劉麗平 1 , 李玉民 2 , 石斌 1 , 李汛 2 , 周文策 2 , 李斌 1 , 張輝 2 , 劉濤 2 , 何雯婷 2
  • 1.蘭州大學第一醫(yī)院ICU科（蘭州 730000）;;
  • 2.蘭州大學第一醫(yī)院普外科（蘭州 730000）;

目的  探討前列腺素I2受體（IP）、血栓素A2受體（TP）與環(huán)氧合酶-2（COX-2）在肝移植缺血再灌注損傷中的相互作用及其機理。
方法  雄性SD大鼠隨機分為3組：正常對照組（n=16）、原位肝移植組（n=32）和尼美舒利（nimesulide）干預組（n=32），分別于手術(shù)后3、6、12 和24 h取血液和肝組織標本備檢。RT-PCR檢測肝組織中IP、TP及COX-2 mRNA表達； 免疫組化法檢測COX-2在肝組織中的定位及表達； HE染色確定組織損傷程度； 檢測血清ALT和AST變化。
結(jié)果  免疫組化染色結(jié)果顯示，原位肝移植組COX-2蛋白表達比正常對照組明顯增強，主要分布于匯管區(qū)肝竇內(nèi)皮細胞、肝細胞及巨噬細胞內(nèi)，尼美舒利干預組COX-2蛋白表達較原位肝移植組明顯減弱。 原位肝移植組中IP mRNA、TP mRN及COX-2 mRNA表達水平均比正常對照組明顯升高，IP/TP比值也明顯升高（P＜0.05）。 尼美舒利干預組IP mRNA和TP mRNA表達水平（術(shù)后6及12 h）比原位肝移植組明顯降低（P＜0.05），IP/TP比值手術(shù)后3、6及24 h較原位肝移植組降低（P＜0.05）； COX-2 mRNA表達水平在術(shù)后6、12及24 h低于原位肝移植組（P＜0.05）。HE染色見原位肝移植組肝損傷明顯，尼美舒利干預組肝損害較原位肝移植組明顯減輕； 血清中各時點AST和3、6及12 h的ALT在原位肝移植組明顯增高于其他2組（P＜0.05），且均在再灌注后6 h達峰值。
結(jié)論  IP/TP的平衡在肝移植缺血再灌注損傷中具有重要作用，抑制COX-2的表達可通過改善IP/TP的失衡從而減輕肝移植缺血再灌注損傷。

引用本文： 劉麗平,李玉民,石斌,李汛,周文策,李斌,張輝,劉濤,何雯婷. 環(huán)氧合酶-2在大鼠肝移植缺血再灌注損傷中對IP/TP的影響. 中國普外基礎(chǔ)與臨床雜志, 2009, 16(7): 534-539. doi: 復制

1. Fondevila C, Busuttil RW, KupiecWeglinski JW. Hepatic ischemia/reperfusion injury-a fresh look [Ｊ]. Exp Mol Pathol, 2003; 74(2): 8693.
2. Guo Y, Bao W, Wu WJ, et al. Evidence for an essential role of cyclooxygenase2 as a mediator of the late phase of ischemic preconditioning in mice [Ｊ]. Basic Res Cardiol, 2000； 95(6): 479484.
3. 李斌， 李玉民， 李汛， 等. 環(huán)氧合酶2對膿毒癥大鼠肝損傷的影響 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2008； 15（4）： 266270.
4. 涂兵， 嚴律南， 劉智敏. 缺血預處理對大鼠移植肝臟缺血再灌注損傷的保護作用 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2002； 9（2）： 8992.
5. 曹曉飛， 張峰， 張偉， 等. PPARγ激動劑15dPGJ2在大鼠肝臟缺血再灌注損傷中的保護作用及機理 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2008； 15（4）： 258261.
6. 李濤， 唐華美， 孫星， 等. “二袖套法”大鼠原位肝移植的技術(shù)改進 [Ｊ]. 中國普通外科雜志, 2005； 14（7）: 486488.
7. Kopff M, Kopff A, Kowalczyk E. [The effect of nonsteroidal antiinflammatory drugs on oxidative/antioxidative balance] [Ｊ]. Pol Merkur Lekarski, 2007; 23(135): 184187.
8. Nanji AA, Miao L, Thomas P, et al. Enhanced cyclooxygenase2 gene expression in alcoholic liver disease in the rat [Ｊ]. Gastroenterology, 1997; 112(3): 943951.
9. Ganey PE, Barton YW, Kinser S, et al. Involvement of cyclooxygenase2 in the potentiation of allyl alcoholinduced liver injury by bacterial lipopolysaccharide [Ｊ]. Toxicol Appl Pharmacol, 2001; 174(2): 113121.
10. Mathurin P, Deng QG, Keshavarzian A, et al. Exacerbation of alcoholic liver injury by enteral endotoxin in rats [Ｊ]. Hepatology, 2000; 32(5): 10081017.
11. Hamada T, Tsuchihashi S, Avanesyan A, et al. Cyclooxygenase2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury [Ｊ]. J Immunol, 2008; 180(3): 18431853.
12. Ozturk H, Gezici A, Ozturk H. The effect of celecoxib, a selective COX2 inhibitor, on liver ischemia/reperfusioninduced oxidative stress in rats [Ｊ]. Hepatol Res, 2006; 34(2): 7683.
13. Bolli R, Shinmura K, Tang XL, et al. Discovery of a new function of cyclooxygenase (COX)2: COX2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning [Ｊ]. Cardiovasc Res, 2002; 55(3): 506519.
14. Tsukada K, Hasegawa T, Tsutsumi S, et al. Roles of cyclooxygenase2 in tissue injury during hemorrhagic shock [Ｊ]. Shock, 2000; 13(5): 392396.
15. Hei ZQ, Huang HQ, Luo CF, et al. Changes of nitric oxide and endothelin, thromboxane A2 and prostaglandin in cirrhotic patients undergoing liver transplantation [Ｊ]. World J Gastroenterol， 2006; 12(25): 40494051.
16. Wilson SJ, Smyth EM. Internalization and recycling of the human prostacyclin receptor is modulated through its isoprenylationdependent interaction with the subunit of cGMP phosphodiesterase 6 [Ｊ]. J Biol Chem, 2006; 281(17): 1178011786.
17. Mochizuki M, Ishii Y, Itoh K, et al. Role of 15deoxy △12,14 prostaglandin J2 and Nrf2 pathways in protection against acute lung injury [Ｊ]. Am J Respir Crit Care Med, 2005; 171(11): 12601266.
18. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2 [Ｊ]. Science, 2002; 296(5567): 539541.
19. Hirata T, Kakizuka A, Ushikubi F, et al. Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder [Ｊ]. J Clin Invest, 1994; 94(4): 16621667.
20. Kobayashi T, Tahara Y, Matsumoto M, et al. Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoEdeficient mice [Ｊ]. J Clin Invest, 2004; 114(6): 784794.
21. Egan KM, Wang M, Fries S, et al. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase2 inhibition combined with thromboxane receptor antagonism [Ｊ]. Circulation, 2005; 111(3): 334342.
22. Bachschmid M, Thurau S, Zou MH, et al. Endothelial cell activation by endotoxin involves superoxide/NOmediated nitration of prostacyclin synthase and thromboxane receptor stimulation [Ｊ]. FASEB J, 2003; 17(8): 914916.
23. Zou MH, Bachschmid M. Hypoxiareoxygenation triggers coronary vasospasm in isolated bovine coronary arteries via tyrosine nitration of prostacyclin synthase [Ｊ]. J Exp Med, 1999； 190(1): 135139.
24. Gendron ME, Thorin E. A change in the redox environment and thromboxane A2 production precede endothelial dysfunction in mice [Ｊ]. Am J Physiol Heart Circ Physiol, 2007; 293(4): H2508H2515.
  1. 1. Fondevila C, Busuttil RW, KupiecWeglinski JW. Hepatic ischemia/reperfusion injury-a fresh look [Ｊ]. Exp Mol Pathol, 2003; 74(2): 8693.
  2. 2. Guo Y, Bao W, Wu WJ, et al. Evidence for an essential role of cyclooxygenase2 as a mediator of the late phase of ischemic preconditioning in mice [Ｊ]. Basic Res Cardiol, 2000； 95(6): 479484.
  3. 3. 李斌， 李玉民， 李汛， 等. 環(huán)氧合酶2對膿毒癥大鼠肝損傷的影響 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2008； 15（4）： 266270.
  4. 4. 涂兵， 嚴律南， 劉智敏. 缺血預處理對大鼠移植肝臟缺血再灌注損傷的保護作用 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2002； 9（2）： 8992.
  5. 5. 曹曉飛， 張峰， 張偉， 等. PPARγ激動劑15dPGJ2在大鼠肝臟缺血再灌注損傷中的保護作用及機理 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2008； 15（4）： 258261.
  6. 6. 李濤， 唐華美， 孫星， 等. “二袖套法”大鼠原位肝移植的技術(shù)改進 [Ｊ]. 中國普通外科雜志, 2005； 14（7）: 486488.
  7. 7. Kopff M, Kopff A, Kowalczyk E. [The effect of nonsteroidal antiinflammatory drugs on oxidative/antioxidative balance] [Ｊ]. Pol Merkur Lekarski, 2007; 23(135): 184187.
  8. 8. Nanji AA, Miao L, Thomas P, et al. Enhanced cyclooxygenase2 gene expression in alcoholic liver disease in the rat [Ｊ]. Gastroenterology, 1997; 112(3): 943951.
  9. 9. Ganey PE, Barton YW, Kinser S, et al. Involvement of cyclooxygenase2 in the potentiation of allyl alcoholinduced liver injury by bacterial lipopolysaccharide [Ｊ]. Toxicol Appl Pharmacol, 2001; 174(2): 113121.
  10. 10. Mathurin P, Deng QG, Keshavarzian A, et al. Exacerbation of alcoholic liver injury by enteral endotoxin in rats [Ｊ]. Hepatology, 2000; 32(5): 10081017.
  11. 11. Hamada T, Tsuchihashi S, Avanesyan A, et al. Cyclooxygenase2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury [Ｊ]. J Immunol, 2008; 180(3): 18431853.
  12. 12. Ozturk H, Gezici A, Ozturk H. The effect of celecoxib, a selective COX2 inhibitor, on liver ischemia/reperfusioninduced oxidative stress in rats [Ｊ]. Hepatol Res, 2006; 34(2): 7683.
  13. 13. Bolli R, Shinmura K, Tang XL, et al. Discovery of a new function of cyclooxygenase (COX)2: COX2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning [Ｊ]. Cardiovasc Res, 2002; 55(3): 506519.
  14. 14. Tsukada K, Hasegawa T, Tsutsumi S, et al. Roles of cyclooxygenase2 in tissue injury during hemorrhagic shock [Ｊ]. Shock, 2000; 13(5): 392396.
  15. 15. Hei ZQ, Huang HQ, Luo CF, et al. Changes of nitric oxide and endothelin, thromboxane A2 and prostaglandin in cirrhotic patients undergoing liver transplantation [Ｊ]. World J Gastroenterol， 2006; 12(25): 40494051.
  16. 16. Wilson SJ, Smyth EM. Internalization and recycling of the human prostacyclin receptor is modulated through its isoprenylationdependent interaction with the subunit of cGMP phosphodiesterase 6 [Ｊ]. J Biol Chem, 2006; 281(17): 1178011786.
  17. 17. Mochizuki M, Ishii Y, Itoh K, et al. Role of 15deoxy △12,14 prostaglandin J2 and Nrf2 pathways in protection against acute lung injury [Ｊ]. Am J Respir Crit Care Med, 2005; 171(11): 12601266.
  18. 18. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2 [Ｊ]. Science, 2002; 296(5567): 539541.
  19. 19. Hirata T, Kakizuka A, Ushikubi F, et al. Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder [Ｊ]. J Clin Invest, 1994; 94(4): 16621667.
  20. 20. Kobayashi T, Tahara Y, Matsumoto M, et al. Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoEdeficient mice [Ｊ]. J Clin Invest, 2004; 114(6): 784794.
  21. 21. Egan KM, Wang M, Fries S, et al. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase2 inhibition combined with thromboxane receptor antagonism [Ｊ]. Circulation, 2005; 111(3): 334342.
  22. 22. Bachschmid M, Thurau S, Zou MH, et al. Endothelial cell activation by endotoxin involves superoxide/NOmediated nitration of prostacyclin synthase and thromboxane receptor stimulation [Ｊ]. FASEB J, 2003; 17(8): 914916.
  23. 23. Zou MH, Bachschmid M. Hypoxiareoxygenation triggers coronary vasospasm in isolated bovine coronary arteries via tyrosine nitration of prostacyclin synthase [Ｊ]. J Exp Med, 1999； 190(1): 135139.
  24. 24. Gendron ME, Thorin E. A change in the redox environment and thromboxane A2 production precede endothelial dysfunction in mice [Ｊ]. Am J Physiol Heart Circ Physiol, 2007; 293(4): H2508H2515.