蛋白酶抑制剂乌司他丁对于创伤失血性休克兔保护作用的实验研究
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摘要
第一部分：乌司他丁对创伤失血性休克兔内源性血管活性物质的影响
目的 评价蛋白酶抑制剂乌司他丁对创伤失血性休克的治疗效果，并观察乌司他丁对内源性血管活性物质的影响。方法 30只新西兰白兔随机分为三组，对照组、创伤失血性休克组和创伤失血性休克乌司他丁治疗组，观察休克前后TXA_2和PGI_2ET和ADM两组内源性血管活性物质的动态变化及乌司他丁对它们的影响。结果 对照组的各种内源性血管活性物质的血浆浓度在整个实验期无明显变化。创伤失血性休克组和创伤失血性休克乌司他丁治疗组休克后ET、ADM和TXA_2的血浆浓度分别在不同的时相点较休克前有显著增高(p＜0.05)，其中乌司他丁治疗组的TXA_2和ET血浆浓度的增高均明显低于休克组(p＜0.05)。乌司他丁组的平均动脉压在复苏期较休克组有显著性增高(P＜0.05)。结论 内源性血管活性物质参与了创伤失血性休克的整个发展过程，并在休克过程中对血管舒缩及血液灌流起重要的调节作用，蛋白酶抑制剂乌司他丁可能通过抑制TXA_2和ET的升高，提高休克时的平均动脉压，并改善灌流。
第二部分：乌司他丁对创伤失血性休克兔肺损伤保护作用的研究
目的 观察蛋白酶抑制剂乌司他丁对创伤失血性休克兔细胞因子及黏附分子的影响，并探讨其对缺血再灌注肺损伤的保护作用。方法 30只新西兰白兔随机分为三组，对照组、创伤失血性休克组和创伤失血性休克乌司他丁治疗组，观察休克前后血清中细胞因子TNF-α、IL-8和sICAM-1的动态变化，并于复苏后4
Part 1 Effects of Ulinastatin on plasma levels of lipid humoral
factors in traumatic hemorrhagic shock in rabbits Objective To evaluate the effects of Ulinastatin, a protease inhibitor, on plasma levels of lipid humoral factors in traumatic hemorrhagic shock. Methods Thirty rabbits were randomly divided into three groups, control group, traumatic hemorrhagic shock group and ulinastatin-treated group. Blood was sampled at four time points: pre-shock, post-shock, as well as 2h and 4h after blood volume compensation. Plasma levels of ET, ADM and TXA2, PGI2 were measured. Results In control group, the plasma concentrations of the four lipid humoral factors showed elevated changes in the duration of experiment, but without statistic significance. And in the other two groups , plasma levels of ET, ADM and TXA2 were significantly higher at the following three observed points than those before shock(p<0.05), while plasma levels of ET and TXA2 in ulinastatin-treated group were significantly lower than that in traumatic shock group(p<0.05). Conclusion Ulinastatin possesses beneficial effects in treatment of traumatic hemorrhagic shock, which maybe related to the reduction of the release of ET and TXA2.
目的 评价蛋白酶抑制剂乌司他丁对创伤失血性休克的治疗效果，并观察乌司他丁对内源性血管活性物质的影响。方法 30只新西兰白兔随机分为三组，对照组、创伤失血性休克组和创伤失血性休克乌司他丁治疗组，观察休克前后TXA_2和PGI_2ET和ADM两组内源性血管活性物质的动态变化及乌司他丁对它们的影响。结果 对照组的各种内源性血管活性物质的血浆浓度在整个实验期无明显变化。创伤失血性休克组和创伤失血性休克乌司他丁治疗组休克后ET、ADM和TXA_2的血浆浓度分别在不同的时相点较休克前有显著增高(p＜0.05)，其中乌司他丁治疗组的TXA_2和ET血浆浓度的增高均明显低于休克组(p＜0.05)。乌司他丁组的平均动脉压在复苏期较休克组有显著性增高(P＜0.05)。结论 内源性血管活性物质参与了创伤失血性休克的整个发展过程，并在休克过程中对血管舒缩及血液灌流起重要的调节作用，蛋白酶抑制剂乌司他丁可能通过抑制TXA_2和ET的升高，提高休克时的平均动脉压，并改善灌流。
第二部分：乌司他丁对创伤失血性休克兔肺损伤保护作用的研究
目的 观察蛋白酶抑制剂乌司他丁对创伤失血性休克兔细胞因子及黏附分子的影响，并探讨其对缺血再灌注肺损伤的保护作用。方法 30只新西兰白兔随机分为三组，对照组、创伤失血性休克组和创伤失血性休克乌司他丁治疗组，观察休克前后血清中细胞因子TNF-α、IL-8和sICAM-1的动态变化，并于复苏后4
Part 1 Effects of Ulinastatin on plasma levels of lipid humoral
factors in traumatic hemorrhagic shock in rabbits Objective To evaluate the effects of Ulinastatin, a protease inhibitor, on plasma levels of lipid humoral factors in traumatic hemorrhagic shock. Methods Thirty rabbits were randomly divided into three groups, control group, traumatic hemorrhagic shock group and ulinastatin-treated group. Blood was sampled at four time points: pre-shock, post-shock, as well as 2h and 4h after blood volume compensation. Plasma levels of ET, ADM and TXA2, PGI2 were measured. Results In control group, the plasma concentrations of the four lipid humoral factors showed elevated changes in the duration of experiment, but without statistic significance. And in the other two groups , plasma levels of ET, ADM and TXA2 were significantly higher at the following three observed points than those before shock(p<0.05), while plasma levels of ET and TXA2 in ulinastatin-treated group were significantly lower than that in traumatic shock group(p<0.05). Conclusion Ulinastatin possesses beneficial effects in treatment of traumatic hemorrhagic shock, which maybe related to the reduction of the release of ET and TXA2.
引文
1. Oborin AN, Chuklin SN, Kobria TM. The prostaglandin I_2 and thromboxane A_2 content of the blood of dogs in the dynamic development of hemorrhagic shock [J]. Gematol Transfuziol 1992; 37: 25-27.
2. Aibi kM, Cook JA. Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxaneB2 production in human monocytes. Crit Care Med 1997; 25: 430-434.
3. Zaitsu M, Hamasaki Y, Tashiro K, et al. Ulinastatin, an elastase inhibitor, inhibits the increased mRNA expression of prostaglandin H2 synthase-type 2 in Kawasaki Diease, The Journal of Infection Diease 2000; 181: 1101-9.
4. Onizuka M, Miyauchi T, Mitsui K, et al. Plasma levels of endothelin-land thrombin-antithrombin complex in patients undergothing open chest operations. J Thorac Cardiovasc Surg 1993; 105: 559-560.
5. Edwards JD, Dovgan PS, Rowley JM, et al. Endothelin-1 levels in ischaemia, reperfusion and hemorrhagic shock in the canine infrarenal aortic revascularisation nodel [J]. Eur J Vasc Surg 1994; 8: 729-734.
6. Kitamura K, Kangawa K, Kawamoto M, et al. A novel hypotensive peptide isolated from human pheochromocytoma. Biophys Res Commun 1993; 192: 553-560.
7. Sugo S, Minamino N, Kangawa K, et al. Endothelial cells actively synthesize and secret adrenomedullin. Biophys Res Commun 1994; 201(1): 1160-1166.
8. Miura M, Sugiura T, Aimi Y. Effects of ulinastatin on PMNL and
vascular endothelial injury in patients undergoing open heart with CPB. Masui 1998 Jan; 47: 29-35.
9. Hiyama A, Takeda J, Kotate Y, et al. A human urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vase Anesth 1997 Aug; 11: 580-4.
10. Sheridan BC, Mcintyre RCJr, Moore EE, et al. Neutrophils mediate pulmonary vasomotor dysfunction in endotoxin-induced acute lung injury. J Trauma: Injury, Infection, Crit Care 1997; 42: 391-397.
11. Jiang JX, Bahrami S, Leichtfried G,et al. Kinetics of endotoxin and tunor necrosis factor apperance in portal and system circulation after hemorrhagic shock. Ann Surg 1995; 221:100-106.
12．朱华栋、周玉淑、于学忠等，创伤性休克后血浆内毒素、细胞因子、一氧化氮的动态变化及意义。中国现代医学杂志，2000；10：1—3。
13. Aihara T, Shiraishi M, Hiroyasu S, et al. Ulinastatin, a protease inhibitor, attenuates hepatic ischemia/reperfusion injury by downregulating TNF-α in the liver. Transplantation Proceedings 1998; 30: 3732-3734.
14. Metinko AP, Kunkel SL, Standiford TJ, et al. Anoxia-hyperoxia induce monocyt-derived interleukin-8. J Clin Invest 1992; 90: 791-798.
15. Churg A, Dai J, Zay K, et al. Alpha-1-antitrypsin and a broad-spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Laboratory
Investigation 2001; 81: 1119-2001.
16. Aosasa S, Ono S, Mochizuki H, et al. Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes. Shock 2001 Feb; 15: 101-105.
17. Sato Y, Ishikaw S, Otaki A, et al. Induction of acute-phase reactive substances during open-heart surgery and efficacy of ulinastatin, inhibiting cytokines and postoperative organ injury. Jpn J Thorac Cardiovasc Surg 2000; 48: 428-434.
18. Downey GP, Graham L, Fukushima T. Initial interaction of leukocytes within the microvasculature: Deformability, adhension, transmigration New Horizons 1995; 3: 219-228.
19. Dole NA, Bhagwan SD, Meek BB, et al. Neutrophil margination, sequestration and emigration in L-selectin mutant mice. J Clin Invest 1997; 99: 526-533.
20. Gearing AJH Newman W. Circulating adhension molecules in diease. Immunology today 1993; 14: 506-512.
21. Endo S, Inada K, Kasai T, et al. Levels of soluble adhesion molecules and cytokines in patients with septic multiple organ failure. J Inflamm 1996, 46: 212-21.
22. Kayal S, Jais JP, Aguini N, et al. Elevated circulating E-selectin, intercellular adhesion molecule-1 in patients with severe infection. Am J Respir Crit Care Med 1998; 157: 776-784.
23．赵擎莲，张春玲，黄子通等。重症败血症患者炎性介质水平对预后的影响。中国危重病急救医学2001；13：671-674。
24. Eppinger MJ, Lemmon G, Miller S, et al. The role of glutamine in skeletal muscle ischemia/reperfusion injury in the rat hind limb model. Am J Surg 1999; 178: 147-150.
25．罗武生，郭兆贵。用髓过氧化物酶法定量测定心肌组织中的中性白细胞。中国药理学通报1990；6：264-266。
26. Goldblum SE, Wu KM, Jay M. Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. J Appl Physiol 1985; 59: 1978-1985.
27. Carden D, Xiao F, Moak C, et al. Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins. Am J Physiol 1998; 275: H385-H392.
28. Springer TA. Adhesion receptors of the immune system. Nature 1990; 346: 425-434.
29. Strieter RM, Kunkel SL. Acute lung injury: the role of cytokines in the elicitation of neutrophils. J Investig Med 1994:42: 640-651.
30. Larson DF, Bowers M, Schechner HW, et al. Neutrophil activation during cardiopulmonary bypass in paediatric and adult patients. Perfusion 1996; 11: 21-27.
31. Miura M, Sugiura T, Aimi Y. Effects of ulinastatin on PMNL and vascular endothelial injury in patients undergoing open heart surgery with CPB. Masui 1998; 47: 29-35.
32. Hiyama A, Takeda J, Kotate Y, et al. Ahuman urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11: 580-584.
33. Hiyama A, Takeda J, Kotate Y, et al. Ahuman urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11: 580-584.
34. Hultberg B, The excrection of N-acetyl-β-glucosaminidase in glomerulonephritis, Clin Nephrol 1981; 15: 32-36.
35. Oshima N, Yamada T, Nakahara H, et al. Effect of ulinastatin on renal function and lactic acidosis during open-heart surgery: comparison with aprotinin. Kyobu Geka 1990; 43: 357-363.
36. Ueki M, Yokono S, Nogaya J, et al. Effects of ulinastatin on postoperative renal function after cardiopulmonary bypass. Masui 1995; 44: 691-697.
37. Yonoko S, Ueki M, Nakayo M, et al. Urinary excretion of ulinastatin and NAG afiercardiopulmonary bypass. Masui 1997;46: 388-392.
38. Ikeda T, Ikeda K, Ohmi A, et al. The influence of ulinastatin on renal function during anesthesia for renal transplantation. Masui 1994; 43: 516.
2. Aibi kM, Cook JA. Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxaneB2 production in human monocytes. Crit Care Med 1997; 25: 430-434.
3. Zaitsu M, Hamasaki Y, Tashiro K, et al. Ulinastatin, an elastase inhibitor, inhibits the increased mRNA expression of prostaglandin H2 synthase-type 2 in Kawasaki Diease, The Journal of Infection Diease 2000; 181: 1101-9.
4. Onizuka M, Miyauchi T, Mitsui K, et al. Plasma levels of endothelin-land thrombin-antithrombin complex in patients undergothing open chest operations. J Thorac Cardiovasc Surg 1993; 105: 559-560.
5. Edwards JD, Dovgan PS, Rowley JM, et al. Endothelin-1 levels in ischaemia, reperfusion and hemorrhagic shock in the canine infrarenal aortic revascularisation nodel [J]. Eur J Vasc Surg 1994; 8: 729-734.
6. Kitamura K, Kangawa K, Kawamoto M, et al. A novel hypotensive peptide isolated from human pheochromocytoma. Biophys Res Commun 1993; 192: 553-560.
7. Sugo S, Minamino N, Kangawa K, et al. Endothelial cells actively synthesize and secret adrenomedullin. Biophys Res Commun 1994; 201(1): 1160-1166.
8. Miura M, Sugiura T, Aimi Y. Effects of ulinastatin on PMNL and
vascular endothelial injury in patients undergoing open heart with CPB. Masui 1998 Jan; 47: 29-35.
9. Hiyama A, Takeda J, Kotate Y, et al. A human urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vase Anesth 1997 Aug; 11: 580-4.
10. Sheridan BC, Mcintyre RCJr, Moore EE, et al. Neutrophils mediate pulmonary vasomotor dysfunction in endotoxin-induced acute lung injury. J Trauma: Injury, Infection, Crit Care 1997; 42: 391-397.
11. Jiang JX, Bahrami S, Leichtfried G,et al. Kinetics of endotoxin and tunor necrosis factor apperance in portal and system circulation after hemorrhagic shock. Ann Surg 1995; 221:100-106.
12．朱华栋、周玉淑、于学忠等，创伤性休克后血浆内毒素、细胞因子、一氧化氮的动态变化及意义。中国现代医学杂志，2000；10：1—3。
13. Aihara T, Shiraishi M, Hiroyasu S, et al. Ulinastatin, a protease inhibitor, attenuates hepatic ischemia/reperfusion injury by downregulating TNF-α in the liver. Transplantation Proceedings 1998; 30: 3732-3734.
14. Metinko AP, Kunkel SL, Standiford TJ, et al. Anoxia-hyperoxia induce monocyt-derived interleukin-8. J Clin Invest 1992; 90: 791-798.
15. Churg A, Dai J, Zay K, et al. Alpha-1-antitrypsin and a broad-spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Laboratory
Investigation 2001; 81: 1119-2001.
16. Aosasa S, Ono S, Mochizuki H, et al. Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes. Shock 2001 Feb; 15: 101-105.
17. Sato Y, Ishikaw S, Otaki A, et al. Induction of acute-phase reactive substances during open-heart surgery and efficacy of ulinastatin, inhibiting cytokines and postoperative organ injury. Jpn J Thorac Cardiovasc Surg 2000; 48: 428-434.
18. Downey GP, Graham L, Fukushima T. Initial interaction of leukocytes within the microvasculature: Deformability, adhension, transmigration New Horizons 1995; 3: 219-228.
19. Dole NA, Bhagwan SD, Meek BB, et al. Neutrophil margination, sequestration and emigration in L-selectin mutant mice. J Clin Invest 1997; 99: 526-533.
20. Gearing AJH Newman W. Circulating adhension molecules in diease. Immunology today 1993; 14: 506-512.
21. Endo S, Inada K, Kasai T, et al. Levels of soluble adhesion molecules and cytokines in patients with septic multiple organ failure. J Inflamm 1996, 46: 212-21.
22. Kayal S, Jais JP, Aguini N, et al. Elevated circulating E-selectin, intercellular adhesion molecule-1 in patients with severe infection. Am J Respir Crit Care Med 1998; 157: 776-784.
23．赵擎莲，张春玲，黄子通等。重症败血症患者炎性介质水平对预后的影响。中国危重病急救医学2001；13：671-674。
24. Eppinger MJ, Lemmon G, Miller S, et al. The role of glutamine in skeletal muscle ischemia/reperfusion injury in the rat hind limb model. Am J Surg 1999; 178: 147-150.
25．罗武生，郭兆贵。用髓过氧化物酶法定量测定心肌组织中的中性白细胞。中国药理学通报1990；6：264-266。
26. Goldblum SE, Wu KM, Jay M. Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. J Appl Physiol 1985; 59: 1978-1985.
27. Carden D, Xiao F, Moak C, et al. Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins. Am J Physiol 1998; 275: H385-H392.
28. Springer TA. Adhesion receptors of the immune system. Nature 1990; 346: 425-434.
29. Strieter RM, Kunkel SL. Acute lung injury: the role of cytokines in the elicitation of neutrophils. J Investig Med 1994:42: 640-651.
30. Larson DF, Bowers M, Schechner HW, et al. Neutrophil activation during cardiopulmonary bypass in paediatric and adult patients. Perfusion 1996; 11: 21-27.
31. Miura M, Sugiura T, Aimi Y. Effects of ulinastatin on PMNL and vascular endothelial injury in patients undergoing open heart surgery with CPB. Masui 1998; 47: 29-35.
32. Hiyama A, Takeda J, Kotate Y, et al. Ahuman urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11: 580-584.
33. Hiyama A, Takeda J, Kotate Y, et al. Ahuman urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11: 580-584.
34. Hultberg B, The excrection of N-acetyl-β-glucosaminidase in glomerulonephritis, Clin Nephrol 1981; 15: 32-36.
35. Oshima N, Yamada T, Nakahara H, et al. Effect of ulinastatin on renal function and lactic acidosis during open-heart surgery: comparison with aprotinin. Kyobu Geka 1990; 43: 357-363.
36. Ueki M, Yokono S, Nogaya J, et al. Effects of ulinastatin on postoperative renal function after cardiopulmonary bypass. Masui 1995; 44: 691-697.
37. Yonoko S, Ueki M, Nakayo M, et al. Urinary excretion of ulinastatin and NAG afiercardiopulmonary bypass. Masui 1997;46: 388-392.
38. Ikeda T, Ikeda K, Ohmi A, et al. The influence of ulinastatin on renal function during anesthesia for renal transplantation. Masui 1994; 43: 516.
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