乌司他丁对脂多糖致小鼠急性肺损伤的保护作用以及与诱导型一氧化氮合酶和c-Jun表达的关系

目的探讨乌司他丁对脂多糖(LPS)致小鼠急性肺损伤的作用及其机制。方法小鼠腹腔注射乌司他丁(50和100 ku.kg-1)或等体积生理盐水30 m in后,分别静脉注射LPS 15 mg.kg-1或等体积生理盐水,于注射LPS后不同时间检测有关各项指标。ELISA法测定血清和肺组织中TNFα水平,RT-PCR法测定TNFαmRNA和iNOS mRNA的表达。W estern b lotting法检测c-Fos,c-Jun及iNOS等蛋白表达。结果乌司他丁100 ku.kg-1能显著降低LPS引起的小鼠的肺脏指数、肺组织及血清中NO水平的增加,下调肺组织c-Jun蛋白表达量和iNOS mRNA及其蛋白的表达量,而对小鼠的血清和肺组织冲洗液中TNFα含量以及肺组织MDA无明显影响。结论乌司他丁对LPS引起的小鼠肺损伤有保护作用,该作用与其抑制c-Jun蛋白和iNOS mRNA的表达有关。     

乌司他丁对小鼠内毒素性急性肺损伤的保护作用

目的探讨乌司他丁（UTI）对内毒素性急性肺损伤的保护作用及其机制。方法将昆明种小鼠50只随机分为脂多糖（LPS）组和UTI组，腹腔注射LPS建立小鼠急性肺损伤模型，直接心脏穿刺抽血查血气分析，用放射免疫法分别测定各组各时相点肺组织匀浆上清液中肿瘤坏死因子α（TNF—α）、白介素-8（IL-8）、白介素-10（IL-10）3种细胞因子的含量，同时观察肺组织形态学改变，进行肺湿／干重比值（W／D）测定。结果两组小鼠肺组织中炎症因子呈明显上升趋势，UTI组促炎因子升高幅度显著低于LPS组（P〈0．01），而抗炎因子升高幅度明显高于LPS组（P〈0．05），且肺组织W／D值明显低于LPS组（P〈0.05），血氧分压（PaO2）高于LPS组（P〈0．05）。结论UTI可减轻炎症因子介导的急性肺损伤，其机制可能是通过调节促炎因子／抗炎因子平衡来实现的。     

乌司他丁对急性肺损伤的保护作用

目的：寻求可有效治疗急性肺损伤并能阻止其发展的临床药物，促进乌司他丁在临床上的应用。方法：介绍了乌司他丁的化学性质、药理学作用及其对蛋白酶、氧自由基、细胞因子的影响。结果和结论：在急性肺损伤的发生发展过程中，乌司他丁具有保护损伤肺脏的药理学基础，对急性肺损伤有较好的应用价值．     

乌司他丁对大鼠SAP肺损伤的保护作用

目的探讨大鼠重症急性胰腺炎(SAP)合并肺损伤的发病因素及乌司他丁对大鼠SAP合并肺损伤模型的保护作用。方法48只SD大鼠随机均分为三组:假手术组(S)、SAP组、乌司他丁治疗组(U),每组再分为术后6小时和12小时亚组。检测血AMY、TNF-α、MDA和肺MPO浓度并对胰、肺组织进行病理评分,比较U组给药后上述指标的变化。结果(1)U组血AMY、TNF-α、MDA和肺MPO浓度及胰、肺病理评分与同时点SAP组相比明显降低(P<0.05);(2)SAP组TNF-α在12小时比6小时明显下降(P<0.05);(3)血AMY、TNF-α、MDA和肺MPO浓度与胰、肺病理评分呈正相关(r=0.343~0.781,P<0.01)。结论(1)TNF-α、MDA和肺组织MPO是引起SAP合并肺损伤的重要因素,乌司他丁能减轻SAP合并肺损伤;(2)通过检测血AMY、TNF-α、MDA和肺MPO浓度可以间接地反映胰、肺损伤的程度。     

乌司他丁对急性肺损伤小鼠肺组织中白细胞介素-10表达的影响

目的探讨鸟司他丁（UTI）对急性肺损伤（Au）小鼠肺组织中白细胞介素-10（IL-10）表达的影响。方法将昆明种小鼠50只随机分为脂多糖（LPs）组和uTI组，腹腔注射LPS建立小鼠急性肺损伤模型，用放射免疫法测定各组各时相点肺组织匀浆上清液中IL-10的含量，同时观察肺组织形态学改变。结果两组小鼠肺组织中IL-10含量均呈上升趋势，UTI组升高幅度明显高于LPS组（P〈0．05）。结论UTI可能通过上调抗炎因子IL-10的表达，对Au小鼠产生保护作用。     

乌司他丁对家兔急性肺损伤保护的实验研究

目的探讨乌司他丁对急性肺损伤（ALI）家兔肺组织肿瘤坏死因子（TNF—α）mRNA表达的影响及其对肺损伤的治疗作用。方法将30只家兔随机分为对照组（A组）,肺损伤对照组（B组）和乌司他丁治疗组（C组）,每组10只,B组和C组采用特制多功能撞击机制成急性肺损伤模型,B组经耳缘静脉给予生理盐水静滴,C组经耳缘静脉给予乌司他丁静滴（100000u／kg）,分别在损伤前,损伤后2、4、6h采血测定TNF—a水平,6h后处死动物,取肺组织测定肺水含量、肺体质量比值及观察病理变化、肺组织TNF—α水平、TNF—αmRNA表达。结果与A组相比,B组损伤后肺水含量及肺体质量比值显著增高（P〈0．05）,镜下见肺间质、肺泡水肿、大量炎细胞浸润。肺组织及血浆TNF-α水平、肺组织TNF-αmRNA表达显著升高（P〈0．05）,PaOz显著降低（P〈0．05）,C组经乌司他丁治疗后,与B组比较,肺水含量及肺体质量比值增加少,肺水肿,减轻肺组织及血浆TNF-α水平、肺组织TNF-αmRNA表达降低（P〈0．05）,PaO2明显升高（P〈O．05）。结论乌司他丁能抑制ALI家兔肺组织肺水含量及肺体质量比值增加少,肺水肿,减轻肺纽织及血浆TNF—α水平、肺组织TNF0mRNA表达降低（P〈0．05）,PaO2明显升高（P〈0．05）,减轻肺组织的病理损害,治疗ALI。     

乌司他丁对感染性休克患者肺损伤的保护作用

目的探讨大剂量乌司他丁对感染性休克患者肺损伤的保护作用。方法80例感染性休克合并肺损伤患者随机均分为两组:A组在综合治疗基础上加用乌司他丁(100万U泵注,每12小时1次,连续应用7d);B组仅采取综合治疗。治疗前及治疗后第3、7天检测肺泡灌洗液肿瘤坏死因子α(TNF-α)和白细胞介素1β(IL-1β)表达及肺血管外肺水含量。比较两组ICU住院时间和疗效。结果与B组比较,A组ICU住院时间缩短[(8.7±2.9)d vs.(11.4±3.5)d](P<0.05),治疗有效率高(75.0%vs.62.5%)(P<0.05),病死率低(15.0%vs.27.5%)(P<0.05)。A组治疗后肺泡灌洗液TNF-α、IL-1β和肺血管外肺水含量低于B组(P<0.05)。结论大剂量乌司他丁可减少感染性休克患者肺部炎症反应及毛细血管渗漏,改善预后。     

乌司他丁对急性肺损伤的保护作用

乌司他丁是由Beuer和Reich于1909年在人类尿液中发现的广谱蛋白水解酶抑制剂（UTI）,同时乌司他丁还能抑制多种炎性反应介质的释放,从而保护机体重要器官的功能。近年来乌司他丁在急性肺损伤的治疗中得到了越来越广泛的临床应用,现将其化学性质、药理作用及肺保护机制做一简介。     

乌司他丁对创伤后急性肺损伤的早期干预效果观察

目的分析乌司他丁早期应用对于创伤后ALI患者的干预效果。方法将67例创伤性急性肺损伤患者分为观察组(n=35)和对照组(n=32),在常规治疗基础上,观察组静注点滴乌司他丁10万U.kg-1加入生理盐水20mL,对照组静滴生理盐水20mL,对照研究两组临床指标与实验室指标的变化。结果观察组临床指标明显改善,入院后24h、3d时的TNF-α、IL-6和IL-8检查结果较入院时明显下降,与对照组比较有显著性差异。结论乌司他丁配合原发病治疗与肺保护性通气,有助于抑制肺组织炎症反应,改善ALI患者呼吸功能及预后。     

咯利普兰对脂多糖诱导的小鼠急性肺损伤的抑制作用

目的探讨磷酸二酯酶4(PDE4)抑制剂治疗急性肺损伤的作用机制。方法气道内滴入脂多糖3 mg.kg-1制备小鼠急性肺损伤模型,10 min后一次性ip不同剂量咯利普兰或地塞米松;同时设假手术和模型组。给药6 h后处死小鼠,观察肺湿重/干重比值和肺组织的病理改变;用细胞形态学方法计数支气管肺泡灌洗液(BALF)中白细胞和中性粒细胞;考马斯亮蓝法测定BALF总蛋白含量;髓过氧化物酶(MPO)活性测定试剂盒测定肺组织匀浆MPO活性;ELISA法测定肺组织匀浆肿瘤坏死因子α(TNF-α)含量;高效液相色谱法测定肺组织匀浆中cAMP-PDE和PDE4活性。结果小鼠气道内滴入脂多糖6 h后,与假手术组比较,模型组肺湿重/干重比值明显升高;肺组织病理观察可见肺血管和气道周围有大量中性粒细胞浸润;BALF中白细胞和中性粒细胞增多,蛋白含量增加;肺组织MPO活性、TNF-α水平、cAMP-PDE和PDE4活性升高。与模型组比较,咯利普兰(0.1,0.3及1.0 mg.kg-1)和地塞米松(0.5 mg.kg-1)可降低肺组织湿重/干重比值,降低BALF中白细胞总数、中性粒细胞数目和蛋白含量,改善肺组织病理变化,肺组织中MPO活性、TNF-α含量、cAMP-PDE和PDE4活性亦明显降低。结论咯利普兰治疗急性肺损伤的作用机制可能与抑制PDE4活性、抑制中性粒细胞黏附和趋化及降低TNF-α水平有关。     

乌司他丁对急性中毒相关肾损伤的保护作用

目的:探讨乌司他丁在治疗急性中毒相关肾损伤的预防和治疗作用。方法:128例急性中毒患者随机分为治疗组和对照组,对照组进行常规治疗,治疗组在常规治疗基础上加用乌司他丁10万U每日2次静脉滴注。观察患者的临床症状改善情况,常规检测患者血清肌酐(Cr)、尿素氮(BUN)及白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平,观察2组之间急性肾损伤的发生率和对急性肾损伤的疗效。结果:治疗组中发病后24h内及72h内患者急性肾损伤发生率分别为3%和7.5%,对照组分别为11.3%和21.2%,2组比较差异有统计学意义(P<0.05);各治疗3、7d后,治疗组均较对照组肾损伤程度显著减轻(P<0.05)。结论:乌司他丁在急性中毒治疗中可以显著减少急性肾损伤的发生率,并可促进已发生急性肾损伤的好转。     

甘草酸单铵对脂多糖致小鼠急性肺损伤的保护作用

采用脂多糖(lipopolysaccharide，LPS)气道滴入诱导小鼠急性肺损伤(acute lung injury，ALI)模型，研究甘草酸单铵(monoammonium glycyrrhizinate，MAG)对ALI的防治作用及其机制。雄性ICR小鼠随机分为生理盐水(NS)对照组、MAG 3、10 及30 mg·kg^-1组、LPS组、地塞米松(dexamethasone，DXM) 5 mg·kg^-1组。MAG各组气道滴入LPS前1 h及滴入后3 h各给药1次，DXM组气道滴入LPS前1 h给药1次。LPS气道滴入后6 h处死动物，测定各组的肺湿重/干重比、肺通透性、肺组织中性粒细胞髓过氧化物酶(myeloperoxidase，MPO)含量、ELISA法检测肺组织匀浆TNF-α、IL-10含量，常规细胞形态学检测中性粒细胞在支气管肺泡灌洗液(bronchoalveolar lavage fluid，BALF)中的比例和肺组织病理改变。结果表明，MAG剂量依赖性减轻气道内滴入LPS诱导的小鼠ALI程度，降低肺湿重/干重比及肺组织伊文斯蓝的渗出，降低BALF中白细胞总数和中性粒细胞数比例，抑制组织MPO的释放，降低肺组织匀浆TNF-α的含量，增加肺组织IL-10的释放。以上结果提示，MAG可能通过调节TNF-α/IL-10的平衡而有效保护脂多糖诱导的急性肺损伤。     

乌司他丁对糖尿病脓毒症大鼠急性肾损伤的保护作用

目的 探讨乌司他丁(UTI)对糖尿病脓毒症大鼠肾损害的作用及其机制.方法 采用高脂饲料喂养+腹腔小剂量注射链脲佐菌素方法制备大鼠2型糖尿病模型,取造模成功的大鼠40只随机分为4组,每组10只:糖尿病组(D组)、糖尿病假手术组(S组)、糖尿病脓毒症组(DS组)、糖尿病脓毒症UTI预处理组(U组).另随机抽取同批次大鼠10只,作C组空白对照.采用盲肠结扎穿孔术(CLP)构建脓毒症模型.U组于CLP前1 h予尾静脉注射UTI 100 kU·kg-1.S组拉出盲肠至腹外放置1 min.于CLP术后12 h,检测各组大鼠肾组织病理情况,定量尿微量白蛋白(UMA),内生肌酐清除率(Ccr),血清肿瘤坏死因子-α(TNF-α)、白细胞介素-18(IL-18)含量,血清丙二醛(MDA)、超氧化物歧化酶(SOD)水平,以及肾组织低氧诱导因子-1α(HIF-1α)的蛋白表达水平.结果 与S组相比,DS组大鼠肾脏病理损害明显,UMA、IL-18、TNF-α、MDA、HIF-1α水平增高,Ccr和SOD活性降低(均P<0.05).DS组相比,U组大鼠肾脏病理损害减轻,UMA、IL-18、TNF-α、MDA含量、HIF-1α水平降低,Ccr和SOD活性增高(均P<0.05).结论 UTI可有效改善糖尿病脓毒症所致急性肾损伤大鼠的肾脏功能,其机制可能与抑制炎性反应、降低氧化应激、改善肾脏缺氧情况有关.     

Rutin improves endotoxin‐induced acute lung injury via inhibition of iNOS and VCAM‐1 expression

Endotoxins exist anywhere including in water pools, dust, humidifier systems, and machining fluids. The major causal factor is endotoxins in many serious diseases, such as fever, sepsis, multi‐organ failure, meningococcemia, and severe morbidities like neurologic disability, or hearing loss. Endotoxins are also called lipopolysaccharide (LPS) and are important pathogens of acute lung injury (ALI). Rutin has potential beneficial effects including anti‐inflammation, antioxidation, anti‐hyperlipidemia, and anti‐platelet aggregation. Pre‐treatment with rutin inhibited LPS‐induced neutrophil infiltration in the lungs. LPS‐induced expression of vascular cell adhesion molecule (VCAM)‐1 and inducible nitric oxide synthase (iNOS) was suppressed by rutin, but there was no influence on expression of intercellular adhesion molecule‐1 and cyclooxygenase‐2. In addition, activation of the nuclear factor (NF)κB was reduced by rutin. Furthermore, we found that the inhibitory concentration of rutin on expression of VCAM‐1 and iNOS was similar to NFκB activation. In conclusion, rutin is a potential protective agent for ALI via inhibition of neutrophil infiltration, expression of VCAM‐1 and iNOS, and NFκB activation. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 185–191, 2016.     

乌司他丁预先给药对单肺通气患者肺损伤的影响

目的评价乌司他丁预先给药对单肺通气患者肺损伤的影响。方法择期行食道下段癌切除术患者60例,随机分为对照组(C组)和乌司他丁组(U组),每组30人。U组按5000 U.kg-1计算乌司他丁用量,半量于入室后缓慢静脉注射,半量持续1 h静脉点滴。C组以等量生理盐水代替。于麻醉诱导前(T1),单肺通气即刻(T2),单肺通气30 min(T3),双肺通气30 min(T4),术毕(T5)取血样,检测血清白细胞介素6(IL-6),肿瘤坏死因子α(TNF-α),肺表面活性蛋白A(SP-A),血清丙二醛(MDA)和8-异前列腺素(8-iso-PGF2a)的浓度。结果与T1时比较,T3,T4,T5时2组血清IL-6,TNF-α水平都升高(P<0.05或P<0.01),而U组升高幅度小,2组比较差异有统计学意义(P<0.05);C组血清SP-A,MDA,8-iso-PGF2a水平升高(P<0.05),U组差异无统计学意义;U组较C组T3,T4,T5时血清IL-6,SP-A,MDA,8-iso-PGF2a升高水平低,差异有统计学意义(P<0.05)。结论乌司他丁预先给药可减轻单肺通气造成的肺损伤。     

卢帕他定干预兔油酸型急性肺损伤的研究

急性肺损伤(ALI)就是通常所定义的急性非心源性的水肿性肺损伤，是临床重症监护病人主要的死亡原因。本研究以油酸静注制备新西兰兔ALI模型，检测动脉血气参数变化，测定支气管肺泡灌洗液(BALF)中蛋白和血小板活化因子(PAF)、细胞间粘附分子-1(ICAM-1)及白细胞介素-8(IL-8)的含量，检测肺湿/干重(W/D)比值，观察组织病理学变化。结果表明，卢帕他定能抑制兔油酸型ALI的Pa_o2的下降，降低BALF中PAF，ICAM-1和IL-8的含量，减少蛋白渗出，降低肺W/D比值，减轻肺组织病理学损伤。卢帕他定可明显改善兔ALI，作用机制可能与抑制炎症因子合成与释放有关。     

Protective effects of pravastatin in murine lipopolysaccharide-induced acute lung injury

1. The present study was designed to determine whether pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, could attenuate acute lung injury (ALI) induced by lipopolysaccharide (LPS) in BALB/c mice. 2. Acute lung injury was induced successfully by intratracheal administraiton of LPS (3 microg/g) in BALB/c mice. Pravastatin (3, 10 and 30 mg/kg, i.p.) was administered to mice 24 h prior to and then again concomitant with LPS exposure. 3. Challenge with LPS alone produced a significant increase in lung index and the wet/dry weight ratio compared with control animals. Pulmonary microvascular leakage, as indicated by albumin content in the bronchoalveolar lavage fluid (BALF) and extravasation of Evans blue dye albumin into lung tissue, was apparently increased in LPS-exposed mice. Lipopolysaccharide exposure also produced a significant lung inflammatory response, reflected by myeloperoxidase activity and inflammatory cell counts in BALF. Furthermore, histological examination showed that mice exposed to LPS also exhibited prominent inflammatory cell infiltration and occasional alveolar haemorrhage. 4. Pravastatin (3, 10 or 30 mg/kg, i.p.) produced a significant reduction in multiple indices of LPS-induced pulmonary vascular leak and inflammatory cell infiltration into lung tissue. Elevated tumour necrosis factor (TNF)-alpha levels in lung tissue homogenates of ALI mice were significantly decreased after administration of 10 or 30 mg/kg pravastatin. 5. These findings confirm significant protection by pravastatin against LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI. The inhibitory effect of pravastatin was associated with its effect in decreasing TNF-alpha.     

Glutamine attenuates hyperoxia-induced acute lung injury in mice

1. Glutamine is an amino acid that is used to treat various diseases. Glutamine has been reported to have protective effects in human pulmonary epithelia-like cells exposed to hyperoxia. However, the effects of glutamine in hyperoxia-induced lung injury have not been investigated in vivo .
2. Mice treated with saline or glutamine [(750 mg/kg) intravenously] were randomly exposed to hyperoxia for 48 or 72 h. Control mice treated with saline or glutamine were exposed to room air. Cytokine levels in bronchoalveolar lavage fluid (BALF), heat shock protein (HSP) 70, the wet/dry (W/D) weight ratio, malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity and pathoglogical findings in lung tissue were evaluated to determine the effects of glutamine on acute lung injury. In addition, survival was monitored.
3. Lung expression of HSP70 was significantly enhanced in both the control (room air) and 48 and 72 h hyperoxic glutamine-treated mice. The W/D ratio, BALF concentrations of tumour necrosis factor-α and interleukin-6, MDA levels, MPO activity, neutrophil infiltration and interstitial oedema in lung tissue were significantly lower at 48 and 72 h of hyperoxia in glutamine-treated mice compared with saline-treated mice.
4. In a separate series of experiments evaluating survival, after 96 h continuous exposure to hyperoxia, all saline-treated mice died. In contrast, all glutamine-treated mice died after 108 h exposure to hyperoxia.
5. The data suggest that glutamine administered to mice during hyperoxia has a protective effect against hyperoxia-induced acute lung injury and improves survival.