戊乙奎醚预处理对脓毒症小鼠肺损伤时MAPK信号转导通路的影响

目的 探讨戊乙奎醚(PHC)预处理对脓毒症小鼠肺损伤时丝裂原活化蛋白激酶(MAPK)信号转导通路的影响.方法 健康雌性昆明小鼠105只,体重20～25 g,随机分为3组(n=35):假手术组(S组)、脓毒症(CLP)组和戊乙奎醚(PHC)组.采用盲肠结扎并穿孔法制备脓毒症模型.PHC组于造模前1 h腹腔注射戊乙奎醚0.45 mg/kg,s组和CLP组于造模前1 h注射等容量生理盐水.于造模后即刻测定肺微血管通透性;造模后12 h时进行动脉血气分析,观察肺组织病理结果,测定肺组织丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性和磷酸化的p38丝裂原活化蛋白激酶(p38MAPK)、细胞外信号调节激酶(ERK1/ERK2)和c-jun氨基末端蛋白激酶(JNK)表达.结果 与S组比较,CLP组PaO2、PaO2/FiO2和pH值降低,肺微血管通透性和肺组织MDA含量升高,SOD活性降低,磷酸化的p38MAPK、ERK1/ERK2和JNK表达上调(P<0.05或0.01);与CLP组比较,PHC组PaO2、PaO2/FiO2和pH值升高,肺微血管通透性和肺组织MDA含量降低,SOD活性升高,磷酸化的p38MAPK和ERK1/ERK2表达下调(P<0.05或0.01).结论 戊乙奎醚预处理可通过抑制MAPK信号转导通路(p38MAPK和ERK1/ERK2)的激活,从而减轻脓毒症小鼠肺损伤.     

丝裂原蛋白激酶信号转导通路在机械通气相关性肺损伤中的作用

目的观察机械通气介导肺损伤（VILI）过程中丝裂原蛋白激酶（MAPK）的活性变化以及对细胞因子的影响，从中探讨VILI发生机制和MAPK的作用。方法72只SD大鼠随机分为未处理的对照组（不行机械通气）、正常通气组、过度通气组和采用MAPK抑制剂SP600125（JNK）、SB203580（p38）、PD98059（ERK）分别预处理上述3组。机械通气4h后取大鼠肺组织采用Western blot方法测定各组的总JNK、ERK、p-38蛋白激酶的表达及其磷酸化水平变化。同时以酶联免疫吸附试验（EUSA）方法测定大鼠肺组织、支气管肺泡灌洗液（BALF）和血浆中的肿瘤坏死因子-α（TNF-α）、巨噬细胞炎性蛋白-2（MIP-2）浓度。结果正常和过度机械通气4h后均能激活JNK、ERK、p38激酶，但以过度通气组为著（P〈0．01）。过度通气组大鼠肺组织、BALF、血浆中的TNF-α、MIP-2含量显著高于其他组（P〈0．01）。JNK、ERK、p38抑制剂显著降低肺组织、BALF中的TNF-α、MIP-2含量（P〈0．05或0．01），且JNK和ERK抑制剂作用强于p38抑制剂。结论过度机械通气激活了肺细胞中的JNK、ERK、p38激酶，且JNK、ERK、p38参与了VILI细胞因子的产生，即MAPK信号转导通路的激活可能是VILI发生机制之一。     

脂肪乳剂对大鼠肢体缺血再灌注所致肺损伤中IL-6、TNF-α的影响

目的探讨脂肪乳剂对肢体缺血再灌注(limb ischemia/reperfusion)所致肺损伤的大鼠中IL-6和TNF-α的影响。方法 20只SD大鼠随机分为脂肪乳剂处理组(ILP组)和肢体缺血再灌注组(IR组)。所有大鼠均进行下肢缺血3小时,再灌注3小时,ILP组大在再灌注前给予20%的脂肪乳5ml/kg;IR组给予等容量的生理盐水。实验末抽取大鼠腹主动脉血后取血浆测定白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)含量;实验末取部分左上肺进行病理观察及PMN计数,其余左上肺用于肺湿/干重比(W/D)。结果与IR组比较,ILP组肺W/D比值和血浆中IL-6、TNF-α含量明显降低(P0.05),肺组织中中性粒细胞(PMN)计数明显降低(P0.05)。结论脂肪乳剂对大鼠下肢缺血再灌注所致肺损伤有保护作用,该作用与降低血浆中炎症介质有关。     

c-Jun氨基端激酶介导细胞自噬参与肠缺血再灌注肺损伤

目的探讨c-Jun氨基端激酶(JNK)信号通路活化在肠缺血再灌注(II/R)肺损伤的作用及其机制。方法夹闭6～8周龄雄性SD大鼠肠系膜上动脉[SCXK(京)2016-006]建立II/R肺损伤模型, 首先用随机数据表法将36只大鼠随机分为假手术组(Sham)及肠缺血45 min后再灌注即刻(0)、2、6、8、16 h组(每组6只), 蛋白质印迹法(Western blot)检测II/R肺组织磷酸化JNK(p-JNK)及活化蛋白-1(AP-1)蛋白表达;然后再取24只大鼠随机分为Sham组, II/R+溶剂对照组(II/R), II/R+JNK抑制剂组(JNK-), II/R+JNK激动剂组(JNK+), 每组6只, JNK抑制剂SP600125或JNK激动剂Anisomycin预处理大鼠, II/R后6 h处死大鼠提取肺组织, Western blot方法检测肺磷酸化JNK(p-JNK)、AP-1蛋白水平, 免疫荧光检测自噬相关蛋白Beclin-1、微管相关蛋白1轻链3B(LC3B)及p62表达, 测量肺组织湿/干重比(W/D)及苏木精-伊红(HE)染色显微镜观察肺组织病理性学改变, ...     

异氟醚对大鼠肺缺血再灌注损伤的保护作用

目的 探讨异氟醚对大鼠肺缺血再灌注损伤的保护作用。方法 120只SD雄性大鼠，随机分成4组（n=30）：假手术组（S组）、缺血再灌注组（IR组）、异氟醚-缺血再灌注组（ISO-IR组）和异氟醚组（ISO-S组）。IR组、ISO-IR组建立肺缺血再灌注模型，ISO-IR组吸入1MAC异氟醚30min时行肺缺血再灌注，ISO-S组吸入1MAC异氟醚，不进行肺缺血再灌注。分别在缺血45min、再灌注30、60、120min处死6只大鼠，测定肺组织湿干比（W／D）、髓过氧化物酶（MPO）活性、中性粒细胞（PMN）膜表面CD18和肺组织ICAM-1mRNA表达、支气管肺泡灌洗液（BALF）中自细胞计数、沉渣白细胞分类和总蛋白（TP）浓度，并进行肺组织病理学检查。结果 再灌注期间IR组肺组织W／D、MPO活性、CDl8和ICAM-1mRNA表达、BALF中PMN百分比、TP浓度及PMN膜表面CD18表达均升高。而异氟醚预先给药减弱了缺血再灌注诱导的上述指标的升高。肺组织病理学检查显示异氟醚预先给药减轻了肺缺血再灌注损伤。结论 通过抑制PMN浸润和肺组织ICAM-1mRNA及CD18表达上调，缺血前吸入异氟醚对肺缺血再灌注损伤有一定的保护作用。     

舒芬太尼后处理对子宫缺血-再灌注大鼠急性肺损伤的影响

目的研究舒芬太尼后处理对子宫缺血-再灌注(IR)大鼠急性肺损伤的影响。方法成年雌性SD大鼠45只,随机分为三组:对照组(C组)、IR组和舒芬太尼后处理组(SPC组),每组15只。IR组、SPC组建立子宫缺血45 min再灌注2 h模型,SPC组给予舒芬太尼后处理。检测大鼠处理后子宫、血清及肺组织中TNF-α、丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性以及肺湿干重比(W/D)、肺通透性指数(LPI)。结果 IR组、SPC组子宫、血浆及肺脏中TNF-α、MDA含量、W/D、LPI明显高于C组(P0.05);SPC组TNF-α、MDA含量、W/D、LPI明显低于IR组(P0.05);IR组、SPC组子宫、血浆以及肺脏中SOD活性明显低于C组(P0.05);SPC组SOD活性明显高于IR组(P0.05)。结论舒芬太尼后处理能减轻子宫缺血-再灌注大鼠急性肺损伤,可能与减少氧自由基和炎症因子的产生,降低肺通透性,减轻肺水肿,从而减轻子宫缺血-再灌注大鼠引发的急性肺损伤有关。     

异丙酚对机械通气相关肺损伤大鼠肺组织p38MAPK信号通路的影响

目的 探讨异丙酚对机械通气相关肺损伤大鼠肺组织p38丝裂原活化蛋白激酶(p38MAPK)信号通路的影响.方法 雄性清洁级Wistar大鼠30只,体重230～300 g,2～3月龄,采用随机数字表法,将大鼠随机分为3组(n=10):对照组(C组)保留自主呼吸;机械通气组(V组)和异丙酚组(P组)行机械通气4h,P组在机械通气开始时静脉注射异丙酚5 mg/kg,机械通气期间以10mg·kg-1 ·h-1的速率静脉输注异丙酚.于机械通气15 min、1h、2h和4h时记录MAP,并采集股动脉血样,进行动脉血气分析,记录PaO2;机械通气结束时,测定支气管肺泡灌洗液(BALF)中总蛋白、TNF-α和巨噬细胞炎性蛋白-2(MIP-2)的浓度;取肺组织,测定湿干重比(W/D比)、MDA含量、SOD活性、细胞间粘附分子-1(ICAM-1)和p38MAPK、磷酸化p38MAPK(p-p38MAPK)蛋白的表达水平,计算p-p38MAPK/p38MAPK,并观察病理学结果,进行肺损伤评分.结果 与C组比较,V组和P组肺损伤评分、W/D比、肺组织MDA含量、ICAM-1表达、BALF中总蛋白浓度、TNF-α和MIP-2浓度和肺组织p-p38MAPK蛋白表达水平和p-p38MAPK/p38MAPK升高,V组肺组织SOD活性降低(P＜0.05),P组SOD活性差异无统计学意义(P＞0.05);与V组比较,P组肺损伤评分、W/D比、肺组织MDA含量、ICAM-1表达、BALF中总蛋白浓度、TNF-α和MIP-2浓度和肺组织p-p38MAPK蛋白表达和p-p38MAPK/p38MAPK降低,肺组织SOD活性、MAP和PaO2升高(P＜0.05).三组肺组织p38MAPK蛋白表达差异无统计学意义(P＞0.05).结论 异丙酚可能通过抑制p38MAPK信号转导通路的活化减轻大鼠机械通气相关肺损伤.     

乌司他丁对大鼠全肝缺血-再灌注肺损伤的保护作用

目的 观察乌司他丁对大鼠全肝缺血-再灌注(I-R)肺损伤的保护作用.方法 24只SD大鼠随机分为全肝缺血-再灌注组(I-R组)、乌司他丁组(U组)及假手术对照组(C组),每组8只.检测支气管肺泡灌洗液(BALF)中总蛋白含量、肺组织干/湿质量比(D/W)、肺组织髓过氧化物酶(MPO)及超氧化物歧化酶(SOD)含量,并以逆转录聚合酶链式反应(RT-PCR)方法检测三组大鼠肺组织基质金属蛋白酶(MMP)14 mRNA的相对表达量.结果 与U组和C组比较,I-R组大鼠肺组织BALF总蛋白和MPO含量明显增高,肺组织D/W和SOD显著降低.MMP14 mRNA相对表达量显著增高(P<0.05).结论 乌司他丁可减轻全肝I-R肺损伤;抑制肺组织MMP14 mRNA的表达可能是其机制之一.     

槲皮素对重症急性胰腺炎相关性肺损伤肺泡中性粒细胞TLR4/NF-κB通路的影响

目的探讨槲皮素(Quercetin)对大鼠重症急性胰腺炎相关性肺损伤(SAP-LI)肺泡中性粒细胞(PMN)TLR4/NF-κB信号通路的影响。方法 48只成年SD大鼠随机分为4组,每组12只,假手术(Sham)组、重症急性胰腺炎(SAP)组、槲皮素低剂量组(50 mg/kg)及槲皮素高剂量组(100 mg/kg)。逆行性胰胆管注射5%牛磺酸钠建立SAP大鼠模型。槲皮素组在胰腺炎模型基础上予槲皮素干预,Sham组、SAP组给予等量生理盐水。计算肺湿/干重比(W/D)和肺通透指数(LPI),经支气管肺泡灌洗分离收集PMN,ELISA检测PMN培养上清液中TNF-α含量,RT-PCR检测PMN TLR4 m RNA表达,Western blotting检测PMN TLR4和NF-κB p65的表达。结果与Sham组比较,其余三组W/D、LPI及TNF-α含量明显升高,TLR4 m RNA及其蛋白和NF-κB p65蛋白表达上调;与SAP组比较,槲皮素处理组W/D、LPI及TNF-α含量降低,TLR4 m RNA及其蛋白和NF-κB p65蛋白表达下调。结论槲皮素减轻SAP引起的肺损伤可能与其抑制PMN TLR4/NF-κB信号通路活化有关。     

异氟醚对大鼠肺缺血-再灌注损伤的影响

目的探讨异氟醚对大鼠肺缺血-再灌注损伤的影响.方法建立在体大鼠肺缺血-再灌注模型.120只SD雄性大鼠,随机分成四组：缺血-再灌注组（IR组）,异氟醚-缺血-再灌注组（ISO-IR组）,异氟醚组（ISO-C组）和手术对照组（C组）,每组30只.分别在缺血45 min、再灌注30、60、120 min处死大鼠行动脉血气分析、肺组织湿干比（W/D）值、丙二醛（MDA）含量及髓过氧化物酶（MPO）活性测定和肺组织病理学检查;此外,各组于再灌注120 min时另处死大鼠行支气管肺泡灌洗,取灌洗液（BALF）行白细胞计数、沉渣白细胞分类和BALF中总蛋白（TP）含量测定.结果再灌注后,IR组和ISO-IR组肺组织W/D值、MDA含量和MPO活性逐渐升高,且显著高于C组（P〈0.05）;但再灌注60 min后,ISO-IR组肺组织W/D值、MDA含量和MPO活性较IR组均有所降低（P〈0.05）.IR组BALF中的中性粒细胞（PMN）所占百分比较C组显著升高（P〈0.05）,而ISO-IR组的升高并不显著但较IR组显著降低;IR组和ISO-IR组BALF中TP含量均较C组显著升高（P〈0.05）,但ISO-IR组又低于IR组（P〈0.05）;肺组织病理学检查示ISO-IR组病理学变化较IR组显著减轻.结论异氟醚的吸入对缺血-再灌注损伤的肺组织具有一定的保护作用.     

Protection of carbon monoxide-releasing molecule against lung injury induced by limb ischemia-reperfusion

Ohiective: To observe the role and mechanism of Coreleasing molecule (CORM)-2 in lung injury induced by ischemia-reperfusion (IR) of hind limbs in rats.Methods: A rat model of lung injury induced by IR of hind limbs was established.A total of 40 Sprague Dawley (SD) rats were randomly divided into 5 groups (n=8):sham,shanl+CORM-2,IR,IR+CORM-2and IR+dimethyl sulfoxide (DMSO).Rats in the IR group received hind limb ischemia for 2 hours and reperfusion for 2 hours,rats in the sham group underwent sham surgery without infrarenal aorta occlusion.rats in the IR+CORM-2 group and in the sham+CORM-2 group were given CORM-2 (10 pmol/kg in travenous bolus) 5 minutes before reperfusion or at the corresponding time points.while rats in the IR+DMSO group was treated with the same dose of vehicle (DMSO) at the same time.The lung tissue structure,polymorphonuclear neutrophil (PMN) count,wet-to-dry weight ratio (W/D),malondialdehyde (MDA) content,myeloperoxidase (MPO) activity,intercellular adhesion molecule-1 (ICAM-1) expression,I κ Bo degradation and nuclear factor (NF)-κB activity in the lungs were assessed.Results: As compared with the sham group.lung PMNs number,W/D,MDA content,MPO activity,ICAM-1 expression and NF-κB activity significantly increased in the IR group,but the level of I κ Bo decresed (P＜0.01).Compared with the IR group,lung PMNs number,W/D,MDA content.MPO activity and ICAM-1 expression significantly decreased in the IR+COMR-2 group (P＜0.01),while the level of I κ Ba increased.Conclusions: These data demonstrate that CORM-2 attenuates limb IR-induced lung injury through inhibiting ICAM-1 protein expression.NF-κ B pathway and the leukocytes sequestration in the lungs following limb IR in rats,suggesting that CORM-2 may be used as a therapeutic agent against lung injury induced by limb IR.     

缺血后处理对骨骼肌缺血再灌注后肺损伤保护作用的机制

目的：探讨缺血后处理（I-postC）对大鼠双侧后肢骨骼肌缺血再灌注（I/R）后肺损伤的保护作用及机制。方法：阻断肾下腹主动脉建立大鼠双侧后肢骨骼肌I/R损伤模型。48只大鼠随机分为3组：I/R组、缺血预处理（IPC）组及I-postC组,每组16只。分别于再灌注后12、24h各处死8只,取肺组织标本,观察肺组织形态学、湿/干重比、丙二醛（MDA）及髓过氧化物酶（MPO）的变化。原位杂交和RT-PCR方法检测肺组织中细胞间黏附分子（ICAM）-1mRNA的表达,Western blot检测ICAM-1蛋白表达。结果：再灌注12或24h后I/R组有明显的弥散功能障碍,表现为间质浸润细胞增多并伴有明显水肿。IPC组和I-postC组的各项指标均较I/R组明显降低,差异有统计学意义（P〈0.01）,但2组之间差异无统计学意义（P〉0.05）。结论：I-postC可以减轻大鼠双侧后肢骨骼肌I/R后肺损伤,与IPC可能存在共同的作用机制。     

丹参及β-七叶皂甙钠对烫伤大鼠急性肺损伤的抑制作用

目的 探讨丹参及β-七叶皂甙钠对烫伤大鼠急性肺损伤(acute lung injury，ALI)的治疗作用及其机制，为临床治疗烧伤后ALI提供理论依据。方法 制作30％TBSAⅢ度大鼠烫伤模型，并随机分为盐水组、丹参组、β-七叶皂甙钠组及联合组，另设假烫对照组，每组9只。烫伤后24h取静脉血测外周血白细胞粘附聚集(LAA)；取肺组织测髓过氧化物酶(MPO)、丙二醛(MDA)、超氧化物歧化酶(SOD)含量及肺组织湿干重量比(W／D)。结果 丹参组、β-七叶皂甙钠组及联合组外周血LAA、肺组织MPO及MDA、肺组织W／D明显低于盐水组，联合组最低；SOD含量明显高于盐水组，联合组最高。外周血LAA与肺组织MPO含量呈正相关。结论 丹参及β-七叶皂甙钠可减轻中性粒细胞(PMN)在肺内的聚集、粘附，减轻氧自由基(OFR)及其代谢产物对肺组织的损伤，增加抗氧化剂含量，降低肺微血管通透性和肺水含量，对烧伤后肺损伤有一定防治作用，联合应用效果更佳。     

右美托咪定对大鼠离体肺缺血-再灌注损伤时RIP K3/MLKL介导程序性坏死的影响

目的评价右美托咪定对大鼠离体肺缺血-再灌注损伤(LIRI)时受体相互作用蛋白激酶3(RIPK3)/混合系列蛋白酶样结构域(MLKL)介导的肺组织细胞程序性坏死的影响。方法成年雄性SD大鼠72只,采用随机数字表法随机分成三组(n=24):缺血-再灌注损伤组(IR组)、右美托咪定组(DEX组)和对照组(C组)。IR组采用IL-2型离体肺灌流系统建立大鼠离体LIRI模型; DEX组在复灌开始时于灌流液中加入右美托咪定10 nmol/L;C组只通气和灌流。测定大鼠肺组织湿/干重比(W/D),光镜下观察肺组织病理学并测定肺泡损伤率(IAR)。测定灌流液中超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量。Western blot法分别检测肺组织中RIPK3和MLKL蛋白含量。结果与C组比较,IR组和DEX组肺组织W/D、IAR和灌流液中MDA含量均明显升高(P0.05),而灌流液中SOD活性均明显降低(P0.05)。与IR组比较,DEX组肺组织W/D、IAR和灌流液中MDA含量均明显降低(P0.05),而灌流液中SOD活性明显升高(P0.05)。光镜显示IR组肺组织形态学结构发生明显损伤,而DEX组则明显减轻。与C组比较,IR组和DEX组肺组织RIPK3和MLKL蛋白含量均明显升高(P0.05);与IR组比较,DEX组肺组织RIPK3和MLKL蛋白含量均明显降低(P0.05)。结论右美托咪定可通过抑制RIPK3/MLKL介导的肺组织细胞程序性坏死来减轻大鼠离体肺缺血-再灌注损伤。     

c-Jun氨基末端激酶在大鼠内毒素性急性肺损伤中的作用

目的 评价c-Jun氨基末端激酶(JNK)在大鼠内毒素性急性肺损伤中的作用.方法 雄性成年SD大鼠80只,体重250～300 g,采用随机数字表法,将其随机分为4组(n=20):对照组(C组)、急性肺损伤组(ALI组)、SP600125组(S组)和二甲基亚砜组(D组).ALI组、S组和D组尾静脉注射LPS 5 mg/kg,C组尾静脉注射等容量生理盐水;S组和D组给予LPS后,分别尾静脉注射JNK抑制剂SP600125 30 mg/kg或二甲基亚砜0.2 ml.于给予LPS后4 h时,各组处死10只大鼠,回收支气管肺泡灌洗液(BALF)并取肺组织,采用ELISA法检测BALF中TNF-α和IL-1β的浓度,计算肺组织湿重/干重比(W/D比),观察肺组织病理学结果,并进行肺损伤评分.各组其余10只大鼠观察至给予LPS后48 h,记录大鼠生存情况.结果 与C组比较,其余各组BALF中TNF-α和IL-1β的浓度、肺组织W/D比和肺损伤评分升高,生存率降低(P<0.05或0.01);与ALI组比较,S组BALF中TNF-α和IL-1度、肺组织W/D比和肺损伤评分降低,生存率升高(P<0.01),D组差异无统计学意义(P>0.05).结论 JNK的活化参与了大鼠内毒素性急性肺损伤的发生发展.

Abstract：

Objective To evaluate the role of c-Jun N-terminal kinase (JNK) in lipopolysaccharide (LPS)-induced acute lung injury ( ALI) in rats.Methods Eighty male SD rats weighing 250-300 g were randomly divided into 4 groups ( n = 20 each) : control group (group C) ; ALI group; LPS + SP600125 (JNK inhibitor)group (group S) and LPS+ DMSO (the solvent) group (group DMSO) . ALI was induced by intravenous LPS 5mg/kg. In S and DMSO groups, SP600125 30 mg/kg and DMSO 0.2 ml were injected intravenously after LPS administration respectively. Ten animals were sacrificed by exsanguinafions at 4 h after LPS administration in each group. The broncho-alveolar lavage fluid (BALF) was colleted. The TNF-α and IL-1β concentrations in BALF were measured. The lungs were removed for microscopic examination and determination of W/D lung weight ratio. The other 10 animals in each group were observed for 48 h survival rate. Results Intravenous LPS significantly increased TNF-α and IL-1β concentrations in BALF and W/D lung weight ratio, decreased 48 h survival rate and induced histologic damage. Intravenous SP600125 30 mg/kg significantly attenuated the above-mentioned LPS-induced changes. Conclusion Activation of JNK is involved in the development of endotoxin-induced ALI in rats.     

内源性一氧化氮在非创伤性缺血预处理中对兔肺的保护作用

目的探讨内源性一氧化氮（NO）在非创伤性缺血预处理（N—WIP）中对兔肺缺血／再灌注（I／R）损伤的保护作用及可能机制。方法采用N-WIP及经典缺血预处理（C-IP）的动物模型，比较两种缺血预处理方法中内源性NO对兔肺在缺血／再灌注损伤中的保护效应。将40只大白兔随机平均分为4组：对照组、I／R组、C—IP组和NWIP组。对比观察各组血清及肺组织中NO2^-／NO3^-、丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性以及肺湿／干重比。结果N—WIP组和C-IP组的兔肺再灌注后NO2^-／NO3^-含量均高于I／R组（P〈0．01），甚至高于对照组（P〈0．05）。两种缺血预处理组SOD活性均高于I／R组（P〈0．01），肺湿／干重比和MDA含量均低于I／R组（P〈0．05，P〈0．01）。结论N-WIP与C-IP对移植肺在缺血／再灌注损伤中具有同等强度的保护作用。其机制可能是通过诱发内源性一氧化氮（NO）舒张血管，从而起到保护血管内皮的效应。     

Pravastatin attenuates lower torso ischaemia-reperfusion-induced lung injury by upregulating constitutive endothelial nitric oxide synthase.

OBJECTIVES: to elicit whether pre-treatment with pravastatin will prevent or ameliorate the acute lung injury that occurs following lower torso ischaemia-reperfusion (IR) in an experimental animal model. MATERIALS AND METHODS: male Sprague-Dawley rats were randomised into three groups (n=7/group). The control group underwent a sham laparotomy and aortic dissection. The second group underwent infrarenal aortic cross clamping for 30 min followed by reperfusion for 120 min. The third group pre-treated with pravastatin sodium (0.4 mg/kg/day over 5 days) were again subjected to an ischaemia-reperfusion (IR) injury. The parameters used to assess lung injury included: Wet to dry lung weight ratio (W:D), myeloperoxidase activity (MPO), protein concentration (BALprot) and neutrophil count (BAL PMN) of bronchoaveolar lavage fluid. Western blotting was used to determine the expression of constitutive endothelial nitric oxide synthase (ecNOS) within lung tissue. RESULTS: IR causes an acute lung injury as indicated by statistically significant differences in W:D lung weight ratios, MPO activity, neutrophil count and BALprotein concentration in the IR group over that of controls. Pre-treatment with pravastatin attenuated this neutrophil infiltration and microvascular leakage. The pravastatin group showed a marked increased expression of ecNOS over that of the IR group and controls. CONCLUSION: this data indicates that pre-treatment with pravastatin protects against ischaemia-reperfusion induced lung injury in an experimental animal model. We believe that its mechanism of action involves an upregulation of ecNOS, which increases basal expression of nitric oxide providing protective effects on the pulmonary circulation against microvascular injury.     

辛伐他汀预处理对肢体缺血再灌注诱发肺损伤大鼠肺组织血红素加氧酶-1表达的影响

目的 评价辛伐他汀预处理对肢体缺血再灌注诱发肺损伤大鼠肺组织血红素加氧酶-1(HO-1)表达的影响.方法 成年雄性SD大鼠48只,体重250～300 g,采用随机数字表法,将大鼠随机分为6组(n=8):假手术组(S组)、肢体缺血再灌注组(IR组)、辛伐他汀1、5、10 mg/kg组(S1组、S2组、S3组)和辛伐他汀对照组(SC组).采用夹闭股动脉2 h,再灌注3 h的方法制备肢体缺血再灌注模型.S组:仅分离股动脉和股静脉,不夹闭;IR组:制备肢体缺血再灌注模型;S1组、S2组、S3组:分别将辛伐他汀1、5、10 mg/kg溶于1 ml蒸馏水,于每13清晨灌胃1次,连续灌胃3 d后制备肢体缺血再灌注模型;SC组:辛伐他汀10 mg/kg溶于1 ml蒸馏水,于每日清晨灌胃1次,连续灌胃3 d.再灌注3 h时取颈动脉血样,行血气分析,记录PaO2和PaCO2,随后处死大鼠,取肺组织,观察病理学结果,计算湿重/干重比(W/D比),测定SOD活性,计数PMN,测定HO-1 mRNA及其蛋白的表达水平.结果 与S组比较,IR组PaO2及PaCO2降低,IR组、S1组和S2组肺组织W/D比和PMN计数升高,SOD活性降低(P＜0.05),S3组和SC组上述指标差异无统计学意义(P＞0.05),IR组、S1组、S2组、S3组和SC 组肺组织H0-1 mRNA及其蛋白表达上调(P＜0.01);与IR组比较,S1组、S2组和S3组PaO2、PaCO2及肺组织SOD活性升高,肺组织W/D比和PMN计数降低,肺组织HO-1 mRNA及其蛋白表达上调(P＜0.05或0.01);S1组、S2组和S3组肺组织WID比和PMN计数依次降低,SOD活性依次升高,HO-1 mRNA及其蛋白表达依次上调(P＜0.05或0.01).S1组、S2组和S3组肺组织病理性损伤较IR组减轻.结论 辛伐他汀预处理可上调肢体缺血再灌注大鼠肺组织HO-1的表达,从而产生肺保护作用,且呈剂量依赖性.

Abstract：

Objective To investigate the effects of simvastatin preconditioning on the pulmonary heme oxygenase-1 (HO-1) expression in rats with lung injury induced by ischemia-reperfusion (I/R) of hind limbs. Methods Forty-eight adult male SD rats weighing 250-300 g were randomly divided into 6 groups ( n = 8 each) : sham operation group (group S) ; I/R group; I/R + simvastatin 1,5, 10 mg/kg groups (S1 , S2, S3 groups) ; simvastatin control group (group SC) . I/R of hind limbs was produced by occlusion of bilateral femoral arteries for 2 h followed by 3 h reperfusion. Croups S1 , S2 , S3 received simvastatin 1, 5, 10 mg/kg respectively via an oro-gastric tube for 3 days before I/R. Group SC received simvastatin 10 mg/kg via an oro-gastric tube for 3 days. Arterial blood samples were taken at 3 h of reperfusion for blood gas analysis and PaO2 and PaCO2 were recorded. The animals were then sacrificed and the lungs removed immediately for pathologic examination and determination of the wet/dry lung weight ratio (W/D ratio), superoxide dismutase (SOD) activity and polymorphonuclear neutrophil (PMN) count . Hie expression of HO-1 mRNA and protein in lung tissues was detected using RT-PCR and Western blot analysis respectively.Results Alveolar edema, localized pulmonary atelectasis and large amount of PMN infiltration were found in I/R group and were ameliorated in S1, S2, S3 groups. Compared with group S, PaO2 and PaCO2 were significantly decreased in I/R group, W/D ratio and PMN count were increased and SOD activity was significantly decreased in I/R, S1 , S2 groups, and expression of HO-1 mRNA and protein was up-regulated in the other five groups ( P ＜ 0.05). PaO2, PaCO2 and SOD activity were significantly increased, W/D ratio and PMN count were significantly decreased, and HO-1 mRNA and protein expression was up-regulated in S1, S2 and S3 groups as compared with I/R group ( P ＜ 0.05 or 0.01). W/D ratio and PMN count were gradually decreased, SOD activity was gradually increased, and HO-1 mRNA and protein expression was gradually up-regulated in S1, S2 and S3 groups. Conclusion Simvastatin preconditioning has protective effect against lung injury induced by I/R of hind limbs in rats through up-regulation of HO-1 expression in the lung tissues and in a dose-dependent manner.