胸部爆炸伤致急性肺损伤的机理及其防治的初步研究
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摘要
胸部爆炸伤是现代战争的常见伤型，其伤情复杂，死亡率高，是战时胸部外伤救治中的重点和难点。胸部爆炸伤致急性肺损伤乃至急性呼吸窘迫综合征是主要死亡原因之一。目前尚无胸部爆炸伤后致急性肺损伤机理及其防治方面的研究报道。本实验拟建立胸部爆炸伤致急性肺损伤动物实验模型，观察肺部损伤特点，从爆炸应激条件下信号转导相关分子的变化情况进一步探讨急性肺损伤的发生机理；同时观察了伤后早期应用地塞米松、山莨菪碱对肺功能的影响，探讨其预防急性肺损伤作用，为胸部爆炸伤后急性肺损伤的救治提供实验基础。研究内容共包括三部分，分述如下：
第一部分：胸部爆炸伤致急性肺损伤动物模型的建立
本部分实验拟建立胸部爆炸伤致ALI动物实验模型，观察肺部损伤特点，为进一步研究胸部爆炸伤后ALI的发病机理及防治措施提供稳定可靠的、符合ALI病理过程和临床特征的动物模型。实验采用健康白色家兔64只(第四军医大学实验动物中心提供)，按爆炸源与致伤动物之间的距离(D)，将其随机分为五组，A组：正常对照组8只；B组：D=5cm12只；C组：D=8cm12只；D组：D=12cm16只：E组：D=15cm12只。实验前家兔禁食6小时以上，采用3％戊巴比妥钠按30mg／kg剂量经耳缘静脉注射麻醉后，分别经右颈总动脉、颈外静脉向心方向插管，同时置心电图导线，采用8#瞬发电雷管作为爆炸源，将雷管固定于自制的致伤架上，采用蓄电池电起爆。动物左侧卧位固定于致伤架下，分布于其径向，均为右侧正对爆心，橡胶护具保护腹部及头部，雷管长轴与致伤动物右侧第五肋间平行，二者之间的垂直距离作为分组标准。致伤前5分钟开始用八道生理记录仪连续观察呼吸频率、外周动脉压、中心静脉压等生理学指标变化，并记录致伤后5、30min，1、3、6、
一
12、24 h各时间点的各生理指标变化；同时在致伤前及伤后以上各时间点，
抽取动脉血标本进行动脉血气分析，计算肺泡－动脉血氧分压差P（A－a）0。；观
察并记录动物的存活时间，统计各致伤组的24－4S小时内死亡率；在伤后不
同时间点胸部X线透视检查，除全面观察肺门大小、形态、位置外，应特别注
意比较两肺门、肺叶的密度有无异常变化；实验结束后立刻取肺组织，称湿
重后置80aC烤箱中干燥24小时至干重恒定，计算肺水含量；取以上各时间点
标本检测血清及支气管肺泡灌洗液中细胞因子 IL－6二L－8和 TNF a含量变化。
结果：在 64只动物中共有 36只（56．3％）出现肺脏的破片伤，所有的
动物＊00％）均有不同程度的肺脏冲击伤，其中极重度伤14只，重度伤7只，
中度伤 25只，轻度伤 10只。B组均为极重度损伤，平均肺出血实变的面积
在80％以上，C、D组平均肺出血实变的面积分别为50％和30％左右，轻度
伤动物绝大部分在E组，仅表现为单个肺叶的部分实变或散在的出血斑。根
据各组肺脏冲击伤程度我们可以将B、C组归为重度爆炸伤组刀组归为中度
爆炸伤组，而E组则归为轻度爆炸伤组；D组除1例动物瞬间死亡外，其余存
活时间均超过 24h，较 B组、C组存活时间明显延长（P＜0．of）。B组动物
均为瞬间死亡，平均存活时间小干5分钟；C组动物存活均未超过12 h，平
均存活时间小于6h，二例动物瞬间死亡。E组动物无早期死亡，均在6小时
内各项生命指标恢复正常水平；各致伤组呼吸频率伤后smin内均较伤前明显
加快（P＜0刀1）。D组伤后lh呼吸频率达最高为87士10次／分，后有所下降，
但伤后24 h仍未完全恢复至伤前水平（P＜0刀5）。E组伤后5－10 ddn之内呼吸
频率达最高，伤后3h内恢复至伤前水平（P＞0刀5）；各组随致伤距离的增加，
肺水含量呈下降趋势，其中0组、E组较8组均有明显下降（P＜0．05）；B、C
组伤后早期即可见明显斑片状和大片融合阴影，右肺较左肺明显，以肺门处为
主，系严重肺出血所致刀组在伤后 12－24小时内主要表现为两肺纹理增重、模
糊为主二4小时后肺内可出现斑片状甚至融合阴影多数是以右肺为主的两侧
分布，少数只发生在右肺，48小时后两肺可广泛分布片状阴影；C、D组均表现
－3－
一
为渐进性的呼吸性酸中毒，氧分压（PaO。）、氧饱和度（SaO。）均明显下降，
伤后3Ormn较伤前有显著差别（P＜0刀5），同时表现为肺循环明显的病理分流
和无效通气（P；。。；Oz升高）。D组伤后30Inin时Paoz由伤前的108．5士
14．60 nunHnunHg降至72．5士9．4InlnHg（尸＜0＊5），并呈持续下降趋势，伤后6h降
至最低49．2士5．IInlnHg（P＜0．of）：D组伤后6h时SaOZ 由伤前的95．4士12．8
％降至 75．4土 13．5％?
Chest explosive trauma is usual in modern war. It is the emphasis and difficulty in the treatment of explosive trauma because of its complexity and high mortality. Acute lung injury(ALI), even acute respiratory distress syndrome(ARDS) after chest explosive trauma is one of main causes of mortality in wartime. The study on the mechanism and treatment of ALI after chest explosive trauma has not been reported until now. The objectives of the present study are to establish the experimental model of ALI after chest explosive trauma, and to evaluate the expression alterations of signal transduction molecules under explosive stress condition, discuss their roles in mechanisms of ALI and potential possibility for NF K B P65 and P38 MARK as therapeutic targets for ALI/ARDS; at the same time, we investigate the influence of dexamethasone and anisodamine on the pulmonary function, discuss their roles in the prophylaxis and treatment of ALI, and provide experimental basis for the treatment of ALI after chest explosive trauma. There are three parts of the study.
Part One. Establishment of animal model of ALI after chest explosive trauma.
The objective of this part is to establish the stable experimental animal model of ALI after explosive trauma, investigate the
characteristics of lung injury and provide basis for further study. 64 rabbits were divided into 5 groups randomly according to the distance between denotator and animal. Group A: normal control, 8 rabbits; B: D=5cm, 12 rabbits; C: D=8cm, 12 rabbits; D: D=12cm, 16 rabbits; E:D=15cm, 12 rabbits. The rabbits were fasted before experiment for at least 6 hours, and anesthetized by 3% pentobarbital sodium intravenous injection through auricular vein. Intubations through right carotid artery and external carotid vein and ECG conducting wires were settled. We used No. 8 denotators as explosive sources and exploded them electrically. The rabbits were fastened to the experimental shelf left lying position, the denotators were fastened to the shelf , too. The axis of denotators paralleled with the intercostal spaces. Physiologic index such as respiratory rate , peripheral artery pressure and central venous pressure were recorded continuously from 5 minutes before explosion; survival time of the animal, blood gas analysis and chest X-ray examination were done at the same time points; in addition to this, rate of lung water and the contents of IL-6, IL-8 and TNF a in plasma and BALF were detected. Results: There were 36 rabbits with lung fragment wounds in the whole 64 rabbits .All the rabbits had lung blast injury of different levels. We can call group B and C, D, E seriously injured groups, moderately injured group and slightly injured group respectively. The area of lung consolidation of group B and C was above 50%, while group D, about 30%. Survival time of group D was above 24 hours except for one immediate death after trauma. It was significantly longer than that of group B and C(p<0.01). All the rabbits in group E recovered in 6 hours after trauma; The respiratory rate raised significantly in 5
minutes after trauma in each group(p<0. 01). It reached the height of 87?0 per minute in 1 hour in group D, then decreased, but could not recover in 24 hours. Rabbits in group E recovered in 3 hours after trauma(p<0. 05); Rate of lung water decreased with the increase of distance between denotator and animal. RLW of group D and E decreased more significantly than that in group D(p<0. 05); X-ray examination showed that there existed patch and fused shadows early after explosion because of pulmonary hemorrhage, and it was more serious in the right lung and hilus of lung than that in the left. But in group D, the changes above mentioned had not been found until 24 hours after trauma, patch shadow was all over the lungs after 48 hours. Gradual respiratory acidosis was found in group C and D, Pa02 and Sa02 decreased sharply after trauma; on the other hand .pathological shunt and invalid ventilation was characterized by the increase of P(A-a)02. Changes of inflammatory cyt
第一部分：胸部爆炸伤致急性肺损伤动物模型的建立
本部分实验拟建立胸部爆炸伤致ALI动物实验模型，观察肺部损伤特点，为进一步研究胸部爆炸伤后ALI的发病机理及防治措施提供稳定可靠的、符合ALI病理过程和临床特征的动物模型。实验采用健康白色家兔64只(第四军医大学实验动物中心提供)，按爆炸源与致伤动物之间的距离(D)，将其随机分为五组，A组：正常对照组8只；B组：D=5cm12只；C组：D=8cm12只；D组：D=12cm16只：E组：D=15cm12只。实验前家兔禁食6小时以上，采用3％戊巴比妥钠按30mg／kg剂量经耳缘静脉注射麻醉后，分别经右颈总动脉、颈外静脉向心方向插管，同时置心电图导线，采用8#瞬发电雷管作为爆炸源，将雷管固定于自制的致伤架上，采用蓄电池电起爆。动物左侧卧位固定于致伤架下，分布于其径向，均为右侧正对爆心，橡胶护具保护腹部及头部，雷管长轴与致伤动物右侧第五肋间平行，二者之间的垂直距离作为分组标准。致伤前5分钟开始用八道生理记录仪连续观察呼吸频率、外周动脉压、中心静脉压等生理学指标变化，并记录致伤后5、30min，1、3、6、
一
12、24 h各时间点的各生理指标变化；同时在致伤前及伤后以上各时间点，
抽取动脉血标本进行动脉血气分析，计算肺泡－动脉血氧分压差P（A－a）0。；观
察并记录动物的存活时间，统计各致伤组的24－4S小时内死亡率；在伤后不
同时间点胸部X线透视检查，除全面观察肺门大小、形态、位置外，应特别注
意比较两肺门、肺叶的密度有无异常变化；实验结束后立刻取肺组织，称湿
重后置80aC烤箱中干燥24小时至干重恒定，计算肺水含量；取以上各时间点
标本检测血清及支气管肺泡灌洗液中细胞因子 IL－6二L－8和 TNF a含量变化。
结果：在 64只动物中共有 36只（56．3％）出现肺脏的破片伤，所有的
动物＊00％）均有不同程度的肺脏冲击伤，其中极重度伤14只，重度伤7只，
中度伤 25只，轻度伤 10只。B组均为极重度损伤，平均肺出血实变的面积
在80％以上，C、D组平均肺出血实变的面积分别为50％和30％左右，轻度
伤动物绝大部分在E组，仅表现为单个肺叶的部分实变或散在的出血斑。根
据各组肺脏冲击伤程度我们可以将B、C组归为重度爆炸伤组刀组归为中度
爆炸伤组，而E组则归为轻度爆炸伤组；D组除1例动物瞬间死亡外，其余存
活时间均超过 24h，较 B组、C组存活时间明显延长（P＜0．of）。B组动物
均为瞬间死亡，平均存活时间小干5分钟；C组动物存活均未超过12 h，平
均存活时间小于6h，二例动物瞬间死亡。E组动物无早期死亡，均在6小时
内各项生命指标恢复正常水平；各致伤组呼吸频率伤后smin内均较伤前明显
加快（P＜0刀1）。D组伤后lh呼吸频率达最高为87士10次／分，后有所下降，
但伤后24 h仍未完全恢复至伤前水平（P＜0刀5）。E组伤后5－10 ddn之内呼吸
频率达最高，伤后3h内恢复至伤前水平（P＞0刀5）；各组随致伤距离的增加，
肺水含量呈下降趋势，其中0组、E组较8组均有明显下降（P＜0．05）；B、C
组伤后早期即可见明显斑片状和大片融合阴影，右肺较左肺明显，以肺门处为
主，系严重肺出血所致刀组在伤后 12－24小时内主要表现为两肺纹理增重、模
糊为主二4小时后肺内可出现斑片状甚至融合阴影多数是以右肺为主的两侧
分布，少数只发生在右肺，48小时后两肺可广泛分布片状阴影；C、D组均表现
－3－
一
为渐进性的呼吸性酸中毒，氧分压（PaO。）、氧饱和度（SaO。）均明显下降，
伤后3Ormn较伤前有显著差别（P＜0刀5），同时表现为肺循环明显的病理分流
和无效通气（P；。。；Oz升高）。D组伤后30Inin时Paoz由伤前的108．5士
14．60 nunHnunHg降至72．5士9．4InlnHg（尸＜0＊5），并呈持续下降趋势，伤后6h降
至最低49．2士5．IInlnHg（P＜0．of）：D组伤后6h时SaOZ 由伤前的95．4士12．8
％降至 75．4土 13．5％?
Chest explosive trauma is usual in modern war. It is the emphasis and difficulty in the treatment of explosive trauma because of its complexity and high mortality. Acute lung injury(ALI), even acute respiratory distress syndrome(ARDS) after chest explosive trauma is one of main causes of mortality in wartime. The study on the mechanism and treatment of ALI after chest explosive trauma has not been reported until now. The objectives of the present study are to establish the experimental model of ALI after chest explosive trauma, and to evaluate the expression alterations of signal transduction molecules under explosive stress condition, discuss their roles in mechanisms of ALI and potential possibility for NF K B P65 and P38 MARK as therapeutic targets for ALI/ARDS; at the same time, we investigate the influence of dexamethasone and anisodamine on the pulmonary function, discuss their roles in the prophylaxis and treatment of ALI, and provide experimental basis for the treatment of ALI after chest explosive trauma. There are three parts of the study.
Part One. Establishment of animal model of ALI after chest explosive trauma.
The objective of this part is to establish the stable experimental animal model of ALI after explosive trauma, investigate the
characteristics of lung injury and provide basis for further study. 64 rabbits were divided into 5 groups randomly according to the distance between denotator and animal. Group A: normal control, 8 rabbits; B: D=5cm, 12 rabbits; C: D=8cm, 12 rabbits; D: D=12cm, 16 rabbits; E:D=15cm, 12 rabbits. The rabbits were fasted before experiment for at least 6 hours, and anesthetized by 3% pentobarbital sodium intravenous injection through auricular vein. Intubations through right carotid artery and external carotid vein and ECG conducting wires were settled. We used No. 8 denotators as explosive sources and exploded them electrically. The rabbits were fastened to the experimental shelf left lying position, the denotators were fastened to the shelf , too. The axis of denotators paralleled with the intercostal spaces. Physiologic index such as respiratory rate , peripheral artery pressure and central venous pressure were recorded continuously from 5 minutes before explosion; survival time of the animal, blood gas analysis and chest X-ray examination were done at the same time points; in addition to this, rate of lung water and the contents of IL-6, IL-8 and TNF a in plasma and BALF were detected. Results: There were 36 rabbits with lung fragment wounds in the whole 64 rabbits .All the rabbits had lung blast injury of different levels. We can call group B and C, D, E seriously injured groups, moderately injured group and slightly injured group respectively. The area of lung consolidation of group B and C was above 50%, while group D, about 30%. Survival time of group D was above 24 hours except for one immediate death after trauma. It was significantly longer than that of group B and C(p<0.01). All the rabbits in group E recovered in 6 hours after trauma; The respiratory rate raised significantly in 5
minutes after trauma in each group(p<0. 01). It reached the height of 87?0 per minute in 1 hour in group D, then decreased, but could not recover in 24 hours. Rabbits in group E recovered in 3 hours after trauma(p<0. 05); Rate of lung water decreased with the increase of distance between denotator and animal. RLW of group D and E decreased more significantly than that in group D(p<0. 05); X-ray examination showed that there existed patch and fused shadows early after explosion because of pulmonary hemorrhage, and it was more serious in the right lung and hilus of lung than that in the left. But in group D, the changes above mentioned had not been found until 24 hours after trauma, patch shadow was all over the lungs after 48 hours. Gradual respiratory acidosis was found in group C and D, Pa02 and Sa02 decreased sharply after trauma; on the other hand .pathological shunt and invalid ventilation was characterized by the increase of P(A-a)02. Changes of inflammatory cyt
引文
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28．王彦彬，蔺锡侯，周宁等．胸外伤并发急性呼吸衰竭的高危因素分析．中华创伤杂志，1998，14(1)：16-18．
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31. Samy TS, Ayala A, Catania RA, et al. Shock, 1998,9(6):443-450.
32. Guillou Pi. Kidney Int, 1998,53(suppl 66):S186-189.
33．姚咏明，田惠民，王亚平等．Re型内毒素抗血清对实验性多器官功能衰竭的防护作用．中华外科杂志，1992，30：244．
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43. Yao YM, Bahrami S, Leichtfried G, et al. Significance of NO in hemorrhage-induced hemodynamic alterations, organ injury, and mortality in rats. Am J Physiol, 1996,270:H1616.
44．梁继河，尹文，虎晓岷 等，山莨菪碱对创伤性急性肺损伤防治作用的实验研究．中华创伤杂志，1998；14(5)：284-287．
45. Weg JG, Balk RA, Tharratt RS, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. JAMA 1994 Nov 9;272(18):1433-8.
46. Wiedemann HP. Surfactant and acquired lung diseases. J Lab Clin Med. 1996 Mar; 127(3): 239-41.
47．毛宝龄，急性肺损伤的治疗．见：黎鳌 主编，创伤后脏器功能不全，第一版,72-79．河北科学技术出版社．
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52．Kang-Hoe Lee,Tow-Keang Lim.急性呼吸窘迫综合征，医学进展．1998，3：31．
53. Tuxen DV. Permissive hypercapnic ventilation. Am J Respir Crit Care Med, 1994,150:870.
54．Kang-Hoe Lee,Tow-Keang Lim.急性呼吸窘迫综合征，医学进展．1998，3：31．
55．Fort P. 高频振荡通气在急性呼吸窘迫综合征中应用的研究．Crit Care Med,1997,25:937．
56. Imanaka HK, Acmarek RM, Ritz R, et al. Tracheal gas insulfflation-pressure control versus volume controlventilation: a lung model study. Am J Respir Grit Care Med, 1996,153:1019.
57．Hirschl RB．全部和部分液体通气疗法对ARDS的气体交换、肺顺应性和肺损伤的影响．Crit Care Med,1996,24:1001．
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62. Miller EJ, Kurdowska A, Nagao S, et al. A Synthetic peptide which specifically inhibits heat-treated interleukin-8 binding and chemotaxis for neutrophils[J]. Agents Actions, 1993,40(3/4):200-208.
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75．ERK1／ERK2、P38 MAPK在肺挫伤复合内毒素血症早期所致肺炎症反应中的作用研究．第三军医大学博士学位论文，2001
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