乌司他丁对原发性冲击伤小鼠早期肺损伤治疗作用的研究  

Therapeutical effect of ulinastatin on early lung injury in mice with primary blast injury

作　　者：胡方超 柴家科[2] 曲毅睿 荀浩怡 刘甜 迟云飞 白海良 吴育寿 苏小薇 孙冉 刘翔宇 HU Fangchao;CHAI Jiake;QU Yirui;XUN Haoyi;LIU Tian;CHI Yunfei;BAI Hailiang;WU Yushou;SU Xiaowei;SUN Ran;LIU Xiangyu(Graduate School,Chinese PLA General Hospital,Beijing 100853,China;Burn Institute,the Fourth Medical Center,Chinese PLA General Hospital,Beijing 100048,China;Hebei North University,Zhangjiakou 075132,Hebei Province,China)

机构地区：[1]解放军总医院研究生院,北京100853 [2]解放军总医院第四医学中心全军烧伤研究所,北京100048 [3]河北北方学院,河北张家口075132

出　　处：《解放军医学院学报》2023年第9期1010-1017,共8页Academic Journal of Chinese PLA Medical School

基　　金：军委后勤保障部重大项目(AWS15J003;ALB19J001)。

摘　　要：背景肺膜的破坏和多形核中性粒细胞穿过基底膜浸润到肺组织,引发过度炎症反应,被认为是原发性冲击伤肺损伤和呼吸功能障碍发病机制中的重要环节。乌司他丁是具有广谱抗炎活性的丝氨酸蛋白酶抑制剂,可能通过抑制中性粒细胞的作用,对原发性冲击伤肺损伤起到治疗作用。目的初步探讨乌司他丁能否通过抑制中性粒细胞作用,对原发性冲击伤小鼠早期肺损伤起到治疗作用。方法136只小鼠随机分为对照组(C组,n=16)、冲击伤组(B组,n=60)、乌司他丁组(U组,n=60)。利用聚黑铝高爆炸药将B组、U组小鼠制成中度原发性冲击伤模型。配制1×10^(4)U/mL乌司他丁溶液,U组致伤后立即按照5×104U/kg的剂量腹腔注射,12 h/次。对C组以及B组、U组伤后6 h、24 h、48 h的小鼠分别进行肺组织病理学、肺组织含水率、血清肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、NF-κB、CXCL-1、中性粒细胞弹性蛋白酶(neutrophil elastase,NE)、基质金属蛋白酶9(matrix metalloproteinase 9,MMP-9)含量、NADPH氧化酶(NADPH oxidase,NAO)活性以及肺组织NE、MMP-9表达水平的检测,并对C组以及B组、U组伤后48 h小鼠肺功能进行检测。结果与对照组相比,B组伤后6 h即可见到较明显中性粒细胞浸润,24 h和48 h有大量炎症细胞浸润,肺泡壁严重增厚,肺泡腔狭窄,组织淤血较多;U组各时间点炎症细胞浸润较B组显著减少,肺泡肿胀和淤血程度较B组显著减轻。伤后6 h、24 h、48 h,U组肺组织含水率均低于B组,差异有统计学意义(P均<0.05)。U组血清TNF-α、NF-κB、CXCL-1含量以及NAO活性显著低于B组(P均<0.05);血清NE、MMP-9含量和肺组织中NE、MMP-9表达水平均较B组显著降低,伤后48 h差异更显著(P均<0.05)。伤后48 h,U组肺功能较B组有所改善,其中潮气量、最大吸气流速升高,呼吸频率、呼气中期流速、Penh降低(P均<0.01)。结论早期应用乌司他丁可以抑制原发性冲�Background The disruption of the pulmonary membrane and the infiltration of polymorphonuclear neutrophil granulocytes across the basement membrane into the pulmonary tissue,resulting in excessive inflammatory response,is considered to be an essential step in the pathogenesis of primary lung injury and respiratory impairment.Ulinastatin,a serine protease inhibitor with broad anti-inflammatory activity,may play a therapeutical role in primary blast lung injury by inhibiting the functions of neutrophils.Objective To investigate whether ulinastatin can protect early lung injury in mice with primary blast injury by inhibiting the effect of neutrophils.Methods Totally 136 mice were randomly divided into control group(group C,n=16),blast injury group(group B,n=60)and ulinastatin group(group U,n=60).Moderate primary blast injury model was made in mice of group B and group U by polyblack aluminum high explosive.Ulinastatin solution(1×104 U/mL)was prepared,and group U was intraperitoneally injected with ulinastatin solution at the dosage of 5×10^(4) U/kg immediately after injury,12h for each time.Mice in the group C,the group B and the group U were sacrificed at 6 h,24 h and 48 h after injury for the determination of lung histopathology,lung tissue water content,levels of TNF-α,NF-κB,CXCL-1,NE,and MMP-9 in serum,NADPH oxidase(NAO)activity,and expression of NE and MMP-9 in lung tissue.And lung functions of mice in the group C along with mice in the group B,the group U at 48 h after injury were also measured.Results Compared with the group C,obvious neutrophil infiltration was observed in the group B at 6 h after injury,and there were a large number of inflammatory cells infiltrated at 24 h and 48 h,with severe thickening of alveolar wall,stenosis of alveolar cavity and more tissue congestion.In group U,the infiltration of inflammatory cells reduced significantly at each time point,and the degree of alveolar swelling and congestion was also significantly decreased,compared with group B.The water content of lung tissue in

关 键 词：原发性冲击伤 肺损伤 乌司他丁 中性粒细胞 炎症反应 

分 类 号：R644[医药卫生—外科学]