甘氨酸和丙酮酸对于局部缺血再灌注后的全身性保护作用

doi:10.3969/j.issn.1009-976X.2020.05.002

摘要/Abstract

摘要： 目的肠系膜上动脉缺血/再灌注可引起小肠局部损伤,甚至休克和心肺功能障碍。丙酮酸和甘氨酸已被证实对缺血再灌注损伤的局部组织器官有保护作用。本文研究其对小肠缺血再灌注之后全身血流动力学以及心肺功能等的影响。方法采用雄性SD大鼠,麻醉后建立血流动力学监测,建立肠系膜上动脉缺血90 min、再灌注120 min的模型。24只大鼠随机分为4组：丙酮酸组（再灌注前给予丙酮酸50 mg/kg,n=6）;甘氨酸组（再灌注前给予甘氨酸20 mg/kg,n=6）;林格组（再灌注前给予林格氏液1 mL,n=6）;假手术对照组（n=6）。术中记录平均动脉压、心脏指数、肺动脉压等,并估计循环血管阻力。采集动脉血进行血气分析和心肌标志物检测。观察结束后处死大鼠,取小肠、心脏、肺脏、肝脏进行组织学观察。结果丙酮酸和甘氨酸均能有效稳定血流动力学参数,维持较好的心功能。其中甘氨酸组复苏所需晶体体积显著少于对照组。丙酮酸、甘氨酸对代谢性酸中毒的抑制作用明显优于林格氏液（P<0.01）。甘氨酸组的小肠、肺、心、肝病理评分和中性粒细胞浸润明显低于林格组（P<0.01）,但仍高于假手术组（P<0.01）。丙酮酸组、甘氨酸组CKMB、肌钙蛋白I水平低于林格组,但仍高于假手术组（P<0.01）。结论丙酮酸和甘氨酸能在严重的局部缺血再灌注之后稳定全身循环状态,改善休克的复苏效果,既可减轻局部组织器官的缺血再灌注损伤,又可保护心肺等器官的功能。

关键词: 小肠缺血再灌注, 休克复苏, 心脏损伤, 肺损伤

Abstract: Objective Superior mesenteric artery （SMA） ischemia/reperfusion （I/R） may cause severe shock and cardiac and lung injury. Pyruvate and glycine have been demonstrated to protect the local tissue after I/R. In this study the effects of these substances on hemodynamics and cardiopulmonary functions are investigated. Methods After anesthesia male SD rats were operated to establish hemodynamic monitoring. Then SMA ischemia was applied for 90 minutes, by reperfusion for 120 minutes. During the reperfusion sufficient Ringer solution was infused for resuscitation. Totally 24 rats were divided into 4 groups： a control group with the sham operation （sham, n=6）; SMA I/R with pyruvate （50 mg/kg, n=6） or glycine （20 mg/kg, n=6） or equal amount of Ringer （1 mL, n=6） given before reperfusion. Mean arterial pressure （MAP）, cardiac index （CI）, pulmonary artery pressure （PAP） etc. were recorded and systemic vascular resistances （SVR） were calculated during the whole operation. Arterial blood samples were taken for gas analysis and myocardial markers. At the end of observation, the rats were sacrificed and the intestine, heart, lung, liver were harvested for histology study. Results Pyruvate and glycine both effectively stabilized the hemodynamic parameters and facilitated the maintenance of CI with less crystal volume for resuscitation than Ringer group. In Pyruvate and glycine groups the pathological score and neutrophil sequestration of the intestine, lung, heart and liver were significantly lower than Ringer group （P<0.01） but still higher than Sham group （P<0.01）. Metabolic acidosis was also inhibited in Pyruvate and Glycine groups than Ringer group （P<0.01）. Creatine kinase-MB and troponin I in Glycine and Pyruvate groups elevated less than the Ringer group but still more than the Sham group （P<0.05）. Conclusion After SMA I/R, pyruvate and glycine could improve the hemodynamic performances, facilitate the resuscitation for circulatory shock, and protect the local tissue against I/R injury and cardiopulmonary functions.

Key words: shock resuscitation, cardiac injury, intestinal ischemia/reperfusion, lung injury

中图分类号:

R-33

王萌, 傅钢兰, 杨艳旗. 甘氨酸和丙酮酸对于局部缺血再灌注后的全身性保护作用[J]. 岭南现代临床外科, 2020, 20(05): 550-556.

WANG Meng, FU Gang-lan, YANG Yan-qi. Protective effects of glycineand pyruvate after intestinal ischemia/reperfusion[J]. Lingnan Modern Clinics in Surgery, 2020, 20(05): 550-556.

参考文献

[1] Gundersen RY, Vaagenes P, Breivik T, et al.Glycine--an important neurotransmitter and cytoprotective agent[J]. Acta Anaesthesiol Scand, 2005, 49(8): 1108-1116.
[2] Zhong Z, Wheeler MD, Li XL, et al.L-glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent[J]. Current Opinion In Clinical Nutrition And Metabolic Care, 2003, 6(2): 229-240.
[3] Cerqueira NF, Hussni CA, Yoshida WB, et al.Systemic evaluation on ischemia and reperfusion injury of splanchnic organs in rats[J]. Acta Cir Bras, 2009, 24(4): 290-295.
[4] Habib MM, Hodgson HJ and Davidson BR. The role of glycine in hepatic ischemia-reperfusion injury[J]. Curr Pharm Des, 2006, 12(23): 2953-2967.
[5] Petrat F, Drowatzky J, Boengler K, et al.Protection from Glycine at Low Doses in Ischemia-Reperfusion Injury of the Rat Small Intestine[J]. Eur Surg Res, 2011, 46(4): 180-187.
[6] de Groot H and Rauen U. Ischemia-reperfusion injury: Processes in pathogenetic networks: A review[J]. Transplant Proc, 2007, 39(2): 481-484.
[7] Kristo G, Yoshimura Y, Niu JL, et al.The intermediary metabolite pyruvate attenuates stunning and reduces infarct size in in vivo porcine myocardium[J]. American Journal Of Physiology-Heart And Circulatory Physiology, 2004, 286(2): H517-H524.
[8] Petrat F, Ronn T and de Groot H. Protection by pyruvate infusion in a rat model of severe intestinal ischemia-reperfusion injury[J]. J Surg Res, 2011, 167(2): e93-e101.
[9] Wang XN, Hu XJ, Yang Y, et al.Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer's disease[J]. Exp Neurol, 2015, 271 145-154.
[10] Yi JS, Kim TY, Kim DK, et al.Systemic pyruvate administration markedly reduces infarcts and motor deficits in rat models of transient and permanent focal cerebral ischemia[J]. Neurobiol Dis, 2007, 26(1): 94-104.
[11] Mallet RT, Sun J, Knott EM, et al.Metabolic cardioprotection by pyruvate: Recent progress[J]. Exp Biol Med, 2005, 230(7): 435-443.
[12] Wang G, Zhao M and Wang EH. Effects of glycine and methylprednisolone on hemorrhagic shock in rats[J]. Chin Med J (Engl), 2004, 117(9): 1334-1341.
[13] Zhong Z, Enomoto N, Connor HD, et al.Glycine improves survival after hemorrhagic shock in the rat.[J]. Shock, 1999, 11 80-80.
[14] Hamburger T, Broecker-Preuss M, Hartmann M, et al.Effects of glycine, pyruvate, resveratrol, and nitrite on tissue injury and cytokine response in endotoxemic rats[J]. J Surg Res, 2013, 183(1): E7-E21.
[15] Yang SL, Koo DJ, Chaudry IH, et al.Glycine attenuates hepatocellular depression during early sepsis and reduces sepsis-induced mortality[J]. Crit Care Med, 2001, 29(6): 1201-1206.
[16] Wang M, Verhaegh R, Tsagakis K, et al.Impact of Acute Intestinal Ischemia and Reperfusion Injury on Hemodynamics and Remote Organs in a Rat Model[J]. Thorac Cardiovasc Surg, 2018, 66(1): 99-108.
[17] Vollmar B and Menger MD. Intestinal ischemia/reperfusion: microcirculatory pathology and functional consequences[J]. Langenbecks Arch Surg, 2011, 396(1): 13-29.
[18] Weinberg JM, Davis JA, Abarzua M, et al.Cytoprotective effects of glycine and glutathione against hypoxic injury to renal tubules[J]. J Clin Invest, 1987, 80(5): 1446-54.
[19] Petrat F, Boengler K, Schulz R, et al.Glycine, a simple physiological compound protecting by yet puzzling mechanism(s) against ischaemia-reperfusion injury: current knowledge[J]. Br J Pharmacol, 2012, 165(7): 2059-2072.
[20] Hoffmann K, Buchler MW, Schemmer P.Supplementation of amino acids to prevent reperfusion injury after liver surgery and transplantation - Where do we stand today?[J]. Clin Nutr, 2011, 30(2): 143-147.
[21] Tepaske R, Velthuis HT, Oudemans-van Straaten HM, et al. Glycine does not add to the beneficial effects of perioperative oral immune-enhancing nutrition supplements in high-risk cardiac surgery patients[J]. J Parenter Enteral Nutr, 2007, 31(3): 173-180.
[22] Schillinger W, Hunlich M, Sossalla S, et al.Intracoronary pyruvate in cardiogenic shock as an adjunctive therapy to catecholamines and intra-aortic balloon pump shows beneficial effects on hemodynamics[J]. Clin Res Cardiol, 2011, 100(5): 433-438.