唐佳佳+张黔
[摘要] 目的 给予脂多糖(LPS)诱导的急性呼吸窘迫综合征大鼠氨溴索(AMB)及地塞米松(DXM)干预后,观察细胞因子的表达及病理学变化,探讨两药联合对急性呼吸窘迫综合征早期的肺保护作用及其可能的机制。 方法 SD大鼠42只,随机分成6组,每组7只:空白对照组(C组),阴性对照组(N组),阳性对照组(L组),AMB干预组(A组),DXM干预组(D组)和AMB联合DXM干预组(AD组)。C组无处理,N组自尾静脉注入生理盐水2 mL,余各组均注入脂多糖(LPS)5 mg/kg,各干预组分别给予AMB(100 mg/kg)、DXM(6 mg/kg)。各组于6 h后进行血气分析;测定肺组织湿重与干重比(W/D);制备肺匀浆,测定其中髓过氧化物酶(MPO)、肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)水平并观察肺组织病理变化。 结果 与对照组比较,各干预组血气分析指标明显改善[氧分压(PO2):C组:(106.4±7.8)mm Hg(1 mm Hg=0.133 kPa),N组:(104.1±7.2)mm Hg,L组:(69.0±4.5)mm Hg,A组:(77.3±5.4)mm Hg,D组:(78.8±6.2)mm Hg,AD组:(86.8±5.6)mm Hg],而在W/D比[C组:(4.42±0.12),N组:(4.39±0.13),L组:(5.42±0.05),A组:(4.95±0.16),D组:(4.90±0.12),AD组:(4.73±0.10)、MPO[C组:(0.35±0.06)U/mg,N组:(0.33±0.04)U/mg,L组:(0.85±0.05)U/mg,A组:(0.55±0.04)U/mg,D组:(0.58±0.05)U/mg,AD组:(0.48±0.04)U/mg]及TNF-α[C组:(228.2±18.3)ng/L,N组:(234.6±19.3)ng/L,L组:(719.4±60.2)ng/L,A组:(479.1±29.2)ng/L,D组:(310.9±20.5)ng/L,AD组:(294.7±17.5)ng/L]、IL-1β[C组:(0.112±0.005)μg/L,N组:(0.116±0.002)μg/L,L组:(0.189±0.008)μg/L,A组:(0.144±0.009)μg/L,D组:(0.139±0.013)μg/L,AD组:(0.130±0.007)μg/L]各项指标检测均明显降低;光镜下观察C组及N组肺组织学正常,L组出现弥漫性肺泡间隔增厚、渗出及水肿明显、透明膜形成,同时可见大量炎症细胞浸润,肺间质弥漫性出血,而A、D及AD组光镜下上述病理表现明显减轻。上述结果在两药联合干预组改善更为明显。 结论 氨溴索与地塞米松合用对脂多糖诱导的急性呼吸窘迫综合征大鼠具有协同肺保护作用,其机制考虑为两者的共同抗炎及促肺泡表面物质生成作用所致。
[关键词] 急性呼吸窘迫综合征;氨溴索;地塞米松;炎症细胞因子
[中图分类号] R826.51 [文献标识码] A [文章编号] 1673-7210(2014)02(c)-0007-05
Effects of Ambroxol combined with Dexamethasone on acute lung injury induced by lipopolysaccharide in rats
TANG Jiajia1 ZHANG Qian2▲
1.Department of Anesthesia, Renji South Courtyard Affiliated to Shanghai Jiaotong University, Shanghai 201112, China; 2.Department of Emergency, the People′s Hospital of Shanghai Pudong New Area, Shanghai 201200, China
[Abstract] Objective To observe the effects and possible mechanismsof Ambroxol (AMB)/Dexamethasone (DXM)-co-administration on the changes of inflammatory cytokines expression as well as the pathological variations of lung in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Methods 42 SD rats were divided randomly into 6 groups with 7 each: blank control group (group C), negative control group (group N), positive control group (group L), AMB intervention group (group A), DXM intervention group (group D), AMB and DXM combined intervention group (group AD). Group C was without treatment, group N was given 2 mL of 0.9% NS injection via tail vein; all the other four groups were given LPS of 5 mg/kg; the intervention groups were given AMB (100 mg/kg), DXM (6 mg/kg). All the rats were killed in 6 hours to analysis arterial blood gas and lung tissue wet/dry weight ratio, and then to observe the levels of myeloperxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), as well as the pathological changes in lung. Results Compared with group C, the blood gas analysisimproved significantly [PO2: group C: (106.4±7.8) mm Hg (1 mm Hg=0.133 kPa), group N: (104.1±7.2) mm Hg, group L: (69.0±4.5) mm Hg, group A: (77.3±5.4) mm Hg, group D: (78.8±6.2) mm Hg, group AD: (86.8±5.6) mm Hg], while the level of W/D ratio [group C: (4.42±0.12), group N: (4.39±0.13), group L: (5.42±0.05), group A: (4.95±0.16), group D: (4.90±0.12), group AD: (4.73±0.10)], MPO [group C: (0.35±0.06) U/mg, group N: (0.33±0.04) U/mg, group L: (0.85±0.05) U/mg, group A: (0.55±0.04) U/mg, group D: (0.58±0.05) U/mg, group AD: (0.48±0.04) U/mg], TNF-α [group C: (228.2±18.3) ng/L, group N: (234.6±19.3) ng/L, group L: (719.4±60.2) ng/L, group A: (479.1±29.2) ng/L, group D: (310.9±20.5) ng/L, group AD: (294.7±17.5) ng/L], and IL-1β [group C: (0.112±0.005) μg/L, group N: (0.116±0.002) μg/L, group L: (0.189±0.008) μg/L, group A: (0.144±0.009) μg/L, group D: (0.139±0.013) μg/L, group AD: (0.130±0.007) μg/L] decreased significantly in all the intervention groups. The group C and group N showed normal under optical microscope. Diffused alveolar septum thickening, exudation, edema, ARDS membrane, and the inflammatory granulocyte infiltrating and significant spotty hemorrhage were observed in group L. The histological changes of group A, D, and AD were better than group L. All the results were much more significantly changed in the group which two drugs were combined. Conclusion The combination use of AMB and DXM has cooperative protective effects on acute respiratory distress syndrome induced by LPS in rats. The mechanism may be associated with the common anti-inflammatory effects, the promotion effect of pulmonary surfactant, and also probably related to the common anti-fibrosis and antioxidant effect, leading to the reconstruction of the balance of oxidation and antioxidant system as well as the resluting lung protection.
[Key words] Acute respiratory distress syndrome; Ambroxol; Dexamethasone; Inflammatory cytokines
急性呼吸窘迫综合征(ARDS)通常存在弥漫的肺泡炎症、肺泡毛细血管壁损害、肺水肿,并导致严重的低氧血症[1]。2012年柏林会议将ARDS分为轻、中、重度,其中轻度ARDS即以往所说的急性肺损伤[2]。ARDS发病率高而预后差,其诊断及治疗拥有很大的挑战性[3-4]。过去十余年中,随着对ARDS的研究进展以及肺保护性通气策略的使用,很多患者的临床症状得以改善,但其病死率仍高达30%~40%[5],且部分患者出现肺纤维化或遗留永久性的肺功能损伤。ARDS发病机制错综复杂,但公认的机制之一为ARDS是肺组织对各种致病因素打击后产生的广泛而过度的炎症反应[2,6]。糖皮质激素(glucocorticoid,GC)具有强大的抗炎作用,它可以干扰由细胞因子介导的炎性通路[7],并阻碍肺纤维化的发展[5]。近年来大剂量氨溴索(AMB)在ARDS早期的治疗中倍受关注,AMB可通过抑制肿瘤坏死因子α(TNF-α)的合成和分泌,发挥抗炎作用[8]。此外,AMB还具有显著的抗氧化及抗细胞凋亡的作用[9]。对于ARDS的治疗,目前建议针对其不同机制联合用药,但当目前为止,大剂量AMB联合GC在ARDS的应用报道尚少。本研究拟观察在大鼠ARDS早期合用大剂量AMB与GC的效果,明确两药是否具有协同作用,并探讨其可能的机制。
1 材料与方法
1.1 材料及检测试剂、仪器
1.1.1 实验材料 脂多糖(LPS,血清型0111和B4,美国Sigma公司,均以5%葡萄糖溶液配制);注射用氨溴索(Ambroxol Hydrochloride for Injection,沈阳新马药业有限公司,批号:H20050242);地塞米松注射液(山东鲁抗辰欣药业有限公司,1 mL∶5mg,批号:H37021969);健康、雄性Sprague Dawley(SD)大鼠42只,体重250~300 g。
1.1.2 检测试剂、仪器 髓过氧化物酶(MPO)、白介素-1β(IL-1β)、TNF-α ELISA试剂盒(美国Peprotech公司);血气分析仪(雅培,iSTAT型)。
1.2 实验方法
1.2.1 动物分组与准备 清洁及健康、雄性SD大鼠42只,随机分6组,分别为空白对照组(C组)、阴性对照组(N组)、阳性对照组(L组)、AMB干预组(A组)、DXM干预组(D组)和AMB联合DXM干预组(AD组),每组7只。C组无处理,N组自尾静脉注入生理盐水2 mL,L组注入脂多糖(LPS)5 mg/kg[7],A组、D组分别注入相同剂量的LPS以及AMB 100 mg/kg[8]、DXM 6 mg/kg[7],AD组同时注入上述剂量的LPS、AMB及DXM。
1.2.2 标本制作 各组于给药后6 h以3.5%水合氯醛10 mL/kg腹腔内注射麻醉成功后,固定大鼠,取腹正中纵行切口,分离腹主动脉并穿刺采集动脉血待检;腹主动脉放血处死大鼠,开胸,暴露心肺,肉眼观察肺组织大体病理改变后剥离结缔组织,并结扎右主支气管后剪下右肺,剪下部分右肺上叶组织,称重后放存冻存管中,标签标注,置入液氮桶,备用于肺匀浆;取右肺中叶称取湿重后置入80℃烤箱中烘干至恒重,再称取干重;取右肺下叶,以4%体积分数的甲醛溶液固定、石蜡包埋、切片、苏木精-伊红(HE)染色,待用观察病理学改变。制备1%肺匀浆[9],于4℃、3000 r/min离心10 min,取上清液置于-70℃保存。
1.2.3 检测指标 观察各组在给药后6 h内临床表现。动脉血做血气分析;计算肺组织湿重与干重比(W/D)比值;光镜下观察病理学改变,并根据肺组织结构损伤、肺不张程度、透明膜形成、肺泡壁增厚程度、炎症细胞浸润程度进行0~4分半定量分析,共分5级,0级为无该项病理改变,1级为病理变化轻且很局限,2级为病理变化中等且局限,3级为病变中等但广泛或局部很显著,4级为非常显著的广泛性病理改变;取肺组织匀浆,按试剂盒说明方法分别测定MPO及、TNF-α以及IL-1β水平。
1.3 统计学方法
实验数据采用SPSS 19.0软件进行统计处理,计量数据以均数±标准差(x±s)表示,组间比较行单因素方差分析,多组间的两两比较方差齐性检验采用LSD及SNK法,以P < 0.05为差异有统计学意义。
2 结果
2.1 一般情况观察
C组及N组大鼠无明显临床改变,L组注射LPS后表现出明显的呼吸窘迫、气促、发绀等症状,符合ARDS表现;各干预治疗组上述表现减轻,其中又以AD组改善更为明显。
2.2 血气分析结果
pH和PO2:N组和C组比较,差异无统计学意义(P > 0.05);L组显著低于C组和N组(P < 0.05);A组、D组及AD组在氧合方面均较L组有明显改善,但仍低于C组,其中又以AD组改善更为明显,且与A组及D组相比差异有统计学意义(P < 0.05),而A组与D组间差异无统计学意义(P > 0.05);各组间PaCO2差异无统计学意义(P > 0.05)。见表1。
表1 各组血气分析及W/D比值比较(x±s)
注:与C组比较,*P < 0.05;与N组比较,△P < 0.05;与L组比较,#P < 0.05;与A组比较,+P < 0.05;与D组比较,※P < 0.05;PO2:氧分压;PCO2:二氧化碳分压;W/D:湿干比;1 mm Hg = 0.133 kPa
2.3 肺组织W/D比结果统计
N组与C组比较,差异无统计学意义(P > 0.05);L组明显高于C组(P < 0.05);A组、D组及AD组W/D比值均明显下降,与L组比较,差异均有统计学意义(P < 0.05),且均高于对照组;其中AD组下降较之A组及D组更为明显,差异有统计学意义(P < 0.05),而A组、D组间差异无明显统计学意义(P > 0.05)。见表1。
2.4 炎症指标统计
肺组织匀浆中MPO活性、TNF-α及IL-1β水平在N组与C组间比较差异均无统计学意义(P > 0.05),而L组均较C组显著升高(P < 0.05);A组、D组及AD组均有明显下降,与L组比较,但仍高于C组,差异均有统计学意义(P < 0.05);MPO活性在AD组的下降较之A组及D组更为明显,差异有统计学意义(P < 0.05);TNF-α在D组及AD组下降均较之A组更明显,差异有统计学意义(P < 0.05),且AD组与D组相比下降亦更为明显(P > 0.05);IL-1β在D组及AD组下降较之A组更明显,差异有统计学意义(P < 0.05),D组亦较之A组下降更为明显,差异亦有统计学意义(P < 0.05)。见表2。
表2 肺组织匀浆中MPO、TNF-α、IL-1β比较(x±s)
注:与C组比较,*P < 0.05;与N组比较,△P < 0.05;与L组比较,#P < 0.05;与A组比较,+P < 0.05;与D组比较,※P < 0.05;MPO:髓过氧化物酶;TNF-α:肿瘤坏死因子-α;IL-1β:白介素-1β
2.5 病理学改变
大体及光镜下观察C组及N组肺组织无明显异常;L组大体标本可见肺组织充血明显,并可见部分斑片状坏死,A、D及AD组肺组织表面充血较L组减轻,斑片状坏死减少,AD组更为明显。光镜下观察L组结构损伤明显,大片肺泡腔萎陷伴不张,透明膜形成,肺泡壁间隔显著增厚,大量红细胞及白细胞渗出、聚集;A、D及AD组上述病理改变较对照组减轻,但A组及D组与L组比较差异无统计学意义(P > 0.05),AD组与L组比较差异有统计学意义(P < 0.05),但AD与A组、D组三组之间比较差异无统计学意义(P > 0.05)。见表3。
表3 光镜下病理评分比较(分)
3 讨论
ARDS是在各种致病因素作用下导致的急性弥漫性肺损伤,其特点是炎性反应使得肺毛细血管通透性增加,引起肺水肿、透明膜形成以及肺泡内出血[2]。其发生机制错综复杂,因而也缺乏特定的治疗方案,但采用低潮气量通气以及抗炎性反应是目前认为有效的治疗方法之一。已有动物实验及临床研究证实,ARDS时肺组织内的炎症因子明显增多,通过抑制炎症因子可减轻肺损伤程度[10]。LPS诱导的大鼠模型是一个经典的ARDS动物模型,本组实验中,大鼠在被注射LPS后均出现了PO2下降,各项炎症指标显著上升,病理学肺损伤改变明显,提示模型建立成功。
AMB作为一种黏液调节剂被广泛在临床上应用多年,近年有不少研究证实大剂量AMB存在抗氧化、减少炎症介质和细胞因子释放、促进肺泡表面活性物质(pulmonary surfactant,PS)生成等作用[9-12],从而在ARDS中发挥肺保护作用。本组实验表明AMB干预组MPO、TNF-α和IL-1β水平下降,肺组织病理损伤减轻,存在肺保护作用。同时本实验也发现,AMB干预组虽然在血气分析、炎症介质水平及病理改变方面均有一定程度的改善,但其效果不如AD组明显,考虑其原因可能在于ARDS时,由于众多的炎症介质释放形成了级联反应或瀑布样效应,而AMB只是抑制了部分炎症介质的产生,因而在ARDS的治疗中需考虑到其复杂的致病机制,针对不同的环节联合用药方可取得较满意的疗效。
GC被用于ARDS的治疗已有很长时间,但近年来对于GC在ARDS中的作用争议不断,反对者主要认为长时间大剂量使用GC存在诸多副作用,如高血糖、骨质疏松、感染加重等,但在ARDS的治疗中,GC确实有其积极作用。本实验可看出,即使给予小剂量GC,D组较之L组在血气分析、炎症指标及组织病理学变化上仍有明显的改善,在一定程度上证实了DXM对LPS诱导的ARDS具有肺保护作用。GC在ARDS治疗中的作用机制体现在多方面。它可以直接或间接作用于炎症细胞或细胞因子[7,13],降低MPO活性,减轻中性粒细胞(PMN)过度激活对组织的损伤[14];GC通过上调肺组织丝裂原活化蛋白激酶磷酸酶-1(MKP-1)表达[15],以及阻碍单核细胞趋化蛋白-1(MCP-1)、中性粒细胞趋化因子(CINC)、P-选择素和细胞间黏附分子-1(ICAM-1)的表达[16],起到减轻气道和肺实质炎性反应的作用;GC可以在缺氧情况下保留部分钠离子通道的活性,减轻肺水肿的发生[17];GC还可以部分逆转肺泡表面活性物质的紊乱[10]。本组实验虽然证实了GC在ARDS中所产生的积极的效果,观察时间还不够,考虑到GC治疗可能带来的相关副作用,GC在ARDS中后续治疗的影响还有待进一步的实验验证。
本组实验证实了AD组在给予了两药联合治疗的方案后,在氧合情况、W/D比以及肺组织匀浆中的炎性介质水平上,AD组均在不同程度上较单药使用组改善,部分具有显著统计学意义,提示AMB及DXM的联合使用对ARDS具有一定的协同保护作用,而在病理学改变上AD组虽然较之单药联合使用组改善无显著统计学差异,但较之L组仍改善明显,这一点考虑到可能与本组实验干预治疗早、观察时间节点较短、ARDS处于早期阶段、病变较轻、组织病理学改变可能未能完全呈现相关,有待进一步的实验验证。由此得出如下结论:① AMB及DXM对LPS诱导的大鼠急性肺损伤在一定程度上有保护作用,可在一定程度上改善氧合,减轻炎症介质的释放,减轻肺部损伤。②AMB与DXM对LPS诱导的大鼠急性肺损伤具有协同保护作用,在血气分析、炎症指标及病理学表现上均优于单药使用,可有效改善氧和,减轻炎症介质的释放,从而减轻全身炎性反应在肺部的集中表现。
两药联合使用的协同作用的机制考虑是基于两种药物对于炎症介质的释放均有抑制作用,联合使用可使这一作用进一步强化,从而减轻肺泡上皮细胞和肺间质的损伤,改善血管通透性,减轻肺渗出及出血;此外两药均可促进PS的合成,从而起到防止肺泡萎陷、减轻肺不张的作用。因而两种药物的联合应用在急性肺损伤的防治中具有良好的应用前景。
[参考文献]
[1] Van S,Deroost K,Deckers J,et al. Pathogenesis of malaria-associated acute respiratory distress syndrome [J]. Trends in Parasitology,2013,29(7):346-358.
[2] Thompson BT,Moss M. A new definition for the acute respiratory distress syndrome [J]. Seminars in Respiratory and Critical Care Medicine,2013,34(4):441-447.
[3] Janz DR,Ware LB. Biomarkers of ALI/ARDS:pathogenesis,discovery,and relevance to clinical trials [J]. Seminars in Respiratory and Critical Care Medicine,2013,34(4):537-547.
[4] Matthay MA,Ware LB,Zimmerman GA. The acute respiratory distress syndrome [J]. The Journal of Clinical Investigation, 2012,122(8):2731-2740.
[5] Erickson SE,Martin GS,Davis JL,et al. Recent trends in acute lung injury mortARDSty:1996-2005[J]. Crit Care Med,2009,37:1574-1579.
[6] Mokra D,Drgova A,Kopincova J,et al. Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury [J]. Advances in ExperiMental Medicine and Biology,2013,756:189-196.
[7] Kim HA,Park JH,Lee S,et al. Combined delivery of Dexamethasone and plasmid DNA in an animal model of LPS-induced acute lung injury[J]. Journal of Controlled Release,2011,156(1):60-69.
[8] 戴新建,王万铁,鲍小欧,等.氨溴索对急性肺损伤兔E一选择素和细胞间黏附分子-1的影响[J].海峡药学,2009, 21(1):68-70.
[9] Jiang K,Wang X,Mao X,et al. Ambroxol alleviates hepatic ischemia reperfusion injury by antioxidant and antiapoptotic pathways [J]. Transplantation Proceedings,2013,45(6):2439-2445.
[10] Mokra D,Drgova A,Kopincova J,et al. Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury [J]. Advances in Experimental Medicine and Biology,2013,756:189-196.
[11] Zhang ZQ,Wu QQ,Huang XM,et al. Prevention of respiratory distress syndrome in preterm infants by antenatal Ambroxol: a Meta-analysis of randomized controlled trials [J]. American Journal of Perinatology,2013,30(7):529-536.
[12] 包龙,徐峰,丁礼,等.大剂量盐酸氨溴索对亚低温治疗老年颅脑损伤患者的肺保护[J].中华老年医学杂志,2013, 32(7):723-726.
[13] 黎静,韩利梅,古丽鲜.油酸型急性呼吸窘迫综合征血清细胞因子TNF-alpha、IL-8、IL-10变化及地塞米松干预的实验研究[J].重庆医科大学学报,2013,38(2):158-160.
[14] Sombra,Marcia A,da Silva C,et al. Acute pulmonary injury induced by experimental muscle trauma[J]. Acta cirurgica brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia,2011,26(1):43-46.
[15] 成勤,陈龙,刘苏,等.地塞米松对内毒素性急性肺损伤大鼠肺组织MKP-1表达的影响[J].中华麻醉学杂志,2012,32(2):214-217.
[16] Yubero S,Manso MA,Ramudo L,et al. Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models [J]. Pulmonary Pharmacology & Therapeutics,2012, 25(4):319-324.
[17] Urner M,Herrmann IK,Booy C,et al. Effect of hypoxia and Dexamethasone on inflammation and ion transporter function in pulmonary cells[J]. Clinical and Experimental Immunology,2012,169(2):119-128.
(收稿日期:2013-10-29 本文编辑:卫 轲)
[参考文献]
[1] Van S,Deroost K,Deckers J,et al. Pathogenesis of malaria-associated acute respiratory distress syndrome [J]. Trends in Parasitology,2013,29(7):346-358.
[2] Thompson BT,Moss M. A new definition for the acute respiratory distress syndrome [J]. Seminars in Respiratory and Critical Care Medicine,2013,34(4):441-447.
[3] Janz DR,Ware LB. Biomarkers of ALI/ARDS:pathogenesis,discovery,and relevance to clinical trials [J]. Seminars in Respiratory and Critical Care Medicine,2013,34(4):537-547.
[4] Matthay MA,Ware LB,Zimmerman GA. The acute respiratory distress syndrome [J]. The Journal of Clinical Investigation, 2012,122(8):2731-2740.
[5] Erickson SE,Martin GS,Davis JL,et al. Recent trends in acute lung injury mortARDSty:1996-2005[J]. Crit Care Med,2009,37:1574-1579.
[6] Mokra D,Drgova A,Kopincova J,et al. Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury [J]. Advances in ExperiMental Medicine and Biology,2013,756:189-196.
[7] Kim HA,Park JH,Lee S,et al. Combined delivery of Dexamethasone and plasmid DNA in an animal model of LPS-induced acute lung injury[J]. Journal of Controlled Release,2011,156(1):60-69.
[8] 戴新建,王万铁,鲍小欧,等.氨溴索对急性肺损伤兔E一选择素和细胞间黏附分子-1的影响[J].海峡药学,2009, 21(1):68-70.
[9] Jiang K,Wang X,Mao X,et al. Ambroxol alleviates hepatic ischemia reperfusion injury by antioxidant and antiapoptotic pathways [J]. Transplantation Proceedings,2013,45(6):2439-2445.
[10] Mokra D,Drgova A,Kopincova J,et al. Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury [J]. Advances in Experimental Medicine and Biology,2013,756:189-196.
[11] Zhang ZQ,Wu QQ,Huang XM,et al. Prevention of respiratory distress syndrome in preterm infants by antenatal Ambroxol: a Meta-analysis of randomized controlled trials [J]. American Journal of Perinatology,2013,30(7):529-536.
[12] 包龙,徐峰,丁礼,等.大剂量盐酸氨溴索对亚低温治疗老年颅脑损伤患者的肺保护[J].中华老年医学杂志,2013, 32(7):723-726.
[13] 黎静,韩利梅,古丽鲜.油酸型急性呼吸窘迫综合征血清细胞因子TNF-alpha、IL-8、IL-10变化及地塞米松干预的实验研究[J].重庆医科大学学报,2013,38(2):158-160.
[14] Sombra,Marcia A,da Silva C,et al. Acute pulmonary injury induced by experimental muscle trauma[J]. Acta cirurgica brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia,2011,26(1):43-46.
[15] 成勤,陈龙,刘苏,等.地塞米松对内毒素性急性肺损伤大鼠肺组织MKP-1表达的影响[J].中华麻醉学杂志,2012,32(2):214-217.
[16] Yubero S,Manso MA,Ramudo L,et al. Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models [J]. Pulmonary Pharmacology & Therapeutics,2012, 25(4):319-324.
[17] Urner M,Herrmann IK,Booy C,et al. Effect of hypoxia and Dexamethasone on inflammation and ion transporter function in pulmonary cells[J]. Clinical and Experimental Immunology,2012,169(2):119-128.
(收稿日期:2013-10-29 本文编辑:卫 轲)
[参考文献]
[1] Van S,Deroost K,Deckers J,et al. Pathogenesis of malaria-associated acute respiratory distress syndrome [J]. Trends in Parasitology,2013,29(7):346-358.
[2] Thompson BT,Moss M. A new definition for the acute respiratory distress syndrome [J]. Seminars in Respiratory and Critical Care Medicine,2013,34(4):441-447.
[3] Janz DR,Ware LB. Biomarkers of ALI/ARDS:pathogenesis,discovery,and relevance to clinical trials [J]. Seminars in Respiratory and Critical Care Medicine,2013,34(4):537-547.
[4] Matthay MA,Ware LB,Zimmerman GA. The acute respiratory distress syndrome [J]. The Journal of Clinical Investigation, 2012,122(8):2731-2740.
[5] Erickson SE,Martin GS,Davis JL,et al. Recent trends in acute lung injury mortARDSty:1996-2005[J]. Crit Care Med,2009,37:1574-1579.
[6] Mokra D,Drgova A,Kopincova J,et al. Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury [J]. Advances in ExperiMental Medicine and Biology,2013,756:189-196.
[7] Kim HA,Park JH,Lee S,et al. Combined delivery of Dexamethasone and plasmid DNA in an animal model of LPS-induced acute lung injury[J]. Journal of Controlled Release,2011,156(1):60-69.
[8] 戴新建,王万铁,鲍小欧,等.氨溴索对急性肺损伤兔E一选择素和细胞间黏附分子-1的影响[J].海峡药学,2009, 21(1):68-70.
[9] Jiang K,Wang X,Mao X,et al. Ambroxol alleviates hepatic ischemia reperfusion injury by antioxidant and antiapoptotic pathways [J]. Transplantation Proceedings,2013,45(6):2439-2445.
[10] Mokra D,Drgova A,Kopincova J,et al. Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury [J]. Advances in Experimental Medicine and Biology,2013,756:189-196.
[11] Zhang ZQ,Wu QQ,Huang XM,et al. Prevention of respiratory distress syndrome in preterm infants by antenatal Ambroxol: a Meta-analysis of randomized controlled trials [J]. American Journal of Perinatology,2013,30(7):529-536.
[12] 包龙,徐峰,丁礼,等.大剂量盐酸氨溴索对亚低温治疗老年颅脑损伤患者的肺保护[J].中华老年医学杂志,2013, 32(7):723-726.
[13] 黎静,韩利梅,古丽鲜.油酸型急性呼吸窘迫综合征血清细胞因子TNF-alpha、IL-8、IL-10变化及地塞米松干预的实验研究[J].重庆医科大学学报,2013,38(2):158-160.
[14] Sombra,Marcia A,da Silva C,et al. Acute pulmonary injury induced by experimental muscle trauma[J]. Acta cirurgica brasileira/Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia,2011,26(1):43-46.
[15] 成勤,陈龙,刘苏,等.地塞米松对内毒素性急性肺损伤大鼠肺组织MKP-1表达的影响[J].中华麻醉学杂志,2012,32(2):214-217.
[16] Yubero S,Manso MA,Ramudo L,et al. Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models [J]. Pulmonary Pharmacology & Therapeutics,2012, 25(4):319-324.
[17] Urner M,Herrmann IK,Booy C,et al. Effect of hypoxia and Dexamethasone on inflammation and ion transporter function in pulmonary cells[J]. Clinical and Experimental Immunology,2012,169(2):119-128.
(收稿日期:2013-10-29 本文编辑:卫 轲)