丙泊酚对肺缺血再灌注大鼠肺上皮细胞凋亡影响的实验研究
摘要
目的探讨丙泊酚对肺脏缺血再灌注大鼠肺上皮细胞凋亡的影响。方法采用大鼠肺原位热缺血模型,缺血1h。170只大鼠随机分为缺血再灌注组(R组),丙泊酚再灌注组(P组)以及相同机械通气时间的假手术组(S组)。按照再灌注时间的不同,分别于缺血1h、再灌注0.5h、1h、2h、4h时间点(或假手术组相应时间点)测定各组动脉血氧分压(Pa02)、支气管肺泡灌洗液(BALF)中中性粒细胞( PMN)百分比、蛋白浓度,以及肺组织丙二醛(MDA)、超氧化物歧化酶(SOD)含量和肺湿干重比(W/D)。采用原位末端脱氧核苷酸转移酶(TdT)介导的dUTP缺口末端标记(TUNEL)技术,测定肺缺血再灌注下(或假手术组相应时间点)肺上皮细胞凋亡指数。结果在缺血1h时间点(或假手术组相应时间点)三组间各种指标无显著差异性(P>0.05)。再灌注后,与相同时点的S组相比,R组和P组的PMN百分比、蛋白浓度、MDA含量及凋亡指数均有所升高且具有显著差异性(P<0.05或P<0.01);而Pa02和SOD含量有所降低且具有显著差异性(P<0.05)。再灌注后,与相同时点的R组相比, P组的PMN百分比、蛋白浓度、MDA含量及凋亡指数均有所降低且具有显著差异性(P<0.05或P<0.01)。P组Pa02下降程度较R组小,但二者之间的差异并无统计学意义(P>0.05);而SOD含量在再灌注后较R组有所升高且在再灌注4h时具有显著差异性(P<0.05)。相关性分析显示,无论R组还是P组其凋亡指数与W/D均呈高度正相关(P<0.01)。
结论丙泊酚对大鼠缺血再灌注肺损伤具有保护作用,可能与其减少缺血再灌注时氧自由基的产生,抑制再灌注损伤肺组织中中性粒细胞的聚集以及抑制肺上皮细胞凋亡有关。
Objective To observe the relationship of propofol attenuating lung injury after reperfusion with apoptosis in rats. Methods The model of situ pulmonary hilum occlusion was applied and warm ischemia was undergone for 1 hour. 170 Sprague-Dawley rats were randomized into 3 groups: reperfusion group and reperfusion group with propofol infusion, as well as time-matched sham group. Neutrophil count percent, protein concentration in BALF and malondialdehyde (MDA), superoxide dismutase(SOD), Wet/Dry (W/D) ratio in lung tissue, arterial blood gas analysis were measured at the time of 1 hour after pulmonary ischemia and 0.5h,1h,2h , 4h after reperfusion (or at the same time in time-matched sham group),respectively. Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediate dUTP nick-end labeling (TUNEL) and apoptosis index were determined. Results There were no significant differences in all parameters in these groups at the time of 1 hour after pulmonary ischemia. Compared with time-matched sham group, neutrophil count percent and protein concentration in BALF, MDA, W/D ratio and apoptosis index in lung tissue increased significantly in reperfusion group and propofol group(P<0.05 or P<0.01), and SOD in lung tissue and PaO2 decreased significantly(P<0.05). Compared with time-matched reperfusion group, neutrophil count percent and protein concentration in BALF, MDA, W/D ratio and apoptosis index in lung tissue decreased significantly in the group with propofol infusion(P<0.05 or P<0.01). There was no significant difference in PaO2 between the reperfusion group and the group with propofol infusion (P>0.05), but there was a tendency of improvement. Compared with time-matched reperfusion group, there was a tendency of increase in SOD in lung tissue in the reperfusion group with propofol infusion and it increased significantly at the time of 4 hours after reperfusion (P<0.05). Correlation analysis showed that apoptosis index of reperfusion group and propofol group were direct correlation with W/D ratio of corresponding group. Conclusion Propofol can attenuate ischemia-reperfusion lung injury. As inhibiting neutrophil activation and oxygen free radical, inhibiting apoptosis is another mechanism of propofol in attenuating lung injury after reperfusion.
结论丙泊酚对大鼠缺血再灌注肺损伤具有保护作用,可能与其减少缺血再灌注时氧自由基的产生,抑制再灌注损伤肺组织中中性粒细胞的聚集以及抑制肺上皮细胞凋亡有关。
Objective To observe the relationship of propofol attenuating lung injury after reperfusion with apoptosis in rats. Methods The model of situ pulmonary hilum occlusion was applied and warm ischemia was undergone for 1 hour. 170 Sprague-Dawley rats were randomized into 3 groups: reperfusion group and reperfusion group with propofol infusion, as well as time-matched sham group. Neutrophil count percent, protein concentration in BALF and malondialdehyde (MDA), superoxide dismutase(SOD), Wet/Dry (W/D) ratio in lung tissue, arterial blood gas analysis were measured at the time of 1 hour after pulmonary ischemia and 0.5h,1h,2h , 4h after reperfusion (or at the same time in time-matched sham group),respectively. Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediate dUTP nick-end labeling (TUNEL) and apoptosis index were determined. Results There were no significant differences in all parameters in these groups at the time of 1 hour after pulmonary ischemia. Compared with time-matched sham group, neutrophil count percent and protein concentration in BALF, MDA, W/D ratio and apoptosis index in lung tissue increased significantly in reperfusion group and propofol group(P<0.05 or P<0.01), and SOD in lung tissue and PaO2 decreased significantly(P<0.05). Compared with time-matched reperfusion group, neutrophil count percent and protein concentration in BALF, MDA, W/D ratio and apoptosis index in lung tissue decreased significantly in the group with propofol infusion(P<0.05 or P<0.01). There was no significant difference in PaO2 between the reperfusion group and the group with propofol infusion (P>0.05), but there was a tendency of improvement. Compared with time-matched reperfusion group, there was a tendency of increase in SOD in lung tissue in the reperfusion group with propofol infusion and it increased significantly at the time of 4 hours after reperfusion (P<0.05). Correlation analysis showed that apoptosis index of reperfusion group and propofol group were direct correlation with W/D ratio of corresponding group. Conclusion Propofol can attenuate ischemia-reperfusion lung injury. As inhibiting neutrophil activation and oxygen free radical, inhibiting apoptosis is another mechanism of propofol in attenuating lung injury after reperfusion.
引文
1. Huang H, Yao T, Wang W, et al. Continuous ultrafiltration attenuates the pulmonary injury that follows open heart surgery with cardiopulmonary bypass. Ann Thorac Surg, 2003, 76(1):136-140.
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11. Eppinger MJ, Jones ML, Deeb GM, et al. Pattern of injury and the role of neutrophils in reperfusion injury of rat lung. J Surg Res, 1995, 58 (6):713-718.
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28. Punch J, Rees R, Cashmer B, et al. Acute lung injury following reperfusion after ischemia in the hind limbs of rats. J Trauma, 1991, 31(6): 760-5; discussion 765-7.
29. Beetsch JW, Park TS, Dugan LL, et al. Xanthine oxidase-derived superoxide causes reoxygenation injury of ischemic cerebral endothelial cells. Brain Res, 1998, 786(1-2): 89-95.
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31. Higgins RS, Letsou GV, Sanchez JA, et al. Improved ultrastructural lung preservation with prostaglandin E1 as donor pretreatment in a primate model of heart-lung transplantation. J Thorac Cardiovasc Surg, 1993, 105(6): 965-971.
32. Horiguchi T, Harada Y. The effect of protease inhibitor on reperfusion injury after unilateral pulmonary ischemia. Transplantation, 1993, 55(2): 254-258.
33. Murata T, Nakazawa H, Mori I, et al. Reperfusion after a two-hour period of pulmonary artery occlusion causes pulmonary necrosis. Am Rev Respir Dis, 1992, 146(4): 1048-1053.
34. Bart P Van Putte, Jozef Kesecioglu, Jeroen MH Hendriks, et al. Cellular infiltrates and injury evaluation in a rat model of warm pulmonary ischemia-reperfusion. Critical Care, 2005, 9: R1-R8.
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38. Takahashi K, Yang GH, Osanai K, et al. Lung tissue injury caused by oxidantant-antioxidant imbalance. Nippon Rinsho, 1999, 57 (9): 1988-1994.
39. Javadov SA, Lim KH, Kerr PM, et al. Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res, 2000, 45 (2): 360-369.
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1. Ware LB, Golden JA, Finkbeiner WE, et al. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med, 1999, 159(3):980-988.
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2. Haydock DA, Trulock EP, Kaiser LR, et al. Management of dysfunction in the transplanted lung: experience with 7 clinical cases. Washington University Lung Transplant Group. Ann Thorac Surg, 1992, 53 (4): 635-641.
3. Ware LB, Golden JA, Finkbeiner WE, et al. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med, 1999, 159(3):980-988.
4. Eppinger MJ, Deeb GM, Bolling SF, et al. Mediators of ischemia-reperfusion injury of rat lung. Am J Pathol, 1997, 150 (5): 1773–1784.
5. Chang DM, Hsu K, Ding YA, et al. Interleukin-1 in ischemia-Reperfusion acute lung injury. Am J Respir Crit Care Med, 1997, 156 (4 Pt 1):1230-1234.
6. Khimenko PL, Bagby GJ, Fuseler J, et al. Tumor necrosis factor-alpha in ischemia and reperfusion injury in rat lungs. J Appl Physiol, 1998, 85 (6): 2005–2011.
7. Moore TM, Khimenko P, Adkins WK, et al. Adhesion molecules contribute to ischemia and reperfusion-induced injury in the isolated rat lung. J Appl Physiol, 1995, 78 (6):2245-2252.
8. Farivar AS, Merry HE, Fica-Delgado MJ, et al. Interleukin-6 regulation of direct lung ischemia reperfusion injury.Ann Thorac Surg, 2006, 82(2):472-8.
9. Akao T, Takeyoshi I, Totsuka O, Arakawa K, et al. Effect of the free radical scavenger MCI-186 on pulmonary ischemia-reperfusion injury in dogs. J Heart Lung Transplant, 2006, 25(8):965-71.
10. Seibert AF, Hayner J, Taylor A, et al. Ischemia-reperfusion injury in the isolated rat lung. Role of flow and endogenous leukocytes. Am Rev Respir Dis, 1993, 147 (2), 270-275.
11. Eppinger MJ, Jones ML, Deeb GM, et al. Pattern of injury and the role of neutrophils in reperfusion injury of rat lung. J Surg Res, 1995, 58 (6):713-718.
12. Fischer S, Cassivi SD, Xavier A, et al. Cell death in human lung transplantation:apoptosis induction in human lungs during ischemia and after transplantation. Ann Surg, 2000,231(3): 424-431.
13. Fischer S, Maclean AA, Liu M, et al. Dynamic changes in apoptotic and necrotic cell death correlate with severity of ischemia-reperfusion injury in lung transplantation. Am J Respir Crit Care Med, 2000, 162 (5): 1932-1939.
14. Martin TR, Hagimoto N , Nakamura M , et al. Apoptosis and epithelial injury in the lungs. Proc Am Thorac Soc, 2005, 2 (3): 214-220.
15. Quadri SM, Segall L, de Perrot M, et al.Caspase inhibition improve ischemia- reperfusion injury after lung transplantation.Am J Transplant, 2005, 5 (2):292-299.
16.张诗海,姚尚龙.异丙酚在成人体外循环中抗氧化效应的研究.中华麻醉学杂志,2000,20(10):594-596.
17. Alvarez-Ayuso L, Calero P, Granado F, et al. Antioxidant effect of gamma- tocopherol supplied by propofol preparations (Diprivan) during ischemia-reperfusion in experimental lung transplantation. Transplant International , 2004, 17 (2): 71-77.
18. Murphy PG, Myers DS, Davies MT, et al. The antioxidant potential of propofol (2, 6-diisopropylphenol). Br J Anaesth, 1992, 68 (6): 613-618.
19. Tsuchiya M, Asada A, Kasahara E, et al. Antioxidant protection of propofol and its recycling in erythrocyte membranes.Am J Respir Crit Care Med, 2002, 165(1): 54-60.
20. Daskalopoulos R, Korcok J, Farhangkhgoee P, et al. Propofol protection of sodium-hydrogen exchange activity sustains glutamate uptake during oxidative stress. Anesth Analg, 2001, 93(5): 1199-204.
21. Hans P, Deby C, Deby-Dupont G, et al. Effect of propofol on in vitro lipid peroxidation induced by different free radical generating systems: a comparison with vitamin E. J Neurosurg Anesthesiol, 1996, 8(2):154-8.
22. Aarts L, van der Hee R, Dekker I, et al. The widely used anesthetic agent propofol can replace alpha-tocopherol as an antioxidant. FEBS Lett, 1995, 357(1):83-5.
23. Bardales RH, Xie SS, Hsu, et al. In situ DNA fragmentation assay for detection apoptosis in paraffin-embedded tissue sections. Technical considerations. Am J Clin Pathol, 1997, 107 (3):332-336.
24. Shimizu N, Miyai Y, Aoe M, et al. The effects of radical scavengers and leukocyte- depleted blood on reperfusion injury of extirpated rabbit lung. Tohoku J Exp Med, 1992, 166(3):321-9.
25. Jurmann MJ, Dammenhayn L, Schaefers HJ, et al. Pulmonary reperfusion injury: evidence for oxygen-derived free radical mediated damage and effects of different free radical scavengers. Eur J Cardiothorac Surg, 1990, 4(12): 665-70.
26. Paull DE, Keagy BA, Kron EJ, et al. Reperfusion injury in the lung preserved for 24 hours. Ann Thorac Surg, 1989, 47(2): 187-92.
27. Kil IS, Seok YM, Kim J, et al. Orchiectomy attenuates post-ischemic oxidative stress and ischemia/reperfusion injury in mice. A role for manganese superoxide dismutase. J Biol Chem, 2006, 281(29): 20349-56.
28. Punch J, Rees R, Cashmer B, et al. Acute lung injury following reperfusion after ischemia in the hind limbs of rats. J Trauma, 1991, 31(6): 760-5; discussion 765-7.
29. Beetsch JW, Park TS, Dugan LL, et al. Xanthine oxidase-derived superoxide causes reoxygenation injury of ischemic cerebral endothelial cells. Brain Res, 1998, 786(1-2): 89-95.
30. Eckhart L, Fischer H, Tschachler E,et al. Phylogenomics of caspase-activated DNA fragmentation factor. Biochem Biophys Res Commun, 2007,356(1): 293-9.
31. Higgins RS, Letsou GV, Sanchez JA, et al. Improved ultrastructural lung preservation with prostaglandin E1 as donor pretreatment in a primate model of heart-lung transplantation. J Thorac Cardiovasc Surg, 1993, 105(6): 965-971.
32. Horiguchi T, Harada Y. The effect of protease inhibitor on reperfusion injury after unilateral pulmonary ischemia. Transplantation, 1993, 55(2): 254-258.
33. Murata T, Nakazawa H, Mori I, et al. Reperfusion after a two-hour period of pulmonary artery occlusion causes pulmonary necrosis. Am Rev Respir Dis, 1992, 146(4): 1048-1053.
34. Bart P Van Putte, Jozef Kesecioglu, Jeroen MH Hendriks, et al. Cellular infiltrates and injury evaluation in a rat model of warm pulmonary ischemia-reperfusion. Critical Care, 2005, 9: R1-R8.
35. Roy N, Friehs I, Cowan DB, et al. Dopamine induces postischemic cardiomyocyteapoptosis in vivo: an effect ameliorated by propofol. Ann Thorac Surg, 2006, 82(6): 2192-9.
36. Luo T, Xia Z, Ansley DM, Ouyang J, et al. Propofol dose-dependently reduces tumor necrosis factor-alpha-Induced human umbilical vein endothelial cell apoptosis: effects on Bcl-2 and Bax expression and nitric oxide generation. Anesth Analg, 2005, 100(6): 1653-9.
37. Yagmurdur H, Aksoy M, Arslan M, et al. The effects of propofol and ketamine on gut mucosal epithelial apoptosis in rats after burn injury. Eur J Anaesthesiol, 2007, 24(1): 46-52.
38. Takahashi K, Yang GH, Osanai K, et al. Lung tissue injury caused by oxidantant-antioxidant imbalance. Nippon Rinsho, 1999, 57 (9): 1988-1994.
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