实验性胸腹撞击伤后外源性CGRP对心肌细胞保护的研究
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摘要
胸腹撞击伤是平时意外事故,特别是交通事故中的常见伤类,患者大多有合并伤和或严重并发症,病情凶险。胸腹撞击所致的钝性心脏损伤以心肌挫伤(myocardial contusion, MC)最为常见,发生率为9%~76%不等[1]。胸腹撞击伤后可引起机体血流动力学不稳定和多种细胞因子的释放,从而造成继发性器官损害。这种状态若得不到及时纠正,是胸腹撞击伤后重要的死亡原因之一,也是临床救治工作中的重点与难点。因此,早期预防与治疗胸腹撞击伤后因心脏功能障碍造成的血液循环紊乱和炎性因子失衡带来的继发性损害是临床救治的关键所在。近年来研究发现降钙素基因相关肽(Calcitonin-gene-related Peptide,CGRP)具有强烈的扩血管作用,且可抑制创伤后血管收缩因子的释放,阻断体内过氧化反应,同时对损伤后的心肌具有一定的保护作用。本研究通过建立胸腹撞击伤动物模型的基础上,采用不同剂量的外源性降钙素基因相关肽预处理、检测胸腹撞击伤伤前与伤后血管内皮素的水平,同时测定典型心脏损伤因子,观察外源性降钙素基因相关肽对创伤后兔心功能的影响及其可能的作用机制,以期能为临床救治提供较可靠的理论依据。
方法:实验动物选择成年新西兰兔,雌雄不限,将其随机分为A、B、C三组。A组:对照组;B组:常规剂量降钙素基因相关肽处理组(0.012μg /kg);C组:大剂量降钙素基因相关肽处理组(0.024μg /kg)。BIM-Ⅳ型生物撞击机撞击动物剑突致伤。测定不同时相点外周血LDH、CK、ET、cTnT及处死动物后心脏组织内MDA、SOD及游离细胞钙离子的平均荧光强度。同时对心、肺、肝损伤的严重程度进行AIS评分和AAST分级、光镜下观察心脏损伤及合并肝、肺损伤的组织病理学特点。
本研究的主要结果与结论如下:
1.本研究建立的肝脏撞击伤模型具有如下特点:①撞击设备操作简便、物理参数容易控制、撞击部位准确及可重复性好等优点;②实验动物心脏损伤的临床病理、类型、伤情与临床较为接近;③撞击伤的同时合并有肋骨骨折、心、肝、肺的损伤,AIS评分1～5分;④可利用致伤模型进行力学因素分析及多项实验指标的检测;⑤为临床研究胸腹撞击伤后各种病理生理变化提供了理想的模型基础。
2.本研究发现,伤前各组间血清ET、LDH、CK水平比较无明显差异(P<0.05),胸腹撞击伤后(伤后1、3、7h),LDH、CK、ET值均显著高于伤前(P>0.01),B组、C组非常显著低于A组(P<0.01),C组非常显著低于B组(P<0.01)。
试验结果表明外源性CGRP能够显著减低外周血ET的水平且呈剂量依赖性,在液体复苏的同时,静脉应用CGRP后,血清cTnT、LDH、CK变化明显小于单纯液体复苏组,且呈剂量依赖性,说明CGRP对严重创伤后心肌损伤有保护作用。其作用机制是CGRP阻断了因创伤后血液内ET含量的升高而引发的血管的强烈收缩及加重心肌损伤的酶的活性增强,而导致的恶性循环这两个主要环节的发生。目前国内外对于CGRP和ET相互作用的研究,主要集中于肝脏慢性疾病和神经系统类病变,而在胸腹撞击伤中直接利用外源性CGRP保护心肌功能尚未见报道。
本研究发现,伤前三组心肌组织内MDA、SOD、cT-nT含量无明显差异(P<0.05),伤后B组、C组非常显著低于A组(P<0.01),且C组明显低于B组(P<0.05);SOD活性B组、C组非常显著高于A组(P<0.01),且C组明显高于B组(P<0.05);同时心肌细胞内[Ca2+]平均荧光强度B组、C组非常显著低于A组(P<0.01),且C组明显低于B组(P<0.05)。
试验结果表明外源性补充CGRP能剂量依赖性地下调MDA。并使SOD活性升高,同时其对脂质过氧化的影响作用与心肌细胞的损伤程度呈高度相关性,说明CGRP抗脂质过氧化作用参与了保护心肌细胞。CGRP与受体结合后,激活腺苷酸环化酶,防止细胞内钙超载、防止创伤后心肌酶漏出和维持心肌细胞膜稳定性是其心肌细胞保护作用的三个主要机制。
4.本研究进一步证实,创伤后外源性补充CGRP可有效解决因血管收缩因子增高而引发的血管持续收缩和心肌细胞持续缺血、缺氧情况。同时,其抗脂质过氧化作用也可防止伤后体内过氧化物的蓄积和心肌细胞内的钙离子超载而造成心肌的损伤,从而对心肌细胞具有肯定的保护作用。因此,胸腹撞击伤后外源性补充CGRP对心肌继发性损害的防治具有重要的临床意义。
The Thoraco-abdominal Injury often causes the instability of organism hemodynamics, it not only caused by the cardiac functional impairment involved in trauma itself including heart and lungs, but also have close relationship with the secondum organ detriment caused by multitude cytokine released after trauma, it also the nodus of clinic remedy and the main death causing.So, precaution and nonage management of treating secondary lesion caused by disord of blood circulation and disequilibrium of inflammatory factor are the key point of clinic remedy. There years, the research have discover that the calcitonin gene-related peptide(CGRP)have intensive angiectasia effect,and could suppress the release of vasoconstriction factor post-traumatic, blocking peroxidatic reaction in vivo, and have protection effect to the injured cardiac muscle at the same time. In this study,we investigate and analyze the effect of extrinsic CGRP (calcitonin-gene-related peptide) on the cardiac function of rabbits with impact injury on processus xiphoideus.
Methods:
To injure thirty adult rabbits (male or female) on their processus xiphoideuses with BIM-IV biological impact machine and divide them into three groups. Group A is treated with intravenous hysiological saline, group B with intravenous CGRP (CGRP 0.012μg /kg), and group C with CGRP in large doses(CGRP 0.024μg /kg). To measure the LDH , CK, CE after injury respectively; to measure the exponent of MDA, the activity of SOD of myocardial tissues, and the data of intracellular dissociated calcium ion in the heart of the dead rabbits, while observing the pathological change and analysis the traumatic condition .
The main outcomes of this research are:
1. The model of LII in animals has the advantages of simple manipulation of impacting equipment, controllable physical parameters and accuracy and repeatability in impacting sites. The pathology, type and wound state of the LII in the animals are similar to those seen in clinical practice. They are in the range of gradeⅢto grade V according to AAST grading standards and 3~5 points in accordance with the AIS scoring. And LII is complicated with costal fracture and injury of the heart and lungs,conform to the stander of multiple injury. The model can be used for analysis of dynamic factors, detection of many indices. The gross anatomy, death rate and death rate change had no significant variability in three group.
2. The LDH、CK、ET data of each group before injury is almost the same (P>0.05).After injury, group B and group C is lower than that of group A (P<0.01), C is lower than that of group B (P<0.01). So, the CGRP can dose-dependent attenuated the serum LDH、CK、ET level.
3. MDA exponent of group B and C is lower than that of group A (p<0.01), and that of group C is lower than that of group B (p<0.05). and SOD activity group B and C is higher than that of group A (p<0.01), and that of group C is higher than that of group B (p<0.05). To compare the exponent of intracellular dissociated calcium ion in the heart of each group, and that of group C is much lower than that of group A (p<0.01), group C lower than group B (p<0.01).
4.CGRP calcitonin-gene-related peptide can effectively protect the cardiac muscle from injury. It probably functions by preventing ET from rising, balancing the activity of SOD and exponent of MDA, and preventing the leak-out of CK and overloading of calcium ion in cardiac muscle.
方法:实验动物选择成年新西兰兔,雌雄不限,将其随机分为A、B、C三组。A组:对照组;B组:常规剂量降钙素基因相关肽处理组(0.012μg /kg);C组:大剂量降钙素基因相关肽处理组(0.024μg /kg)。BIM-Ⅳ型生物撞击机撞击动物剑突致伤。测定不同时相点外周血LDH、CK、ET、cTnT及处死动物后心脏组织内MDA、SOD及游离细胞钙离子的平均荧光强度。同时对心、肺、肝损伤的严重程度进行AIS评分和AAST分级、光镜下观察心脏损伤及合并肝、肺损伤的组织病理学特点。
本研究的主要结果与结论如下:
1.本研究建立的肝脏撞击伤模型具有如下特点:①撞击设备操作简便、物理参数容易控制、撞击部位准确及可重复性好等优点;②实验动物心脏损伤的临床病理、类型、伤情与临床较为接近;③撞击伤的同时合并有肋骨骨折、心、肝、肺的损伤,AIS评分1～5分;④可利用致伤模型进行力学因素分析及多项实验指标的检测;⑤为临床研究胸腹撞击伤后各种病理生理变化提供了理想的模型基础。
2.本研究发现,伤前各组间血清ET、LDH、CK水平比较无明显差异(P<0.05),胸腹撞击伤后(伤后1、3、7h),LDH、CK、ET值均显著高于伤前(P>0.01),B组、C组非常显著低于A组(P<0.01),C组非常显著低于B组(P<0.01)。
试验结果表明外源性CGRP能够显著减低外周血ET的水平且呈剂量依赖性,在液体复苏的同时,静脉应用CGRP后,血清cTnT、LDH、CK变化明显小于单纯液体复苏组,且呈剂量依赖性,说明CGRP对严重创伤后心肌损伤有保护作用。其作用机制是CGRP阻断了因创伤后血液内ET含量的升高而引发的血管的强烈收缩及加重心肌损伤的酶的活性增强,而导致的恶性循环这两个主要环节的发生。目前国内外对于CGRP和ET相互作用的研究,主要集中于肝脏慢性疾病和神经系统类病变,而在胸腹撞击伤中直接利用外源性CGRP保护心肌功能尚未见报道。
本研究发现,伤前三组心肌组织内MDA、SOD、cT-nT含量无明显差异(P<0.05),伤后B组、C组非常显著低于A组(P<0.01),且C组明显低于B组(P<0.05);SOD活性B组、C组非常显著高于A组(P<0.01),且C组明显高于B组(P<0.05);同时心肌细胞内[Ca2+]平均荧光强度B组、C组非常显著低于A组(P<0.01),且C组明显低于B组(P<0.05)。
试验结果表明外源性补充CGRP能剂量依赖性地下调MDA。并使SOD活性升高,同时其对脂质过氧化的影响作用与心肌细胞的损伤程度呈高度相关性,说明CGRP抗脂质过氧化作用参与了保护心肌细胞。CGRP与受体结合后,激活腺苷酸环化酶,防止细胞内钙超载、防止创伤后心肌酶漏出和维持心肌细胞膜稳定性是其心肌细胞保护作用的三个主要机制。
4.本研究进一步证实,创伤后外源性补充CGRP可有效解决因血管收缩因子增高而引发的血管持续收缩和心肌细胞持续缺血、缺氧情况。同时,其抗脂质过氧化作用也可防止伤后体内过氧化物的蓄积和心肌细胞内的钙离子超载而造成心肌的损伤,从而对心肌细胞具有肯定的保护作用。因此,胸腹撞击伤后外源性补充CGRP对心肌继发性损害的防治具有重要的临床意义。
The Thoraco-abdominal Injury often causes the instability of organism hemodynamics, it not only caused by the cardiac functional impairment involved in trauma itself including heart and lungs, but also have close relationship with the secondum organ detriment caused by multitude cytokine released after trauma, it also the nodus of clinic remedy and the main death causing.So, precaution and nonage management of treating secondary lesion caused by disord of blood circulation and disequilibrium of inflammatory factor are the key point of clinic remedy. There years, the research have discover that the calcitonin gene-related peptide(CGRP)have intensive angiectasia effect,and could suppress the release of vasoconstriction factor post-traumatic, blocking peroxidatic reaction in vivo, and have protection effect to the injured cardiac muscle at the same time. In this study,we investigate and analyze the effect of extrinsic CGRP (calcitonin-gene-related peptide) on the cardiac function of rabbits with impact injury on processus xiphoideus.
Methods:
To injure thirty adult rabbits (male or female) on their processus xiphoideuses with BIM-IV biological impact machine and divide them into three groups. Group A is treated with intravenous hysiological saline, group B with intravenous CGRP (CGRP 0.012μg /kg), and group C with CGRP in large doses(CGRP 0.024μg /kg). To measure the LDH , CK, CE after injury respectively; to measure the exponent of MDA, the activity of SOD of myocardial tissues, and the data of intracellular dissociated calcium ion in the heart of the dead rabbits, while observing the pathological change and analysis the traumatic condition .
The main outcomes of this research are:
1. The model of LII in animals has the advantages of simple manipulation of impacting equipment, controllable physical parameters and accuracy and repeatability in impacting sites. The pathology, type and wound state of the LII in the animals are similar to those seen in clinical practice. They are in the range of gradeⅢto grade V according to AAST grading standards and 3~5 points in accordance with the AIS scoring. And LII is complicated with costal fracture and injury of the heart and lungs,conform to the stander of multiple injury. The model can be used for analysis of dynamic factors, detection of many indices. The gross anatomy, death rate and death rate change had no significant variability in three group.
2. The LDH、CK、ET data of each group before injury is almost the same (P>0.05).After injury, group B and group C is lower than that of group A (P<0.01), C is lower than that of group B (P<0.01). So, the CGRP can dose-dependent attenuated the serum LDH、CK、ET level.
3. MDA exponent of group B and C is lower than that of group A (p<0.01), and that of group C is lower than that of group B (p<0.05). and SOD activity group B and C is higher than that of group A (p<0.01), and that of group C is higher than that of group B (p<0.05). To compare the exponent of intracellular dissociated calcium ion in the heart of each group, and that of group C is much lower than that of group A (p<0.01), group C lower than group B (p<0.01).
4.CGRP calcitonin-gene-related peptide can effectively protect the cardiac muscle from injury. It probably functions by preventing ET from rising, balancing the activity of SOD and exponent of MDA, and preventing the leak-out of CK and overloading of calcium ion in cardiac muscle.
引文
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7.商立军,臧益民,王春梅,等.降钙素基因相关肽对心肌细胞缺血缺氧状态下胞内钙的影响[J].第四军医大学学报,2000,21(4):408.
8.商立军,臧益民,臧伟进. CGRP对正常及模拟缺血缺氧状态下豚鼠心肌细胞钙通道电流的影响[J].中国药理学通报,2000,16(5):503.
9.商立军,臧益民,王四旺,等.降钙素基因相关肽与心律失常[J].心功能杂志,1999,11(4):250.
10. Mullenheim J, Schlack W, Frassdorf J,etal·Additive protective effects of late and early ischaemic preconditioning are mediated by the opening of KATP channels in vivo [J]·Pflugers Arch, 2001, 442 (2): 178~187·
11. Li Y J, Peng J·The cardioprotection of calcitonin gene-related peptide-mediated preconditioning [J]·Eur J Pharmacol, 2002, 442(3): 177·
12. Hampton C R, Shimamoto A, Rothnie C L,etal·HSP70·1 and-70·3 are required for late-phase protection induced by ischemic precon-ditioning of mouse hearts [J]·Am J Physiol Heart Circ Physiol, 2003, 285 (2): H866~874·
13. He S Y, Deng H W, Li Y J·Monophosphoryl lipid A-induced delayed preconditioning ismediated by calcitonin gene-related peptide [J]·Eur J Pharmacol, 2001, 420 (2~3): 143~149
14.陈克正,高晓燕.内皮素致肺出血及降钙素基因相关肽拮抗内皮素作用的研究[J].中华儿科杂志,2004,42(6):446.
15.中华医学会儿科学会新生儿血组.新生儿肺出血的诊断及治疗方案[J].中华儿科杂志,2001,39(4):248.
16.陈克正,王卫.新生大鼠肺出血动物模型的建立及对临床的启示[J].中国当代儿科杂志,2002,4(5):357.
17. Scherer EQ,Herzog M,Wangemann P.et al. Endothelin-1-Induced Vasospasms of SpiralModiolar Artery AreMediated by Rho-Kinase-In-duced Ca2+Sensitization of Contractile Apparatus and Reversed by Calci-tonin Gene-Related Peptide[J]. Stroke,2002,33(12):2965.
18.陈克正,王卫,吕回.肺出血新生鼠肺组织病理与肺内氧自由基关系[J].小儿急救医学,2002,9(4):207
19. Springer J, Amadesi S, TrevisaniM, et al. Effectsof alpha calcitonin gene-related peptide in human bronchial smooth muscle and pulmonary artery [J].Regul Pept, 2004,118(3):127.
20. Roh J, Chang CL, Bhalla Aet al.Intermedin is a calcitonin/calci-tonin gene-related peptide family peptide acting through the calci-tonin receptor-like receptor/receptor activity-modifying protein re-ceptor complexes.J Biol Chem,2004 ,279(8):7 264-7 724.
21. Takei Y, Inoue K, Ogoshi Met al. Identification of novel adrenomedullin in mammals: a potentcardiovascular and renal regulator.FEBS Lett, 2004,556(1-3):53-58.
22. Burak Kandilci H, Gumusel B, Wasserman Aet al. Intermedin/a-drenomedullin-2 dilatesthe rat pulmonary vascular bed: Dependence on CGRP receptors and nitric oxide release.Peptides,2006,1(9):on-line.
23. Fujisawa Y, Nagai Y, Miyatake Aet al. Renal effects of a new member of adrenomedullin family,adrenomedullin2, in rats.European Journal of Pharmacology , 2004,497:75-80.