 group, and among the three groups of IPO group, ATP group and CGS-21680 group (P>0.05).
Conclusion Ischemic postconditioning and ATP postconditioning attenuate the myocardial IR injury via activation of adenosine A2a receptor. The mechanism may be associated with the up-regulation of Bcl-2 mRNA expression and the down-regulation of caspase-3 expression, which inhibits oxidation stress and decreases cell apoptosis.
方法60只健康新西兰大白兔随机分成5组,即缺血再灌注组(I/R组)、IPO组、ATP后处理组、CGS-21680后处理组、SCH58261+IPO组(即SCH58261组),每组12只。建立兔心肌I/R模型,于再灌注末,由颈静脉取血用硫代巴比妥酸法测定丙二醛(MDA)的活性及黄嘌呤氧化酶法测定超氧化物歧化酶(SOD)的活力。采用伊文思蓝和NBT染色方法计算各组兔的心肌梗死面积。用HE染色法观察心肌组织病理形态变化。以末端脱氧核苷酸转移酶介导的dUTP末端缺口标记(TUNEL)法检测心肌细胞凋亡指数。用实时荧光定量反转录聚合酶链反应(RT-PCR)法检测各组心肌组织中凋亡基因caspase-3 mRNA和Bcl-2 mRNA的表达。
结果①与I/R组和SCH58261组比较,IPO组、ATP组和CGS21680组血清MDA水平及心肌梗死面积显著降低(P＜0.05),而血清SOD的活力明显升高(P<0.01)。②TUNEL法检测结果显示,IPO组、ATP组和CGS-21680组的细胞凋亡指数,与I/R组和SCH58261组相比明显降低,心肌组织的损伤显著减轻(P＜0.01)。③与I/R组和SCH58261组比较,IPO组、ATP组和CGS-21680组caspase-3 mRNA的表达明显下调(P<0.01), Bcl-2 mRNA的表达显著上调(P<0.01)。以上检测指标,I/R组和SCH58261组2组间比较,IPO组、ATP组和CGS-21680组3组间比较差异均无统计学意义(P＞0.05)
结论缺血后处理与ATP后处理均可减轻MIRI发挥保护作用。二者的保护作用与腺苷A2a受体的激活有关,其机制可能与上调Bcl-2基因和下调caspase-3基因的表达,抑制氧自由基的氧化应激损伤,减少细胞的凋亡有关。
Objective To investigate the effects of ischemic postconditioning (IPO), adenosine triphosphate (ATP) and adenosine receptor agonist CGS-21680 and antagonist SCH58261 pharmacological postconditioning on myocardial ischemia reperfusion injury (MIRI), and to explore the mechanism.
Methods Sixty New Zealand white rabbits were randomly divided into five groups (n=12 each):I/R group, IPO group, ATP group, CGS-21680 group and SCH58261+IPO group (SCH58261 group).The model of myocardial I/R was established. Malondialdaldehyde (MDA) and superoxide dismutase (SOD) in the five groups were evaluated at the end of 3h reperfusion. Ischemic and infarct areas were measured by Evans blue and NBT staining. The light microscope was used to observe the tissue changes of myocardium. Apoptosis was identified and quantified as apoptosis index (AI) using TUNEL method. The mRNA expression of caspase-3 and Bcl-2 in myocardial tissue was determined by real-time quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR).
Results Compared with those in I/R group and SCH58261 group, myocardial infarct size and the level of MDA markedly decreased in IPO group, in ATP group and CGS-21680 group (P<0.05). The levels of SOD increased significantly (P<0.01). TUNEL method showed that AI significantly decreased and the histopathological changes of the myocardium were relieved obviously in IPO group, in ATP group and CGS-21680 group compared with those in IR group and SCH58261 group (P<0.01). The results of real-time RT-PCR showed that the mRNA expression of caspase-3 was down-regulated, while Bcl-2 was up-regulated in IPO group, in ATP and CGS-21680 group (P<0.01).No significant difference was observed between I/R group and SCH58261 group, and among the three groups of IPO group, ATP group and CGS-21680 group (P>0.05).
Conclusion Ischemic postconditioning and ATP postconditioning attenuate the myocardial IR injury via activation of adenosine A2a receptor. The mechanism may be associated with the up-regulation of Bcl-2 mRNA expression and the down-regulation of caspase-3 expression, which inhibits oxidation stress and decreases cell apoptosis.
引文
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemia myocardium [J]. Circulation,1986,74:1124-1136.
2. Zhao.ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic post-conditioning during reperfusio: comparison with ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2003,285:H579-H588.
3. Wang HY, Wang GL, Yu YH, et al. Propofol provides ischemia postconditioning on myocardial ischemia-reperfusion injury in rats [J]. Zhonghua Yi Xue Za Zhi, 2009,89(1):54-8.
4. Hofmann U, Burkard N, Vogt C, et al. Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischemia-reperfu.sion[J].Cardiovasc Res,2009,83(2):285-93.
5. Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts [J].J Surg Res,2008,145(2):287-94
6. Lian ZX, Liu F, Liu S, et al. Cardioprotection of ischemic postconditioning and ATP-postconditioning in rabbits is associated with the activation of adenosine receptors[J]. European Heart Journal,2006,27(suppl):72.
7.刘方,廉哲勋,王永彬,等.缺血后处理、ATP后处理减轻兔缺血再灌注损伤：与腺苷受体激活有关[J].现代生物医学进展,2007,7(3)：353-355.
8. Yang J, Yang J, Ding JW, et al. Effects of adenosine postconditioning on the myocardial ischemia-reperfusion injury in rats [J].Med J Chin PLA,2008, 33 (2):136-139.
9. R. Ray Morrison, Xing Lin Tan, Catherine Ledent, et al. Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning [J]. Am J Physiol Heart Circ Physiol,2007,293(4):H2523-9.
10. Freude B, Masters TN, Robicsek F, et al. Apoptosis is inhibited by myocardial ischemia and executed during reperfusion [J]. JMol Cell Cardilo,2000,32 (2) 197-208.
11. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart[J]. Circulation,2005,112:2143-2148.
12. Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduced infarct size via adenosine receptor activation by endogenous adenosine [J]. Cardiovasc Res,2005, 67(1):124-133.
13. Paillard M, Gomez L, Augeul L, et al. Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential [J]. J Mol Cell Cardiol,2009,46(6):902-909.
14. Reeve JL, Duffy AM,0'Brien T, et al. Don't lose heart-therapeutic value of apoptosis prevention in the treatment of cardiovascular disease [J]. J Cell Mol Med,2005,9:609-22.
15. Li Y, Cohen R. Caspase inhibitors and myocardial apoptosis[J]. Int Anesthesiol Clin,2005,43(2):77-89.
16. Adams JM, Cory S. The Bcl-2 protein family:arbiters of cell survival [J]. Science,1998,281(5381):1322-1326.
17. Honsch A, Theuring N, Ebner B, et al. Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-Ⅲ inhibition [J]. Basic Res Cardiol,2010,105(2):155-167.
18. Tsang A, Hausenloy DJ, Mocanu MM, et al. Post-conditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway [J]. Circ Res,2004,95(3):230-232.
19. Bopassa JC, Ferrera R, Gateau RO, et al. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning[J]. Cardiovasc Res,2006,69(1):178-185.
20. Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation [J]. Basic Res Cardiol, 2005,100:57-63.
21. Rossana Berti*, Anthony J Williams, John R Moffett, et al. Quantitative Real-Time RT-PCR Analysis of Inflammatory Gene Expression Associated With Ischemia-Reperfusion Brain Injury[J]. Journal of Cerebral Blood Flow & Metabolism,2002,22:1068-1079.
1. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020:Global Burden of Disease Study. Lancet,1997,349 (9046):1498-1504.
2. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemia myocardium [J]. Circulation,1986,74:1124-1136.
3. Zhao ZQ, Corvera JS, HalkosME, et al. Inhibition of myocardial injury by ischemic post-conditioning during reperfusion:comparison with ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2003,285:H579-H588.
4. Tsang A, Hausenloy DJ, Mocanu MM, et al. Post-conditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway [J]. Circ Res,2004,95 (3):230-232.
5. Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways [J]. Am Coll Cardiol,2004,44 (5):1103-1110.
6.Kin H, Zhao ZQ, Sun HY, et al. Postconditioning attenuates myocardial ischemia reperfusion injury by inhibiting events in the early minutes of reperfusion[J]. Cardiovasc Res,2004,62(1):74-85.
7. Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation [J]. Basic Res Cardiol, 2005,100:57-63.
8. Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion[J]. J Cardiovasc Pharmacol Ther,2006,11 (1): 55-63.
9. Halkos ME, Kerendi F, Corvera JS, et al. Myocardial protection with postconditioning is not enhanced by ischemic preconditioning. Ann Thorac Surg,2004,78(3):961-969.
10.刘胜辉,霍玉娥,尹博英.缺血后处理对大鼠缺血/再灌注心肌髓过氧化物酶及细胞间粘附分子的影响[J].心血管康复医学杂志,2009,18(2)：107-109.
11. Bopassa JC, Ferrera R, Gateau RO, et al. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning[J]. Cardiovasc Res, 2006,69(1):178-185.
12. Argaud L, GateauRoesch 0, Raisky 0, et al. Postconditioning inhibits mitochondrial permeability transition[J]. Circulation,2005,111(2):194-197.
13.刘旭,徐平.心肌缺血再灌注损伤与细胞凋亡[J].中华实用中西医杂志,2005,18(18)：981-983.
14.石凤梧,张文立,刘苏等.猪心肌缺血后处理对心肌细胞凋亡及Bcl-2、Bax蛋白表达的影响[J].山东医药,2007,47(7)：15-16.
15.石凤梧,蔡文清,陈子英等.缺血后处理对猪心肌细胞Fas基因蛋白表达及caspase-3活性的影响[J].中华实验外科杂志,2006,23(6)：709-712.
16. Honsch A, Theuring N, Ebner B, et al. Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-Ⅲ inhibition. Basic Res Cardiol,2010,105(2):155-167.
17. Li Y, Tao L, Zang YM, et al. Effects of ischemic postconditioning on myocardial apoptosis and infarction in rabbits with acute myocardial ischemia and reperfusion [J]. J Fourth Mil Med Univ,2002,23 (18):1690-1693.
18. Zhang JF, Ma YT, Yang YN, et al. Effects of ischemia postconditioning on ischemia-reperfusion injury and reperfusion injury salvage kinase signal transduction pathways in isolated mouse hearts [J]. Zhonghua Xin Xue Guan Bing Za Zhi,2008,36(2):161-6.
19. Paillard M, Gomez L, Augeul L, et al. Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential [J]. J Mol Cell Cardiol,2009,46(6)1:902-9.
20. Argaud L.GateauRoesch O.Raisky O, et al. Postconditioning inhibits mitochondrial permeability transition[J]. Circulation,2005,111(2):194-197.
21. Mykytenko J, Reeves JG, Kin H, et al. Persistent beneficial effect of postconditioning against infarct size:role of mitochondrial K (ATP) channels during reperfusion [J]. Basic Res Cardiol,2008,103(5):472-84.
22. Yang X, Downey JM, Cohen MV, Multiple brief coronary occlusions during early reperfusion protect rabbit hearts by activation of ERK and production of nitric oxide[J]. Circulation,2003,108:158-62.
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25. Honisch A, Theuring N, Ebner B, et al. Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-Ⅲ inhibition. [J]. Basic Res Cardiol,2010,105(2):155-67.
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2. Zhao.ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic post-conditioning during reperfusio: comparison with ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2003,285:H579-H588.
3. Wang HY, Wang GL, Yu YH, et al. Propofol provides ischemia postconditioning on myocardial ischemia-reperfusion injury in rats [J]. Zhonghua Yi Xue Za Zhi, 2009,89(1):54-8.
4. Hofmann U, Burkard N, Vogt C, et al. Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischemia-reperfu.sion[J].Cardiovasc Res,2009,83(2):285-93.
5. Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts [J].J Surg Res,2008,145(2):287-94
6. Lian ZX, Liu F, Liu S, et al. Cardioprotection of ischemic postconditioning and ATP-postconditioning in rabbits is associated with the activation of adenosine receptors[J]. European Heart Journal,2006,27(suppl):72.
7.刘方,廉哲勋,王永彬,等.缺血后处理、ATP后处理减轻兔缺血再灌注损伤：与腺苷受体激活有关[J].现代生物医学进展,2007,7(3)：353-355.
8. Yang J, Yang J, Ding JW, et al. Effects of adenosine postconditioning on the myocardial ischemia-reperfusion injury in rats [J].Med J Chin PLA,2008, 33 (2):136-139.
9. R. Ray Morrison, Xing Lin Tan, Catherine Ledent, et al. Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning [J]. Am J Physiol Heart Circ Physiol,2007,293(4):H2523-9.
10. Freude B, Masters TN, Robicsek F, et al. Apoptosis is inhibited by myocardial ischemia and executed during reperfusion [J]. JMol Cell Cardilo,2000,32 (2) 197-208.
11. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart[J]. Circulation,2005,112:2143-2148.
12. Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduced infarct size via adenosine receptor activation by endogenous adenosine [J]. Cardiovasc Res,2005, 67(1):124-133.
13. Paillard M, Gomez L, Augeul L, et al. Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential [J]. J Mol Cell Cardiol,2009,46(6):902-909.
14. Reeve JL, Duffy AM,0'Brien T, et al. Don't lose heart-therapeutic value of apoptosis prevention in the treatment of cardiovascular disease [J]. J Cell Mol Med,2005,9:609-22.
15. Li Y, Cohen R. Caspase inhibitors and myocardial apoptosis[J]. Int Anesthesiol Clin,2005,43(2):77-89.
16. Adams JM, Cory S. The Bcl-2 protein family:arbiters of cell survival [J]. Science,1998,281(5381):1322-1326.
17. Honsch A, Theuring N, Ebner B, et al. Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-Ⅲ inhibition [J]. Basic Res Cardiol,2010,105(2):155-167.
18. Tsang A, Hausenloy DJ, Mocanu MM, et al. Post-conditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway [J]. Circ Res,2004,95(3):230-232.
19. Bopassa JC, Ferrera R, Gateau RO, et al. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning[J]. Cardiovasc Res,2006,69(1):178-185.
20. Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation [J]. Basic Res Cardiol, 2005,100:57-63.
21. Rossana Berti*, Anthony J Williams, John R Moffett, et al. Quantitative Real-Time RT-PCR Analysis of Inflammatory Gene Expression Associated With Ischemia-Reperfusion Brain Injury[J]. Journal of Cerebral Blood Flow & Metabolism,2002,22:1068-1079.
1. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020:Global Burden of Disease Study. Lancet,1997,349 (9046):1498-1504.
2. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemia myocardium [J]. Circulation,1986,74:1124-1136.
3. Zhao ZQ, Corvera JS, HalkosME, et al. Inhibition of myocardial injury by ischemic post-conditioning during reperfusion:comparison with ischemic preconditioning [J]. Am J Physiol Heart Circ Physiol,2003,285:H579-H588.
4. Tsang A, Hausenloy DJ, Mocanu MM, et al. Post-conditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway [J]. Circ Res,2004,95 (3):230-232.
5. Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways [J]. Am Coll Cardiol,2004,44 (5):1103-1110.
6.Kin H, Zhao ZQ, Sun HY, et al. Postconditioning attenuates myocardial ischemia reperfusion injury by inhibiting events in the early minutes of reperfusion[J]. Cardiovasc Res,2004,62(1):74-85.
7. Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation [J]. Basic Res Cardiol, 2005,100:57-63.
8. Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion[J]. J Cardiovasc Pharmacol Ther,2006,11 (1): 55-63.
9. Halkos ME, Kerendi F, Corvera JS, et al. Myocardial protection with postconditioning is not enhanced by ischemic preconditioning. Ann Thorac Surg,2004,78(3):961-969.
10.刘胜辉,霍玉娥,尹博英.缺血后处理对大鼠缺血/再灌注心肌髓过氧化物酶及细胞间粘附分子的影响[J].心血管康复医学杂志,2009,18(2)：107-109.
11. Bopassa JC, Ferrera R, Gateau RO, et al. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning[J]. Cardiovasc Res, 2006,69(1):178-185.
12. Argaud L, GateauRoesch 0, Raisky 0, et al. Postconditioning inhibits mitochondrial permeability transition[J]. Circulation,2005,111(2):194-197.
13.刘旭,徐平.心肌缺血再灌注损伤与细胞凋亡[J].中华实用中西医杂志,2005,18(18)：981-983.
14.石凤梧,张文立,刘苏等.猪心肌缺血后处理对心肌细胞凋亡及Bcl-2、Bax蛋白表达的影响[J].山东医药,2007,47(7)：15-16.
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