抑肽酶在体外循环再灌注损伤中的抗炎作用
摘要
前言
体外循环诱发全身炎症反应与术后器官功能失调相关，它能引起术后的多种并发症，如心律失常、心力衰竭等。全身炎症反应包括循环中白细胞粘附到微血管内皮和以后的白细胞游出。内皮细胞激活是全身炎症反应的重要环节。目前认为内皮细胞的激活可分两个时相：第一个时相主要是补体活性成分诱发的快速相；体外循环时补体活性成分C_(5a)水平的提高与内皮细胞激活快速相的发生密切相关。C_(5a)是内皮细胞表达粘附分子P-选择素的激动剂，而P-选择素在内皮细胞激活时能迅速经细胞排列作用表达于内皮细胞表面，触发PMN在内皮细胞表面的粘附反应。PMN表达CD_(11b)／CD_(18)等粘附分子，而CD_(11b)／CD_(18)可与内皮细胞表面的细胞间粘附分子-1(ICAM-1)相结合。C_(5a)还能活化血小板和单核细胞，促进细胞因子等炎症介质的释放及PMN与内皮细胞的粘附。可提高内皮细胞对肿瘤坏死因子(TNF-α)等炎症介质的敏感性，增进PMN的粘附反应。第二个时相是细胞因子、脂多糖及炎症介质等与内皮细胞表面的特异性受体结合，经细胞内信号传导通路增加E-选择素、ICAM-1、VCAM-1等基因表达的过程，其中NFκB-IKB复合物是调节上述基因表达主要的翻译调节因子。NFκB通常与胞浆中的抑制蛋白IKB结合处于无活性状态，但能对各种外在刺激发生反应而激活。激活后NFκB就转移至细胞核内，并与相应的DNA片段结合，改变基因转录结构的构象，促进活化基因的转录。这个时相称延迟相。
抑肽酶是一种非特异的丝氨酸蛋白酶抑制剂，现已广泛应用在体外循环术后的止血，它对血小板的保护作用已被人们所接受。
本实验通过细胞因子’INF－a、IL－6及粘附分子 SICAM－1在体
外循环过程中的变化分析体外循环中的炎症反应及抑肽酶应用后
根据三项指标的变化情况来推断抑肽酶的抗炎作用。
实验材料与方法
通过选取200上 上002J的27例瓣膜置换术病人，年龄在
34－71岁之间，心功能在 2－3级，肝、肾功能、凝血功能、白细胞
计数及分属在正常范围。将它们随机分成两组，常规麻醉、手术，
术前、术中、术后常规用药。采用膜肺，中度低温p6－28℃L平
均动脉压维持在60－80rnmHg，转流中血红蛋白在70－80g／l，灌
注指数为Z4－2．6ndAfof。预充液为平衡液和血定安，心肌保护
采用主动脉根部灌注冷钾停跳液，心肌局部低温。实验组于全麻、
穿刺成功后，将 10 X 56单位抑肽酶加人生理盐水中静脉输人，其
余 10 X 56单位加人体外循环机中。对照组不用抑肽酶，其余同
实验组。
分另于缩、挠动脉穿刺成功后；阻断升主动脉；停机及术后
24小时从挠动脉抽取动脉血4Inl，加肝素抗凝。其中0．SInl送检
验中心化验血常规，余下部分在2400转／秒的离心机离心20分
钟，取上清液存于一20℃冰箱中保存。
待标本收集完成后，用ELISA方法测定SICAM习。用放射免
疫方法检测IL－6、TNF一队所有数据均用红细胞压积较正。数
据以XLS表示，先分别进行完全随机设计的多样本均数比较及
两两比较，再分别进行两组间样本均数比较，检验水平 a二0．05。
结 果
两组病的年龄、体重、手术时间、从手术开始至升主动脉阻断
·二·
时间、体外循环并行时间、主动脉阻断时间无显著性差异h＞0．
05人每组病人的TNF一队IL－6和SICAM叫水平在阻断时、停
机后、术后24小时均较CPB前增高，且呈逐渐上升趋势，到24 ／J＼
时达到高峰。它们之间两两比较差异有显著性肿＜0．05人实验
组与对照组在 CPB前的三项指标无明显差异师＞0．05人而对照
组的三项指标在阻断时、停机后、术后24小时与实验组在同一水
平比较可观察到明显升高，两组间有为显著性差异h＜队 05人
讨 论
心脏外科手术后心肌缺血再灌注损伤是一种急性炎症反应，
激活的淋巴细胞和内皮细胞在这一过程中起着决定性作用。我们
的实验通过三项指标来观察体外循环过程中的炎症反应。观察到
H项指标在体外循环后和术后24小时明显较术前升高，说明了体
外循环后可以造成全身炎症反应。
’INF－a，是一种多肽细胞因子，主要由激活的单核及巨噬细
胞产生，其半衰期短，以分泌型发挥其主要生物学作用。TNF－a
对多种组织器具有生物学作用，血管内皮细胞是其作用的主靶细
胞之一。TNF－a在免疫调节、增强炎症反应以及由此引发的组
织破坏、抗瘤和组织代谢等方面具有广泛的生物学作用。许多研
究报道CPB中和术后TNF－a水平增加，这与CPB过程中由于手
术的激刺，中性粒细胞与管道接触激活，手术过程中局部组织缺
血，循环血内毒素增加，特别是肠道低灌注造成内毒素进人循环，
导致中性粒细胞、单核细胞的激活致使大量的TNF－a释放人血，
造成血中TNF－a升高。
IL－6是由 184个氨基酸组成的糖蛋白，可由多种细胞产生，
包括单就巨噬细胞J细胞J细胞、成纤维细胞、内皮细胞等产
生。IL－6不仅与其它细胞因子一样，在局部起作用，而病理状态
Preface
Cardiopulmonary bypass surgery is often accompanied by a systemic inflammatory response, which can cause postoperaterateve complications , lengthened duration of hospital stay, and in the morst case scenario, multiole organ failure, the etiology of this inflammatory response has been trace to the stress of surgery and contact activation of platelets and leuckocyteswithin the bypass circuit, which leads to an increase in arvulating cytokine levels such as tumor necrosis factor (TNF -α) , interleukin - 1, interliukin - 6, and interliukin - 8. Inflammatory eytokines in turn cause endothelial cell ( EC) activation and exprecesion of vascular adhesion molecules involved in recruitment of leukocytes to sites of inflammation or tissue injury.
Tree distinct phase have been described ( 1 ) initial attachment and roUing of leuckcytes along the vessel well. ( 2 ) firm adhesion , and ( 3 ) transmigration into the extravascular tissue. Aprotinin is a nonspecific serine protease inhibitor that has been used extensively in cardiac operations, it possesesbroad hemostatic properties that mediated by blocking pathways of complement activation and fibronolysis as well as by inhibiting the action of proteinases, such as trypsin, plasmin , ans kallikrein . we conducted this study to investigate whether aprotinin could exert anti - inflammatory effects.
Materials and methods
wenty - seven patients who underwent heart valve replacement from October 1,2001 ,to March 10,2002 were randomized in double - blind fashion into two groups: control group ( n =11) and aprotinin group (n = 16) , Aprotinin was given at 11200u during CPB in the aprotinin group. Exclusion criteria were impaired renal function, advanced hepatic dysfunction, and hematologic disease. The aprotinin group received 560u in 20 minute before the skin incision, 560u in the priming solution of the extracorporeal circuit, and continuors infusion during the operation. The control group didnt receive aprotinin. The anesthetic was standardized: each patient was premedicated with intramuscular scopolamine (0. 5mg) , intramuscular morphine (0. Img/ kg). Anesthesia was induced with fentanyl(0.02mg/kg) and midazo-lam(0. 15mg/kg) in patients . muscle relaxation was obtained with pancuronium bromide (0.1mg/kg). Anesthesia was maintained with fentanyl(up to o. o5mg/kg) , an infusion of midaxolam(0. 1 -0.2mg/ kg/h) in patient and is
oflurane and pancuronium as needed. All patients were operated on through a median sternotomy. Before aortic cannulation, porcine mucous heparin(3mg/kg) was injected, and further heparin was administered to maintain a kaolinactivated coagulation time above 480 seconds. A hollow - fiber membrane oxygenator was used, and the priming solution of the circuit consisted of 1750 ml of a balanced crystalloid/colloid. Nonpulsatile blood flow was obtained with a roller pump(2.0-2.41/min/itf ) . Blood temperature was kept between 32℃ and 35℃. myocardial protection during aortic cross-clamping was achieved with the Buckberg method of blood cardiople-
gia. The total dose of heparin administered during CPB was reversed with protamine sulfate(ratio 1:1). After anesthesia was induced, we performed radial puncture. We collected the blood as four times: the first sample was 4ml arterial blood which was drawed from radial after radial puncture. The blood was anti - cogulation with heparin. 0.5ml blood was sent to the center of check to analysis the blood routine. 3. 5ml blood was centufugated at 2400 rpm. The upper plasm was drawed and store in - 20℃. The second sample was collected during aortic crossclamping. The method was same as the first. The third sample was collected at sloping inventory. After operation the fourth sample was done. The method was as the first.
When we fimished the sample. sICAM - 1 was determinated in ELISA. IL - 6 and TNF - awas detected by radio - immunity analysis. All data were expressed as X± S. All data were analyzed by T test (a =0.05) .
Results
There was no significant differece in age, body weight, operation
体外循环诱发全身炎症反应与术后器官功能失调相关，它能引起术后的多种并发症，如心律失常、心力衰竭等。全身炎症反应包括循环中白细胞粘附到微血管内皮和以后的白细胞游出。内皮细胞激活是全身炎症反应的重要环节。目前认为内皮细胞的激活可分两个时相：第一个时相主要是补体活性成分诱发的快速相；体外循环时补体活性成分C_(5a)水平的提高与内皮细胞激活快速相的发生密切相关。C_(5a)是内皮细胞表达粘附分子P-选择素的激动剂，而P-选择素在内皮细胞激活时能迅速经细胞排列作用表达于内皮细胞表面，触发PMN在内皮细胞表面的粘附反应。PMN表达CD_(11b)／CD_(18)等粘附分子，而CD_(11b)／CD_(18)可与内皮细胞表面的细胞间粘附分子-1(ICAM-1)相结合。C_(5a)还能活化血小板和单核细胞，促进细胞因子等炎症介质的释放及PMN与内皮细胞的粘附。可提高内皮细胞对肿瘤坏死因子(TNF-α)等炎症介质的敏感性，增进PMN的粘附反应。第二个时相是细胞因子、脂多糖及炎症介质等与内皮细胞表面的特异性受体结合，经细胞内信号传导通路增加E-选择素、ICAM-1、VCAM-1等基因表达的过程，其中NFκB-IKB复合物是调节上述基因表达主要的翻译调节因子。NFκB通常与胞浆中的抑制蛋白IKB结合处于无活性状态，但能对各种外在刺激发生反应而激活。激活后NFκB就转移至细胞核内，并与相应的DNA片段结合，改变基因转录结构的构象，促进活化基因的转录。这个时相称延迟相。
抑肽酶是一种非特异的丝氨酸蛋白酶抑制剂，现已广泛应用在体外循环术后的止血，它对血小板的保护作用已被人们所接受。
本实验通过细胞因子’INF－a、IL－6及粘附分子 SICAM－1在体
外循环过程中的变化分析体外循环中的炎症反应及抑肽酶应用后
根据三项指标的变化情况来推断抑肽酶的抗炎作用。
实验材料与方法
通过选取200上 上002J的27例瓣膜置换术病人，年龄在
34－71岁之间，心功能在 2－3级，肝、肾功能、凝血功能、白细胞
计数及分属在正常范围。将它们随机分成两组，常规麻醉、手术，
术前、术中、术后常规用药。采用膜肺，中度低温p6－28℃L平
均动脉压维持在60－80rnmHg，转流中血红蛋白在70－80g／l，灌
注指数为Z4－2．6ndAfof。预充液为平衡液和血定安，心肌保护
采用主动脉根部灌注冷钾停跳液，心肌局部低温。实验组于全麻、
穿刺成功后，将 10 X 56单位抑肽酶加人生理盐水中静脉输人，其
余 10 X 56单位加人体外循环机中。对照组不用抑肽酶，其余同
实验组。
分另于缩、挠动脉穿刺成功后；阻断升主动脉；停机及术后
24小时从挠动脉抽取动脉血4Inl，加肝素抗凝。其中0．SInl送检
验中心化验血常规，余下部分在2400转／秒的离心机离心20分
钟，取上清液存于一20℃冰箱中保存。
待标本收集完成后，用ELISA方法测定SICAM习。用放射免
疫方法检测IL－6、TNF一队所有数据均用红细胞压积较正。数
据以XLS表示，先分别进行完全随机设计的多样本均数比较及
两两比较，再分别进行两组间样本均数比较，检验水平 a二0．05。
结 果
两组病的年龄、体重、手术时间、从手术开始至升主动脉阻断
·二·
时间、体外循环并行时间、主动脉阻断时间无显著性差异h＞0．
05人每组病人的TNF一队IL－6和SICAM叫水平在阻断时、停
机后、术后24小时均较CPB前增高，且呈逐渐上升趋势，到24 ／J＼
时达到高峰。它们之间两两比较差异有显著性肿＜0．05人实验
组与对照组在 CPB前的三项指标无明显差异师＞0．05人而对照
组的三项指标在阻断时、停机后、术后24小时与实验组在同一水
平比较可观察到明显升高，两组间有为显著性差异h＜队 05人
讨 论
心脏外科手术后心肌缺血再灌注损伤是一种急性炎症反应，
激活的淋巴细胞和内皮细胞在这一过程中起着决定性作用。我们
的实验通过三项指标来观察体外循环过程中的炎症反应。观察到
H项指标在体外循环后和术后24小时明显较术前升高，说明了体
外循环后可以造成全身炎症反应。
’INF－a，是一种多肽细胞因子，主要由激活的单核及巨噬细
胞产生，其半衰期短，以分泌型发挥其主要生物学作用。TNF－a
对多种组织器具有生物学作用，血管内皮细胞是其作用的主靶细
胞之一。TNF－a在免疫调节、增强炎症反应以及由此引发的组
织破坏、抗瘤和组织代谢等方面具有广泛的生物学作用。许多研
究报道CPB中和术后TNF－a水平增加，这与CPB过程中由于手
术的激刺，中性粒细胞与管道接触激活，手术过程中局部组织缺
血，循环血内毒素增加，特别是肠道低灌注造成内毒素进人循环，
导致中性粒细胞、单核细胞的激活致使大量的TNF－a释放人血，
造成血中TNF－a升高。
IL－6是由 184个氨基酸组成的糖蛋白，可由多种细胞产生，
包括单就巨噬细胞J细胞J细胞、成纤维细胞、内皮细胞等产
生。IL－6不仅与其它细胞因子一样，在局部起作用，而病理状态
Preface
Cardiopulmonary bypass surgery is often accompanied by a systemic inflammatory response, which can cause postoperaterateve complications , lengthened duration of hospital stay, and in the morst case scenario, multiole organ failure, the etiology of this inflammatory response has been trace to the stress of surgery and contact activation of platelets and leuckocyteswithin the bypass circuit, which leads to an increase in arvulating cytokine levels such as tumor necrosis factor (TNF -α) , interleukin - 1, interliukin - 6, and interliukin - 8. Inflammatory eytokines in turn cause endothelial cell ( EC) activation and exprecesion of vascular adhesion molecules involved in recruitment of leukocytes to sites of inflammation or tissue injury.
Tree distinct phase have been described ( 1 ) initial attachment and roUing of leuckcytes along the vessel well. ( 2 ) firm adhesion , and ( 3 ) transmigration into the extravascular tissue. Aprotinin is a nonspecific serine protease inhibitor that has been used extensively in cardiac operations, it possesesbroad hemostatic properties that mediated by blocking pathways of complement activation and fibronolysis as well as by inhibiting the action of proteinases, such as trypsin, plasmin , ans kallikrein . we conducted this study to investigate whether aprotinin could exert anti - inflammatory effects.
Materials and methods
wenty - seven patients who underwent heart valve replacement from October 1,2001 ,to March 10,2002 were randomized in double - blind fashion into two groups: control group ( n =11) and aprotinin group (n = 16) , Aprotinin was given at 11200u during CPB in the aprotinin group. Exclusion criteria were impaired renal function, advanced hepatic dysfunction, and hematologic disease. The aprotinin group received 560u in 20 minute before the skin incision, 560u in the priming solution of the extracorporeal circuit, and continuors infusion during the operation. The control group didnt receive aprotinin. The anesthetic was standardized: each patient was premedicated with intramuscular scopolamine (0. 5mg) , intramuscular morphine (0. Img/ kg). Anesthesia was induced with fentanyl(0.02mg/kg) and midazo-lam(0. 15mg/kg) in patients . muscle relaxation was obtained with pancuronium bromide (0.1mg/kg). Anesthesia was maintained with fentanyl(up to o. o5mg/kg) , an infusion of midaxolam(0. 1 -0.2mg/ kg/h) in patient and is
oflurane and pancuronium as needed. All patients were operated on through a median sternotomy. Before aortic cannulation, porcine mucous heparin(3mg/kg) was injected, and further heparin was administered to maintain a kaolinactivated coagulation time above 480 seconds. A hollow - fiber membrane oxygenator was used, and the priming solution of the circuit consisted of 1750 ml of a balanced crystalloid/colloid. Nonpulsatile blood flow was obtained with a roller pump(2.0-2.41/min/itf ) . Blood temperature was kept between 32℃ and 35℃. myocardial protection during aortic cross-clamping was achieved with the Buckberg method of blood cardiople-
gia. The total dose of heparin administered during CPB was reversed with protamine sulfate(ratio 1:1). After anesthesia was induced, we performed radial puncture. We collected the blood as four times: the first sample was 4ml arterial blood which was drawed from radial after radial puncture. The blood was anti - cogulation with heparin. 0.5ml blood was sent to the center of check to analysis the blood routine. 3. 5ml blood was centufugated at 2400 rpm. The upper plasm was drawed and store in - 20℃. The second sample was collected during aortic crossclamping. The method was same as the first. The third sample was collected at sloping inventory. After operation the fourth sample was done. The method was as the first.
When we fimished the sample. sICAM - 1 was determinated in ELISA. IL - 6 and TNF - awas detected by radio - immunity analysis. All data were expressed as X± S. All data were analyzed by T test (a =0.05) .
Results
There was no significant differece in age, body weight, operation
引文
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2． Miller BE, Levy J. The inflammatory response to cardiopulmonary bypass. J Cardiothorac Vasc Anesth, 1997,11:355-366
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10． 曹彬，房士琦，李清泉，等。抑肽酶抑制体外循环期间血小板激活反应。中华胸心血管外科杂志,1997,13:25-27
11． Hughes B,Parratt JR. The effects of the protease inhibitor, aprotin-in,on the course of shock induced by endotoxin in cats . Br J Pharmacol, 1995,86:399-403
12． 康敢军．细胞因子与心肌损伤的研究进展。医学综述,2001, 7:451-452
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17． Affect of aprotinin on endothelial cell activation. J Thorac cardio-vasc surg 2001; 122:123-8
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tion with integrin alpha V beta 3． Cell 1996;85:683-93．
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20． Moons L,Shi C,Ploplis V,Plow E,Haber E,Collen D, et al. re-duced transplant arteriosclerosis in plasminogen-deficient mice . J Clin Invest 1998; 102:1788-79
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12． 康敢军．细胞因子与心肌损伤的研究进展。医学综述,2001, 7:451-452
13． Meldrum DR,Cleveland Jr JC,Cain BS,et al. Increased myocardi-altumor necrosis factor-alpha in a crystalloidperfused model of cardiac ischemia-reperfusion injury. Amm Thorac Surg, 1998, 65:439-443
14． Wan S,LeClere JL, Vincent JL. Cytokines responseato cardiopul-monary bypass: lessons leamd from cardiac transplantation . Ann Thorac Surg, 1997,116:260-276
15． Boyle EM,Pohlman TH,Johnson MC,et al. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Tharac Surg, 1997,63:277-284．
16． Ballantyn CE, Moinolfi FB, Young NT. Pro-gnostic value of in-creased levels of circulating ICAM-1 after heart transplantation. Clin Res, 1992,29:285-290．
17． Affect of aprotinin on endothelial cell activation. J Thorac cardio-vasc surg 2001; 122:123-8
18． Brooks PC , Stromblad S, Sanders LC, von schalscha TL,Aimes RT, Stetler-Stevenson WG, et al. Localisation of matrix metallo-proteinase ( MMP)-2 to the surface of invasive cells by interac-
tion with integrin alpha V beta 3． Cell 1996;85:683-93．
19． Carmeliet P,Moons L,Lifnen R,Baes M,Lemaitre V,Tipping p,et al. Urokinase-generated plasmin activates matrix metalloprotein-ases during aneurysm formation. Nat Genet 1997;17:439-44
20． Moons L,Shi C,Ploplis V,Plow E,Haber E,Collen D, et al. re-duced transplant arteriosclerosis in plasminogen-deficient mice . J Clin Invest 1998; 102:1788-79
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