1、牛磺酸及血管紧张素转化酶抑制剂对大鼠急性肺损伤的保护作用研究 2、ALI/ARDS影响因素分析
|
摘要
目的
急性肺损伤（ALI）是由各种外源性因素打击，导致的急性、进行性缺氧性呼吸衰竭。ALI发病机制复杂，有效治疗手段少，死亡率高。本研究通过提前腹腔注射微量细菌脂多糖预激后，再次静脉注射细菌脂多糖诱导，建立急性肺损伤大鼠动物模型，观察急性肺损伤大鼠的病理生理改变及肺血管内皮细胞损伤的变化；分别给予牛磺酸、血管紧张素转换酶抑制剂及二药联合干预急性肺损伤大鼠，观察其治疗效果，探讨牛磺酸及血管紧张素转化酶抑制剂对大鼠急性肺损伤的保护作用及其相关机制。
方法
1分组：将126只SD清洁级大鼠随机分成5组：（1）正常对照组（n=6）；（2）急性肺损伤组：于静脉注射脂多糖后，分为3h、6h、9h、12h、24h五个时间点，每个时间点（n=6）；（3）牛磺酸治疗组：于静脉注射脂多糖后分为上述五个时间点，每个时间点（n=6）；（4）卡托普利治疗组：于静脉注射脂多糖后分为上述五个时间点，每个时间点（n=6）；（5）牛磺酸和卡托普利联合治疗组：于静脉注射脂多糖后分为上述五个时间点，每个时间点（n=6）。
2建立急性肺损伤模型：腹腔注射脂多糖（LPS）（0.5mg/kg体重）预激12小时后，静脉注射LPS（5mg/kg体重），建立急性肺损伤动物模型，分别于静脉注射LPS后3h、6h、9h、12h、24h时间点采集标本。
3正常对照组与治疗组：（1）正常对照组：生理盐水腹腔注射12小时，静脉注射生理盐水；（2）牛磺酸治疗组：LPS预激12小时后，腹腔注射牛磺酸（50mg/kg体重），静脉注射LPS；（3）卡托普利治疗组：LPS预激12小时后，腹腔注射卡托普利（1.25mg/kg体重），静脉注射LPS；（4）牛磺酸联合卡托普利治疗组：脂多糖预激12小时后，腹腔注射牛磺酸（50mg/kg体重）及卡托普利（1.25mg/kg体重），静脉注射LPS；正常对照组静脉注射生理盐水后3h、各治疗组静脉注射LPS后3h、6h、9h、12h、24h时间点采集标本。
4检测指标：（1）测定肺湿干比重（W/D ratio）；（2）动脉血氧分压(PaO2)；（3）肺组织病理学观察,计算肺损伤病理学评分；（4）采用ELISA法检测血浆中的血管性血友病因子（vWF）的水平、内皮素-1（ET-1）、可溶性细胞间黏附分子-1（sICAM-1）、血栓调节蛋白（TM）、血小板活化因子(PAF)；（5）采用ELISA法检测肺泡灌洗液中的血管性血友病因子（vWF）的水平、内皮素-1（ET-1）、可溶性细胞间黏附分子-1（sICAM-1）、血栓调节蛋白（TM）、血小板活化因子(PAF)的水平。
5统计学分析：所产生数据均采用SPSS11.5统计软件进行，计量资料以x±s表示；成组设计的多样本均数的比较采用单因素方差分析进行检验；组间多重比较采用SNK检验，取a=0.05，以P<0.05有统计学意义。
结果
1肺湿干比重(W/D ratio)：与正常组比较，W/D ratio值在肺损伤组五个时间点均明显升高（P<0.05），12h、24h时间点升高比较突出；与肺损伤组相比较，牛磺酸治疗组、卡托普利治疗组及两者联合治疗组各时间点W/D ratio值均较肺损伤组有不同程度的降低（P<0.05），但略高于正常组水平，以两者联合治疗后W/D ratio值降低明显（P<0.05）。
2动脉血氧分压(PaO2)：与正常组比较，肺损伤组动脉血氧分压（PaO2）在各个时间点较正常对照组明显降低（P<0.05）；各时间点PaO2值接近，无变化趋势；与肺损伤组比较，牛磺酸治疗组、卡托普利治疗组及两者联合干预后PaO2值在各时间点均较肺损伤组有提高（P<0.05），但仍低于正常组PaO2值；以牛磺酸和卡托普利联合干预后PaO2值升高显著，尤其在12h、24h时间点升高较为突出。
3病理学组织切片观察：与正常对照组比较，肺损伤组肺泡正常结构部分破坏，局灶性出血，炎症细胞浸润，肺泡间隔明显增厚，肺泡腔变窄，部分肺泡萎陷。牛磺酸组、卡托普利组及两药联合干预后能使上述病理变化改善。肺损伤病理学评分：与正常对照组比较，肺损伤组的病理学评分较正常对照组明显升高（P<0.05）；牛磺酸组、卡托普利组及两药联合干预后，所有治疗组肺损伤组织病理学评分明显低于肺损伤组（P<0.05），在9h、12h、24h时间点降低较突出；但各治疗组肺损伤病理学评分仍略高于正常组；以两药联合干预后肺损伤病理学评分降低最显著（P<0.05）。
4血浆中vWF、 ET-1、sICAM-1、TM、PAF因子水平检测：与正常对照组相比，血浆中各因子水平在肺损伤组几乎所有时间点均升高，多数分别在3h、6h、9h时间点升高明显（P<0.05）；在牛磺酸组、卡托普利组及两药联合治疗组干预后血浆各因子水平在多数时间点较肺损伤组降低（P<0.05），以两者联合治疗后血浆各因子水平较肺损伤组降低较明显（P<0.05）；但所有治疗组血浆各因子水平在多数时间点依然略高于正常对照组。
5肺泡灌洗液中vWF、 ET-1、sICAM-1、TM、PAF水平检测：与正常对照组相比，肺泡灌洗液中各种因子水平在肺损伤组所有时间点均较正常组升高（P<0.05），多数在3h、6h、9h时间点升高明显（P<0.05）；在牛磺酸组、卡托普利组及两药联合治疗组干预后各组多数时间点较肺损伤组降低（P<0.05），以两者联合干预降低较明显（P<0.05）；但各治疗组BALF中各因子水平多数依然略高于正常对照组。
结论：
1本研究通过提前腹腔注射小剂量内毒素预激，联合静脉内注射内毒素，大鼠肺湿干比重增加，动脉血氧分压降低，肺病理变化明显，肺损伤病理学评分升高，证明成功地建立了内毒素诱导型大鼠急性肺损伤的动物模型，模型稳定，此种制模方法目前较少见。
2急性肺损伤时存在肺血管内皮细胞的活化和损伤，反应内皮细胞活化和损伤的血浆及肺泡灌洗液中的细胞因子水平增高明显，无相对固定的变化规律。
3牛磺酸对急性肺损伤及其肺血管内皮细胞有治疗和保护作用。
4血管紧张素转换酶抑制剂对急性肺损伤及其肺血管内皮细胞有治疗和保护作用。
5牛磺酸及血管紧张素转换酶抑制剂联合应用对急性肺损伤及其肺血管内皮细胞有治疗和保护作用，效果优于单药干预治疗，提示可以考虑联合应用。目前国内尚未见两药联合治疗ALI的研究报道。
目的：
通过收集宁夏医科大学总医院ICU科ALI/ARDS患者的临床资料，对可能导致ALI/ARDS的发生、影响病情发展及预后的相关临床影响因素进行分析，以提高对ALI/ARDS的致病因素早期识别，早期预防，减少ALI/ARDS的发生率，降低死亡率，提高救治率。
方法：
回顾性研究2010年3月到2012年12月宁夏医科大学总医院综合ICU科收治的病人，将其中符合ALI/ARDS诊断标准的患者列为研究观察对象，这些病例被分为三组：①初次诊断为ALI组与ARDS组；②ALI好转组与ALI转化为ARDS组；③ARDS存活组与死亡组；对这三组患者分别从病因学；基本状况，年龄、性别、是否合并慢性疾病；是否合并急性器官障碍及其种类及数目；血气分析指标、APACHEII评分等多个临床因素进行统计分析。统计学分析:用统计学软件SPSS11.5进行统计学分析，数值变量采用x±s表示：计量资料两组间比较采用独立样本的t检验，计数资料采用单因素方差分析（x2检验）；多因素分析采用条件Logistic回归方法。
结果：
14125例病人中诊断ALI154例、ALI的构成比3.73%；诊断ARDS221例, ARDS的构成比5.36%；ALI/ARDS总构成比9.09%。ALI中18例死亡，病死率11.69%；ARDS中118例死亡，病死率53.40%；ALI/ARDS总病死率36.27%。
2ALI中女性41例（26.62%），男性113例（73.38%），平均年龄为51.05±18.03岁；病因中创伤58例（37.66%），感染45例（29.22%），合并慢性病36例（24.68%），合并≥3个急性器官功能障碍39例(25.32%)； APACHEII评分均数16.47±7.79；平均住院天数为13.86±13.54天。
3ARDS中女性61例(27.6%)，男性160例(72.4%)，平均年龄为53.57±16.38岁；病因中创伤93例(42.08%)，感染109例(49.32%)，合并慢性病77例(34.8%)，合并≥3个急性器官功能障碍101例(45.70%)；APACHEII评分16.77±6.80。平均住院天数为14.28±12.57天。
4初始诊断ALI组与ARDS组结果示：原发致病因素中，肺部感染(P=0.003)、感染性休克(P=0.008)、其他部位感染(P=0.015)、手术术后（P<0.001）、不明原因（P=0.001）有统计学差异；多因素分析示纳入研究的各影响因素无统计学差异。
5ALI好转组与ALI转化为ARDS组结果示：原发致病因素中，肺部感染(P<0.001)、脓毒症（P=0.008）、感染性休克(P=0.011)、手术术后（P<0.001）有统计学差异；多因素分析示纳入研究的各影响因素中，急性心血管系统障碍（P=0.016）、急性肝脏系统障碍（P=0.004）、急性神经系统障碍（P=0.006）、pH值大小（P=0.038）有统计学意义；其他观察指标无统计学意义。
6ARDS存活组与死亡组结果示：原发致病因素中，创伤（P=0.004）、肺部感染（P=0.006）、感染性休克（P=0.013）、不明原因（P=0.040）有统计学差异；多因素分析提示纳入研究的各影响因素中年龄（P<0.001）、急性心血管系统障碍（P=0.001）、PCO2（P=0.005）有统计学意义。其它观察指标无统计学意义。
结论：
1本院ALI的构成比3.73%，ARDS的构成比5.36%，ALI/ARDS总构成比9.09%。ALI的病死率11.69%%，ARDS病死率53.40%，ALI/ARDS总病死率36.27%。 ALI/ARDS发病以男性、中老年人多见；致病因素以创伤、感染多见；入院APACHEII评分均高，住院天数大于10天。
2其他部位感染及手术术后和一些不明确原因较易诱发ALI；肺部感染、感染性休克较易诱发ARDS。肺部感染、手术术后所致的ALI好转率相对高，预后相对较好；感染性休克和脓毒症所致的ALI预后相对较差，较易发展为ARDS。创伤所致的ARDS预后相对较好，肺部感染和感染性休克所致的ARDS预后较差。
3急性心血管系统、肝脏系统、神经系统的器官以及PH值大小可能为ALI病情恶化转化为ARDS的独立危险因素。合并≥3个器官功能障碍时，对ALI/ARDS的病情的发生发展及预后都有非常不良的影响。
4年龄、心血管系统功能障碍、二氧化碳分压值可能成为影响ARDS预后的独立危险因素。
Objective:
Acute lung injury is a critical illness syndrome consisting of acuteprogressive hypoxemic respiratory failure arising either from a variety ofdirect (pulmonary) or indirect (extrapulmonary) insults. Duing to thecomplex lung injury pathophysiology of ALI, it remains underdiagnosed andundertreated. At present，therapeutic interventions to treat ALI remainlimited. Mortality from ALI is substantial. To observe lung pathophysiologyand endothelial activation and injury in rats with ALI, we established theanimal model of ALI by intraperitoneal injection of mindose of LPS inadvance combined with intravenous injection of LPS. Therefore toinvestigate the protective effect by taurine and angiotensin convertingenzyme inhibitor on acute lung injury and its relative mechanism, we treatedrats with ALI by intraperitoneal injection of taurine, captopril，and both durgrespectively.
Methods:
1Subgrop:126male SD rats were randomly divided into five groups: (1) normal control group (n=6).(2) acute lung injury (LPS) group: ratswere divided into five time points at3h,6h,9h,12h,24h after intravenousinjection of LPS and there were6rats in every time point (n=6);(3) thetaurine group: rats were divided into above-mentioned five time points afterintravenous injection of LPS and there were6rats in every time point (n=6);(4) the captopril group: rats were divided into above-mentioned five timepoints after intravenous injection of LPS and there were6rats in every timepoint (n=6),(5) the taurine and the captopril group: rats were divided intoabove-mentioned five time points after intravenous injection of LPS andthere were6rats in every time point (n=6).
2Estabished ALI model: Rats were pre-activated by intraperitonealinjection of LPS(0.5mg/kg) in advance. Then after pre-activating for12hours, rats were induced by intravenous injection of LPS (5mg/kg.).Specimens were collected after intravenous injection of LPS at five timepoint.
3The normal control group and treatment group:(1) The normalcontrol group: Intraperitoneal injection of saline for12hours, saline wasinjected intravenously.(2) The taurine group: After LPS preactivating for12hours, taurine50mg/kg was injected intraperitoneally and LPS was injectedintravenously.(3) The captopril group:After LPS pre-activating for12hours,captopril1.25mg/kg was injected intraperitoneally and LPS was injectedintravenously.(4)The taurine and captopril group: After LPS preactivating for12hours, taurine50mg/kg and the captopril1.25mg/kg were injectedintraperitoneally and LPS was injected intravenously. Specimens werecollected at3h after intravenous injection of saline in normal group and at3h,6h,9h,12h,24h time point after intravenous injection of LPS in alltreatment group respectively.
4Measurement: Measurement of lung wet-dry weight and arterialpartial pressure of oxygen (PaO2). Lung histopathology were observed andanalyzed. Von Willebrand factor (vWF), endothelin-1(ET-1), Solubleintercellular adhesion molecule-1(sICAM-1), thrombomodulin (TM),platelet-activating factor (PAF) levels were detected in plasma andbronchoalveolar lavage fluid (BALF) by ELISA.
5Statistical Analysis: Data are expressed as mean±SD. Statisticalanalyses was done using SPSS11.5statistical software. Statisticaldifferences between the data were determined with one-way analysis ofvariance and mutltiple comparisons were tested withStudent-Newman-Keuls-test(SNK), and a P value,0.05was consideredsignificant.
Resuls:
1Lung wet-dry weight ratio: Lung W/D ratio showed a significantincreasing in lung injury group（P<0.05）, and it increased obviously at12h、24h time point. Lung W/D ratio decreased in varying degrees in taurinegroup, captopril group and taurine and captopril group, but still higher than the normal group（P<0.05）. The decreasing mostly is in the combinedtreatment group.
2Arterial partial pressure of oxygen (PaO2) levels: PaO2levels in thelung injury group were significantly lower than the control group（P<0.05）,but increased in taurine group and captopril group, and increased mostsignificantly after the combined treatment intervention（P<0.05）and it wasobvious at9h、12h、24h time point.
3Lung histology: Lung injury group showed marked inflammation andmild lung edema with marked thickening of alveolar septa and alveolarspace narrowing. Improved the pathological changes were observed in thetaurine group, captopril group and both combined. The score of lung injury:the score of lung injury in the acute lung injury group were significantlyhigher than the normal group and decreased in taurine group and captoprilgroup and both combined group（P<0.05）,and decreased mostsignificantly after the combined treatment intervention. It improvedobviously at9h、12h、24h time point
4The plasma levels of vWF，ET-1, sICAM-1, TM and PAF：Theplasma levels of vWF，ET-1, sICAM-1, TM and PAF were increased in lunginjury group than in the control group（P<0.05）. Most of them wereimproved at3h,6h,9h time point obviously. But after the intervention, theywere lower in taurine treatment group, captopril group, and both treantmentgroup at the most of different time point than in the acute lung injury group（P<0.05）. The levels of them in the joint intervention were lowerthan the lung injury group obviously.
5The BLAF levels of vWF，ET-1, sICAM-1, TM and PAF：TheBLAF levels of vWF,ET-1, sICAM-1, TM and PAF were increased in lunginjury group than in the control group at the different time point andincreased obviously at3h、6h、9h time point. After the treatment, they werelower in taurine treatment group, captopril group, and both treantment groupat the most of different time point than in acute lung injury group. Thelevels of them in the joint intervention group were lower than the lung injurygroup obviously and were still a little higer than the normal control group.
Conclusion:
1We successfully established the animal model of ALI byintra-peritoneal injection of mindose of LPS in advance combined withint-ravenous injection of LPS. It was porved by the increasing lung wet-dryweight ratio, the decreasing PaO2levels, the changes of Lung histology andthe increasing score of lung injury. The way of making animal model isrelatively rare at present.
2There was lung endothelial cell activation and injury in ALI and itwas expressed by the increasing levels of plasma and BLAF vWF，ET-1,sICAM-1, TM and PAF which represented the lung endothelial cellactivation and injury.
3Taurine had a protective effect on acute lung injury and the i-njuried pulmonary vascular endothelial cells.
4Angiotensin-converting enzyme inhibitors had protective effect onacute lung injury and the injuried pulmonary vascular endothelial cells.
5It prompted that two-drug combination had a more protective effecton lung injury and pulmonary vascular endothelial cells, and it was betterthan single drug-intervention group. The study showed that we can treat ALIwith joint treatment of taurine and captopril. The treatment of these twodrugs combination on ALI was not reported in domestic at present.
Objective:
To recognize and prevent the clinical influential factors in ALI/ARDSearly, reduce mortality and improve the cure rate, we collected the clinicaldata of patients with ALI/ARDS in ICU of Ningxia Medical UniversityGeneral Hospital and analyzed the influential factors that led to ALI/ARDS,affected disease progression and prognosis.
Method:
The clinical data of375patients from March2010to December2012were retrospectively analyzed. The patients were divided into three groups.①the initial diagnosis of ALI group and the initial diagnosis of ARDSgroup.②ALI improved group and ALI aggravated into ARDS group.③thesurvivor group of ARDS and the non-survivor group of ARDS. Etiology,age, gender, chronic disease, acute organ dysfunction, blood-gas analysis,APACHEII score of patients in theses three groups within24hours ofdiagnosis were analyzed. Statistical analyses was done using SPSS11.5statistical software. Data are expressed as mean±SD. All data were analyzedby univariate test, one-way analysis of variance and multiple logistic regression method.
Results:
1154patients(3.73%) developed initial diagnosis of ALI and221patients (5.36%) met criteria for initial diagnosis of ARDS in all4125patients.Total constituent ratio of ALI/ARDS was9.09%.18patients diedand mortality was11.69%%in ALI.118patients died and mortality was53.40%in ARDS. Total mortality was36.27%.
2There were41female (26.62%) and113male (73.38%) patients inALI. The mean age was51.05±18.03. Lung injury occurred most commonlyin the setting of trauma(58/154;37.66%), infection (45/154;29.22%),complicating chronic disease (36/154;24.68%）, and complicating morethan three acute organ dysfunction（39/154;25.32%）. The mean score ofAPACHEII was16.47±7.79and the mean hospital day was13.86±13.54days.
3There were61female (27.6%) and160male (73.38%) patients inARDS. The mean age was53.57±16.38. Lung injury occurred mostcommonly in the setting of trauma(93/221;42.08%), infection (109/221;49.32%), complicating chronic disease (77/221;34.8%), and complicatingmore than three acute organ dysfunction（101/221;45.70%）. The meanscore of APACHEII was16.77±6.80and the mean hospital day was14.28±12.57days.
4The initial diagnosis of ALI and ARDS group: pneumonia (P<0.001), septic shock (P=0.008), infection of other parts except for lung (p=0.015),post operation （P<0.001）, unexplained （P=0.001） were statisticalsingnificance from etiology. And no factors included into this study reachedstatistical singnificance from the multivariater logistic regression.
5The initial diagnosis of ALI improved group and aggravated intoARDS group: pneumonia (P<0.001), sepsis (p=0.008), septicshock(P=0.011), post operation（P<0.001, unexplained（P=0.001）reachedstatistical singnificancein etiology. Acute circulatory systemdysfunction(P=0.016), acute liver system disfunction(p=0.004), acutenervous system disfunction(p=0.006), pH value(p=0.038) are statisticalsingnificantfrom the multivariater logistic regression.
6The survivor group and the non-survivor group of ARDS:trauma(p=0.004), pneumonia(p=0.006), septic shock(p=0.013),unexplained(p=0.040) are statistical singnificant in etiology. Andage(p<0.001), acute circulatory system disfunction(P=0.001), PCO2(P=0.005) are statistical singnificant from the multivariater logisticregression.
Conclusion:
1The constituent ratio was3.73%in initial diagnosis of ALI and5.36%in the initial diagnosis of ARDS. Total constituent ratio ofALI/ARDS was9.09%in Ningxia. The mortality was11.69%in ALI andwas53.40%in ARDS. Total mortality was36.27%in Ningxia. ALI/ARDS was developed in male and older people. Lung injury occurred mostcommonly in the setting of trauma and infection. There was a high score ofAPACHEII and hospital day was commonly more than ten days.
2Infection of other parts except for lung, post operation, unexplainedreasons are tend to induce ALI. Pneumonia and septic shock are morelikely to induce ARDS.ALI induced by pneumonia and post operation has abetter improvement rate and prognosis, yet ALI induced by septic shockand sepsis has a poor prognosis, and is tend to aggravate into ARDS. ARDSinduced by traumah as a better prognosis, relatively, ARDS induced bypneumonia, septic shock has a poor prognosis.
3Acute circulatory system dysfunction, acute liver system dysfunction,acute nervous system dysfunction, pH value may be the independent riskfactors for ALI aggravating into ARDS. There was a significant badinfluence upon the development and poor prognosis of ALI/ARDS whenthe patients complicated more than three acute organ dysfunction.
4Age, acute circulatory system dysfunction, PaCO2may be theindependent risk factors for ARDS.
急性肺损伤（ALI）是由各种外源性因素打击，导致的急性、进行性缺氧性呼吸衰竭。ALI发病机制复杂，有效治疗手段少，死亡率高。本研究通过提前腹腔注射微量细菌脂多糖预激后，再次静脉注射细菌脂多糖诱导，建立急性肺损伤大鼠动物模型，观察急性肺损伤大鼠的病理生理改变及肺血管内皮细胞损伤的变化；分别给予牛磺酸、血管紧张素转换酶抑制剂及二药联合干预急性肺损伤大鼠，观察其治疗效果，探讨牛磺酸及血管紧张素转化酶抑制剂对大鼠急性肺损伤的保护作用及其相关机制。
方法
1分组：将126只SD清洁级大鼠随机分成5组：（1）正常对照组（n=6）；（2）急性肺损伤组：于静脉注射脂多糖后，分为3h、6h、9h、12h、24h五个时间点，每个时间点（n=6）；（3）牛磺酸治疗组：于静脉注射脂多糖后分为上述五个时间点，每个时间点（n=6）；（4）卡托普利治疗组：于静脉注射脂多糖后分为上述五个时间点，每个时间点（n=6）；（5）牛磺酸和卡托普利联合治疗组：于静脉注射脂多糖后分为上述五个时间点，每个时间点（n=6）。
2建立急性肺损伤模型：腹腔注射脂多糖（LPS）（0.5mg/kg体重）预激12小时后，静脉注射LPS（5mg/kg体重），建立急性肺损伤动物模型，分别于静脉注射LPS后3h、6h、9h、12h、24h时间点采集标本。
3正常对照组与治疗组：（1）正常对照组：生理盐水腹腔注射12小时，静脉注射生理盐水；（2）牛磺酸治疗组：LPS预激12小时后，腹腔注射牛磺酸（50mg/kg体重），静脉注射LPS；（3）卡托普利治疗组：LPS预激12小时后，腹腔注射卡托普利（1.25mg/kg体重），静脉注射LPS；（4）牛磺酸联合卡托普利治疗组：脂多糖预激12小时后，腹腔注射牛磺酸（50mg/kg体重）及卡托普利（1.25mg/kg体重），静脉注射LPS；正常对照组静脉注射生理盐水后3h、各治疗组静脉注射LPS后3h、6h、9h、12h、24h时间点采集标本。
4检测指标：（1）测定肺湿干比重（W/D ratio）；（2）动脉血氧分压(PaO2)；（3）肺组织病理学观察,计算肺损伤病理学评分；（4）采用ELISA法检测血浆中的血管性血友病因子（vWF）的水平、内皮素-1（ET-1）、可溶性细胞间黏附分子-1（sICAM-1）、血栓调节蛋白（TM）、血小板活化因子(PAF)；（5）采用ELISA法检测肺泡灌洗液中的血管性血友病因子（vWF）的水平、内皮素-1（ET-1）、可溶性细胞间黏附分子-1（sICAM-1）、血栓调节蛋白（TM）、血小板活化因子(PAF)的水平。
5统计学分析：所产生数据均采用SPSS11.5统计软件进行，计量资料以x±s表示；成组设计的多样本均数的比较采用单因素方差分析进行检验；组间多重比较采用SNK检验，取a=0.05，以P<0.05有统计学意义。
结果
1肺湿干比重(W/D ratio)：与正常组比较，W/D ratio值在肺损伤组五个时间点均明显升高（P<0.05），12h、24h时间点升高比较突出；与肺损伤组相比较，牛磺酸治疗组、卡托普利治疗组及两者联合治疗组各时间点W/D ratio值均较肺损伤组有不同程度的降低（P<0.05），但略高于正常组水平，以两者联合治疗后W/D ratio值降低明显（P<0.05）。
2动脉血氧分压(PaO2)：与正常组比较，肺损伤组动脉血氧分压（PaO2）在各个时间点较正常对照组明显降低（P<0.05）；各时间点PaO2值接近，无变化趋势；与肺损伤组比较，牛磺酸治疗组、卡托普利治疗组及两者联合干预后PaO2值在各时间点均较肺损伤组有提高（P<0.05），但仍低于正常组PaO2值；以牛磺酸和卡托普利联合干预后PaO2值升高显著，尤其在12h、24h时间点升高较为突出。
3病理学组织切片观察：与正常对照组比较，肺损伤组肺泡正常结构部分破坏，局灶性出血，炎症细胞浸润，肺泡间隔明显增厚，肺泡腔变窄，部分肺泡萎陷。牛磺酸组、卡托普利组及两药联合干预后能使上述病理变化改善。肺损伤病理学评分：与正常对照组比较，肺损伤组的病理学评分较正常对照组明显升高（P<0.05）；牛磺酸组、卡托普利组及两药联合干预后，所有治疗组肺损伤组织病理学评分明显低于肺损伤组（P<0.05），在9h、12h、24h时间点降低较突出；但各治疗组肺损伤病理学评分仍略高于正常组；以两药联合干预后肺损伤病理学评分降低最显著（P<0.05）。
4血浆中vWF、 ET-1、sICAM-1、TM、PAF因子水平检测：与正常对照组相比，血浆中各因子水平在肺损伤组几乎所有时间点均升高，多数分别在3h、6h、9h时间点升高明显（P<0.05）；在牛磺酸组、卡托普利组及两药联合治疗组干预后血浆各因子水平在多数时间点较肺损伤组降低（P<0.05），以两者联合治疗后血浆各因子水平较肺损伤组降低较明显（P<0.05）；但所有治疗组血浆各因子水平在多数时间点依然略高于正常对照组。
5肺泡灌洗液中vWF、 ET-1、sICAM-1、TM、PAF水平检测：与正常对照组相比，肺泡灌洗液中各种因子水平在肺损伤组所有时间点均较正常组升高（P<0.05），多数在3h、6h、9h时间点升高明显（P<0.05）；在牛磺酸组、卡托普利组及两药联合治疗组干预后各组多数时间点较肺损伤组降低（P<0.05），以两者联合干预降低较明显（P<0.05）；但各治疗组BALF中各因子水平多数依然略高于正常对照组。
结论：
1本研究通过提前腹腔注射小剂量内毒素预激，联合静脉内注射内毒素，大鼠肺湿干比重增加，动脉血氧分压降低，肺病理变化明显，肺损伤病理学评分升高，证明成功地建立了内毒素诱导型大鼠急性肺损伤的动物模型，模型稳定，此种制模方法目前较少见。
2急性肺损伤时存在肺血管内皮细胞的活化和损伤，反应内皮细胞活化和损伤的血浆及肺泡灌洗液中的细胞因子水平增高明显，无相对固定的变化规律。
3牛磺酸对急性肺损伤及其肺血管内皮细胞有治疗和保护作用。
4血管紧张素转换酶抑制剂对急性肺损伤及其肺血管内皮细胞有治疗和保护作用。
5牛磺酸及血管紧张素转换酶抑制剂联合应用对急性肺损伤及其肺血管内皮细胞有治疗和保护作用，效果优于单药干预治疗，提示可以考虑联合应用。目前国内尚未见两药联合治疗ALI的研究报道。
目的：
通过收集宁夏医科大学总医院ICU科ALI/ARDS患者的临床资料，对可能导致ALI/ARDS的发生、影响病情发展及预后的相关临床影响因素进行分析，以提高对ALI/ARDS的致病因素早期识别，早期预防，减少ALI/ARDS的发生率，降低死亡率，提高救治率。
方法：
回顾性研究2010年3月到2012年12月宁夏医科大学总医院综合ICU科收治的病人，将其中符合ALI/ARDS诊断标准的患者列为研究观察对象，这些病例被分为三组：①初次诊断为ALI组与ARDS组；②ALI好转组与ALI转化为ARDS组；③ARDS存活组与死亡组；对这三组患者分别从病因学；基本状况，年龄、性别、是否合并慢性疾病；是否合并急性器官障碍及其种类及数目；血气分析指标、APACHEII评分等多个临床因素进行统计分析。统计学分析:用统计学软件SPSS11.5进行统计学分析，数值变量采用x±s表示：计量资料两组间比较采用独立样本的t检验，计数资料采用单因素方差分析（x2检验）；多因素分析采用条件Logistic回归方法。
结果：
14125例病人中诊断ALI154例、ALI的构成比3.73%；诊断ARDS221例, ARDS的构成比5.36%；ALI/ARDS总构成比9.09%。ALI中18例死亡，病死率11.69%；ARDS中118例死亡，病死率53.40%；ALI/ARDS总病死率36.27%。
2ALI中女性41例（26.62%），男性113例（73.38%），平均年龄为51.05±18.03岁；病因中创伤58例（37.66%），感染45例（29.22%），合并慢性病36例（24.68%），合并≥3个急性器官功能障碍39例(25.32%)； APACHEII评分均数16.47±7.79；平均住院天数为13.86±13.54天。
3ARDS中女性61例(27.6%)，男性160例(72.4%)，平均年龄为53.57±16.38岁；病因中创伤93例(42.08%)，感染109例(49.32%)，合并慢性病77例(34.8%)，合并≥3个急性器官功能障碍101例(45.70%)；APACHEII评分16.77±6.80。平均住院天数为14.28±12.57天。
4初始诊断ALI组与ARDS组结果示：原发致病因素中，肺部感染(P=0.003)、感染性休克(P=0.008)、其他部位感染(P=0.015)、手术术后（P<0.001）、不明原因（P=0.001）有统计学差异；多因素分析示纳入研究的各影响因素无统计学差异。
5ALI好转组与ALI转化为ARDS组结果示：原发致病因素中，肺部感染(P<0.001)、脓毒症（P=0.008）、感染性休克(P=0.011)、手术术后（P<0.001）有统计学差异；多因素分析示纳入研究的各影响因素中，急性心血管系统障碍（P=0.016）、急性肝脏系统障碍（P=0.004）、急性神经系统障碍（P=0.006）、pH值大小（P=0.038）有统计学意义；其他观察指标无统计学意义。
6ARDS存活组与死亡组结果示：原发致病因素中，创伤（P=0.004）、肺部感染（P=0.006）、感染性休克（P=0.013）、不明原因（P=0.040）有统计学差异；多因素分析提示纳入研究的各影响因素中年龄（P<0.001）、急性心血管系统障碍（P=0.001）、PCO2（P=0.005）有统计学意义。其它观察指标无统计学意义。
结论：
1本院ALI的构成比3.73%，ARDS的构成比5.36%，ALI/ARDS总构成比9.09%。ALI的病死率11.69%%，ARDS病死率53.40%，ALI/ARDS总病死率36.27%。 ALI/ARDS发病以男性、中老年人多见；致病因素以创伤、感染多见；入院APACHEII评分均高，住院天数大于10天。
2其他部位感染及手术术后和一些不明确原因较易诱发ALI；肺部感染、感染性休克较易诱发ARDS。肺部感染、手术术后所致的ALI好转率相对高，预后相对较好；感染性休克和脓毒症所致的ALI预后相对较差，较易发展为ARDS。创伤所致的ARDS预后相对较好，肺部感染和感染性休克所致的ARDS预后较差。
3急性心血管系统、肝脏系统、神经系统的器官以及PH值大小可能为ALI病情恶化转化为ARDS的独立危险因素。合并≥3个器官功能障碍时，对ALI/ARDS的病情的发生发展及预后都有非常不良的影响。
4年龄、心血管系统功能障碍、二氧化碳分压值可能成为影响ARDS预后的独立危险因素。
Objective:
Acute lung injury is a critical illness syndrome consisting of acuteprogressive hypoxemic respiratory failure arising either from a variety ofdirect (pulmonary) or indirect (extrapulmonary) insults. Duing to thecomplex lung injury pathophysiology of ALI, it remains underdiagnosed andundertreated. At present，therapeutic interventions to treat ALI remainlimited. Mortality from ALI is substantial. To observe lung pathophysiologyand endothelial activation and injury in rats with ALI, we established theanimal model of ALI by intraperitoneal injection of mindose of LPS inadvance combined with intravenous injection of LPS. Therefore toinvestigate the protective effect by taurine and angiotensin convertingenzyme inhibitor on acute lung injury and its relative mechanism, we treatedrats with ALI by intraperitoneal injection of taurine, captopril，and both durgrespectively.
Methods:
1Subgrop:126male SD rats were randomly divided into five groups: (1) normal control group (n=6).(2) acute lung injury (LPS) group: ratswere divided into five time points at3h,6h,9h,12h,24h after intravenousinjection of LPS and there were6rats in every time point (n=6);(3) thetaurine group: rats were divided into above-mentioned five time points afterintravenous injection of LPS and there were6rats in every time point (n=6);(4) the captopril group: rats were divided into above-mentioned five timepoints after intravenous injection of LPS and there were6rats in every timepoint (n=6),(5) the taurine and the captopril group: rats were divided intoabove-mentioned five time points after intravenous injection of LPS andthere were6rats in every time point (n=6).
2Estabished ALI model: Rats were pre-activated by intraperitonealinjection of LPS(0.5mg/kg) in advance. Then after pre-activating for12hours, rats were induced by intravenous injection of LPS (5mg/kg.).Specimens were collected after intravenous injection of LPS at five timepoint.
3The normal control group and treatment group:(1) The normalcontrol group: Intraperitoneal injection of saline for12hours, saline wasinjected intravenously.(2) The taurine group: After LPS preactivating for12hours, taurine50mg/kg was injected intraperitoneally and LPS was injectedintravenously.(3) The captopril group:After LPS pre-activating for12hours,captopril1.25mg/kg was injected intraperitoneally and LPS was injectedintravenously.(4)The taurine and captopril group: After LPS preactivating for12hours, taurine50mg/kg and the captopril1.25mg/kg were injectedintraperitoneally and LPS was injected intravenously. Specimens werecollected at3h after intravenous injection of saline in normal group and at3h,6h,9h,12h,24h time point after intravenous injection of LPS in alltreatment group respectively.
4Measurement: Measurement of lung wet-dry weight and arterialpartial pressure of oxygen (PaO2). Lung histopathology were observed andanalyzed. Von Willebrand factor (vWF), endothelin-1(ET-1), Solubleintercellular adhesion molecule-1(sICAM-1), thrombomodulin (TM),platelet-activating factor (PAF) levels were detected in plasma andbronchoalveolar lavage fluid (BALF) by ELISA.
5Statistical Analysis: Data are expressed as mean±SD. Statisticalanalyses was done using SPSS11.5statistical software. Statisticaldifferences between the data were determined with one-way analysis ofvariance and mutltiple comparisons were tested withStudent-Newman-Keuls-test(SNK), and a P value,0.05was consideredsignificant.
Resuls:
1Lung wet-dry weight ratio: Lung W/D ratio showed a significantincreasing in lung injury group（P<0.05）, and it increased obviously at12h、24h time point. Lung W/D ratio decreased in varying degrees in taurinegroup, captopril group and taurine and captopril group, but still higher than the normal group（P<0.05）. The decreasing mostly is in the combinedtreatment group.
2Arterial partial pressure of oxygen (PaO2) levels: PaO2levels in thelung injury group were significantly lower than the control group（P<0.05）,but increased in taurine group and captopril group, and increased mostsignificantly after the combined treatment intervention（P<0.05）and it wasobvious at9h、12h、24h time point.
3Lung histology: Lung injury group showed marked inflammation andmild lung edema with marked thickening of alveolar septa and alveolarspace narrowing. Improved the pathological changes were observed in thetaurine group, captopril group and both combined. The score of lung injury:the score of lung injury in the acute lung injury group were significantlyhigher than the normal group and decreased in taurine group and captoprilgroup and both combined group（P<0.05）,and decreased mostsignificantly after the combined treatment intervention. It improvedobviously at9h、12h、24h time point
4The plasma levels of vWF，ET-1, sICAM-1, TM and PAF：Theplasma levels of vWF，ET-1, sICAM-1, TM and PAF were increased in lunginjury group than in the control group（P<0.05）. Most of them wereimproved at3h,6h,9h time point obviously. But after the intervention, theywere lower in taurine treatment group, captopril group, and both treantmentgroup at the most of different time point than in the acute lung injury group（P<0.05）. The levels of them in the joint intervention were lowerthan the lung injury group obviously.
5The BLAF levels of vWF，ET-1, sICAM-1, TM and PAF：TheBLAF levels of vWF,ET-1, sICAM-1, TM and PAF were increased in lunginjury group than in the control group at the different time point andincreased obviously at3h、6h、9h time point. After the treatment, they werelower in taurine treatment group, captopril group, and both treantment groupat the most of different time point than in acute lung injury group. Thelevels of them in the joint intervention group were lower than the lung injurygroup obviously and were still a little higer than the normal control group.
Conclusion:
1We successfully established the animal model of ALI byintra-peritoneal injection of mindose of LPS in advance combined withint-ravenous injection of LPS. It was porved by the increasing lung wet-dryweight ratio, the decreasing PaO2levels, the changes of Lung histology andthe increasing score of lung injury. The way of making animal model isrelatively rare at present.
2There was lung endothelial cell activation and injury in ALI and itwas expressed by the increasing levels of plasma and BLAF vWF，ET-1,sICAM-1, TM and PAF which represented the lung endothelial cellactivation and injury.
3Taurine had a protective effect on acute lung injury and the i-njuried pulmonary vascular endothelial cells.
4Angiotensin-converting enzyme inhibitors had protective effect onacute lung injury and the injuried pulmonary vascular endothelial cells.
5It prompted that two-drug combination had a more protective effecton lung injury and pulmonary vascular endothelial cells, and it was betterthan single drug-intervention group. The study showed that we can treat ALIwith joint treatment of taurine and captopril. The treatment of these twodrugs combination on ALI was not reported in domestic at present.
Objective:
To recognize and prevent the clinical influential factors in ALI/ARDSearly, reduce mortality and improve the cure rate, we collected the clinicaldata of patients with ALI/ARDS in ICU of Ningxia Medical UniversityGeneral Hospital and analyzed the influential factors that led to ALI/ARDS,affected disease progression and prognosis.
Method:
The clinical data of375patients from March2010to December2012were retrospectively analyzed. The patients were divided into three groups.①the initial diagnosis of ALI group and the initial diagnosis of ARDSgroup.②ALI improved group and ALI aggravated into ARDS group.③thesurvivor group of ARDS and the non-survivor group of ARDS. Etiology,age, gender, chronic disease, acute organ dysfunction, blood-gas analysis,APACHEII score of patients in theses three groups within24hours ofdiagnosis were analyzed. Statistical analyses was done using SPSS11.5statistical software. Data are expressed as mean±SD. All data were analyzedby univariate test, one-way analysis of variance and multiple logistic regression method.
Results:
1154patients(3.73%) developed initial diagnosis of ALI and221patients (5.36%) met criteria for initial diagnosis of ARDS in all4125patients.Total constituent ratio of ALI/ARDS was9.09%.18patients diedand mortality was11.69%%in ALI.118patients died and mortality was53.40%in ARDS. Total mortality was36.27%.
2There were41female (26.62%) and113male (73.38%) patients inALI. The mean age was51.05±18.03. Lung injury occurred most commonlyin the setting of trauma(58/154;37.66%), infection (45/154;29.22%),complicating chronic disease (36/154;24.68%）, and complicating morethan three acute organ dysfunction（39/154;25.32%）. The mean score ofAPACHEII was16.47±7.79and the mean hospital day was13.86±13.54days.
3There were61female (27.6%) and160male (73.38%) patients inARDS. The mean age was53.57±16.38. Lung injury occurred mostcommonly in the setting of trauma(93/221;42.08%), infection (109/221;49.32%), complicating chronic disease (77/221;34.8%), and complicatingmore than three acute organ dysfunction（101/221;45.70%）. The meanscore of APACHEII was16.77±6.80and the mean hospital day was14.28±12.57days.
4The initial diagnosis of ALI and ARDS group: pneumonia (P<0.001), septic shock (P=0.008), infection of other parts except for lung (p=0.015),post operation （P<0.001）, unexplained （P=0.001） were statisticalsingnificance from etiology. And no factors included into this study reachedstatistical singnificance from the multivariater logistic regression.
5The initial diagnosis of ALI improved group and aggravated intoARDS group: pneumonia (P<0.001), sepsis (p=0.008), septicshock(P=0.011), post operation（P<0.001, unexplained（P=0.001）reachedstatistical singnificancein etiology. Acute circulatory systemdysfunction(P=0.016), acute liver system disfunction(p=0.004), acutenervous system disfunction(p=0.006), pH value(p=0.038) are statisticalsingnificantfrom the multivariater logistic regression.
6The survivor group and the non-survivor group of ARDS:trauma(p=0.004), pneumonia(p=0.006), septic shock(p=0.013),unexplained(p=0.040) are statistical singnificant in etiology. Andage(p<0.001), acute circulatory system disfunction(P=0.001), PCO2(P=0.005) are statistical singnificant from the multivariater logisticregression.
Conclusion:
1The constituent ratio was3.73%in initial diagnosis of ALI and5.36%in the initial diagnosis of ARDS. Total constituent ratio ofALI/ARDS was9.09%in Ningxia. The mortality was11.69%in ALI andwas53.40%in ARDS. Total mortality was36.27%in Ningxia. ALI/ARDS was developed in male and older people. Lung injury occurred mostcommonly in the setting of trauma and infection. There was a high score ofAPACHEII and hospital day was commonly more than ten days.
2Infection of other parts except for lung, post operation, unexplainedreasons are tend to induce ALI. Pneumonia and septic shock are morelikely to induce ARDS.ALI induced by pneumonia and post operation has abetter improvement rate and prognosis, yet ALI induced by septic shockand sepsis has a poor prognosis, and is tend to aggravate into ARDS. ARDSinduced by traumah as a better prognosis, relatively, ARDS induced bypneumonia, septic shock has a poor prognosis.
3Acute circulatory system dysfunction, acute liver system dysfunction,acute nervous system dysfunction, pH value may be the independent riskfactors for ALI aggravating into ARDS. There was a significant badinfluence upon the development and poor prognosis of ALI/ARDS whenthe patients complicated more than three acute organ dysfunction.
4Age, acute circulatory system dysfunction, PaCO2may be theindependent risk factors for ARDS.
引文
[1] Dunne PJ, Macintyre NR, Schmidt UH, et al. Respiratory care year in review2011:long-term oxygen therapy, pulmonary rehabilitation, airway management, acutelung injury, education, and management[J]. Respir Care.2012,57(4):590-606
[2] Beasley MB. The pathologist′s approach to acute lung injury[J].Arch Pathol LabMed.2010,134(5):719-27
[3] Moraes TJ,Zurawska JH, Doweny GP. Neutrophil granule contents in thepathogenesis of lung injury[J].Curr Opin Hematol.2006,13(1):21-27
[4]钱桂生.急性肺损伤和急性呼吸窘迫综合征的诊断与治疗[J].解放军医学杂志.2009,34（4）：371-373
[5] Lucas R, Verin AD, Black SM, et al. Regulators of endothelial and epithelial barrierintegrity and function in acute lung injury[J].BiochemPharmacol.2009,77(12):1763-1772
[6] Calfee CS, Matthay MA. Nonventilatory treatment for acute lung injury andARDS[J].Chest.2007,13(3):913-920
[7] Anon. Ventilation with lower tidal volumes as compared with traditionaltidalvolumes for acute lung injury and the acute respiratory distress syndrome.Theacute Respiratory Distress Syndrome Network [J].N Engl J Med.2000,342(18):1301-1308
[8] Phua J, Badia JR,Adhikari NK, et al.Has motality from acute respiratory distresssyndrome decreased over time?[J].Am J Respir Crit CareMed.2009,179(3):220-227
[9] Bhargava M, Wendt CH. Biomarkers in acute lung injury[J]. Transl Res.2012,159(4):205-17
[10]Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophilextraacellular traps contribute to acute lung injury of influenza pneumonitis[J].Am J Pathol.2011,179(1):199-210
[11]Abraham E, Albert R,Amato M,et al. Round table conference: Acute lunginjury[J].Am J Respir Crit Care Med.1998,158:675-679
[12]Bhavsar TM, Cantor JO, Patel SN, et al. Attenuating effect of taurine onlipopolysaccharide-induced acute lung injury in hamsters[J].PharmacolRes.2009,60(5):418-428
[13]Neyrinck AP, Matthay MA. The role of angiotensin-converting enzyme inhibitionin endotoxin-induced lung injury in rats[J].Crit Care Med.2009,37(2):776-777
[14]中华医学会重症医学分会.急性肺损伤/急性呼吸窘迫综合征诊断与治疗指南（2006）[J].中华内科杂志.2007,46（5）:430-435
[15]白涛,田阿勇,王俊科.谷氨酰胺对内毒素性急性肺损伤大鼠肺组织肿瘤坏死因子-a表达的影响[J].中华麻醉学杂志,2006,26(11),1013-1015
[16]Smith KM, Mrozek JD, Sim ont on SC, et al. Prolonged partical liquid ventilationusing convent ional and hing frequency ventilatory techniques: gasexchange andlung pathology in an animal model of respiratory distress syndrome[J].Crit CareMed.1997,25(11):1888-1897
[17]钱桂生.急性肺损伤和急性呼吸窘迫综合征研究现状与展望[J].解放军医学杂志.2003，28（2）：97-101
[18]The ACCP/SCCM Consensus Conference Committee[J].Chest.1992,101：1644-1655
[19]Ranieri V M, Rubenfeld G D, Thoposon B T, et al.Acute respiratory distresssyndrome(ARDS):The Belin Definition[J].Jama.2012,307:2526-2533
[20]Hough CL, Herridge MS. Long-term outcome after acute lung injury. Curr OpinCrit Care.2012,18(1):8-15
[21]Lu Y, Song Z, Zhou X,et al.A12-month clinical survey of incidence and outcome ofacute respiratory distress syndrome in Shanghai intensive care units[J].IntensiveCare Med.2004,30(12):2197-2203
[22]北京市科委重大项目MODS课题组.1998-2003年北京地区重症加强治疗病房急性呼吸窘迫综合征的临床流行病学调查[J].中国危重病急救学.2007,19(4):201-204
[23]Carmen SV. Acute lung injury and acute respiratory distress syndrome: diagnostichurdles[J].J Bras Pneumo.2007,33(4):338-9
[24]Ferguson ND, Frutos-Vivar F, Esteban A, et al.Acute respiratory distresssyndrome:under recognition by clinicians and diagnostic accuracy of three clinicaldefinitions[J].Critical Care Med.2005,33(10):2228-2234
[25]Gordon DR, Ellen C.Incidence and Outcomes ofAcute Lung Injury[J].N Engl JMed.2005,3(53):1685-93
[26]Claude AP, David AS. The Acute Respiratory Distress Syndrome[J].Ann InternMed.2004,14(1):460-70
[27]Lorraine B. Pathophysiology of acute lung injury and the acute respiratory distresssyndrome[J].Semin Respiratory Critical Care Med.2006,27(4):337-349
[28]Wheeler AP, Bernard GR. Acute lung injury and the acute respirato-ry distresssyndrome,A Clinical Review[J].Lancet.2007,369:1553-1564
[29]侯一峰，周艳春，周永双.全身炎症反应综合征一急性肺损伤大鼠模型的研究[J].中国实验动物学报.2003,11(3):147-150
[30]白春学，孙波.急性呼吸窘迫综合征[M].上海：复旦大学出版社.2005,p331
[31]徐涛,曾邦雄,李兴旺.中性粒细胞胶原酶在内毒素性急性肺损伤中的作用[J].中华麻醉学杂志.2004,24(1):29-32
[32]Xu T，Zeng BX，Li XW. The role of neutrophil collagenase in endotoxic acute lunginjury[J].Hua zhong Univ Sci Technolog Med Sci.2004,24(2):196-198
[33]Shen Y, Wang D, Wang X. Role of CCR2and IL-8in acute lung injury: a newmechanism and therapeutic target[J]. Expert Rev Respir Med.2011,5(1):107-14
[34]Pugin J, Schurer MC, Leturcq D, et al. Lipopolyscchride-binding protein andsoluble CD14[J].Proc Natl Acad Sci USA.1993,90:2744-2748
[35]Bevilacqua MP, Pober JS, Wheeler ME, et al.Interleukin1acts on cultures hamanvascular endothelium to increse the adhesion of polymorphnuclear leukocytes,monocytes and related leukocyte cell lines[J]. JClin Invest.1985,76:2003
[36]Nieuwenhuijzen GA, Knapen MF, Oyen WJ, et al. Organ damages is preceded bychanges in protein extravasation in an experimental model ofmultiple organdusfunction syndrome[J].Shock.1997,7:98-104
[37]Garcia JG, Schaphorst KM. Regulation of endothelial cell gap formation andparacellular permeability[J].J Invest Med.1995,43:117-126
[38]Louise CB, Tran MC, Obrig TG.Sensitazation of human umbilical vein endothelialcells to Shiga toxin: invovelment of protein kinase C and NF-kB[J].InfectImmun.1997,65:3337-3344
[39]Banneman DD, Goldblum SE.Endotoxin induces endothelial barrier dysfunctionthrough protein tyrosine phosphorylation[J].Am J Physiol.1997,273(1):217-226
[40]Blann AD, Lip GYH.The endothelium in atherothrombotic dis-eases:assessment offunction, mechanisms and clinical implications[J].Blood Coag Fibrinolys.1998,9:297-306
[41]Odanos S E, Mavrommati I, Korovesi I, et a1.Pulmonary endotheliumin acute lunginjury from basic science to the critically ill[J].Intensive CareMed.2004,30(9):1702-1714
[42]Ware LB, Eisner MD, Taylor Thampson B, et al.Significance of von willebrandfactor in septic and nonseptic patients with acute lung injury[J].Am J Respir CritCare Med.2004,170(7):766-772
[43]Heidi R, Flori MD, Lorraine B, Ware MD,et al.Early elevation of plasma vonwillebrand factor antigen in pediatric acute lung injury is associated withanincreased risk of death and prolonged mechanical ventilation[J].Pediatr Crit CareMed.2007,8(2),96-101
[44]Rubin DB, Wiener K, Murray JF,et al.Elevated yon Willebrand factor antigen is anearly plasma predictor of acute lung injury in nonpulmonary sepsissyndrome[J].JClin Invest.1990,86(2):474-480
[45]Comellas AP,Briva A.Role of endothelin-1in acute lung injury [J].TranslRes.2009,153(6):263-271
[46]Motte S,Mc Entee K,Naeije R.Endothelin receptor antagonists [J].PharmacolTherapeutics.2006,110(3):386-414
[47]Habre W,Petá k F,Ruchonnet Met railler I,et al.The role of endothelin-1inhyperoxia-induced lung injury in mice [J].Respir Res.2006,7:45-51
[48]Berger MM,Rozendal CS,Schieber C,et al.The effect of endothelin-1on alveolarfluid clearance and pulmonary edema formation in the rat[J].AnesthAanalg.2009,108(1):225-231
[49]Blackwell TS, Debelak JP, VenkatakrishnanA, et al. Acute lung injury afterhepatic cryoablation: Correlation with NF-kappaB activeation and cytokineproduction[J].Surgery.1999,1263:518-526
[50]Drllm lW, StelterRL, WaldhauslW, et al. Endothelin-1in adult respirstory distresssyndrome[J].Am Rev Respir Dis.1993,1487:1169-1173
[51]Mc Clintock D, Zhuo H, Wickersham N, et al.Biomarkers ofinflammation,coagulation and fibrinolysis pridict mortality in adute lunginjury[J].Crit Care.2008,12(2):R41
[52]Calfee CS,Eisner MD, Parsons PE, et al.Soluble intercellular adhesion molecule-1and clinical outcomes in patients with acute lung injury[J].Intensive CareMed.2009,35(2):248-257
[53]ChenKH,Reece LM,Leary JF.Mitochondrial glutathione modulates TNFα-inducedendothelial cell dysfunction[J].Fre Rad Bio Mled.1999,27(1):100-109
[54]Boyle EM,Kovacich JC,Cant TG,etal.Inhibition of nuclear factor-KBnuclearlocation reduces human E-selectin expression and the systemicin-flammatoryresponse[J].Circulation.1998,98(19supple):282-288.
[55]KacimiR,KarlinerJS,KoudssiF,etal.Expression and regulation ofadhesionmoleculesinCardiac cellsby cytokines response to acute hypoxia [J].Circ Res.1998,82(5):576-586
[56]Esmon CT,Owen WG.Identification of an endothelial cell cofactor for thrombincatalyzed activation of protein C[J].Proc Natl Acad Sci USA.1981,78(4):2249
[57]Esmon NL,OwenWG,Esmon CT.Isolation of a membrane-bound co factor forthrombin catalyzedactivationofproteinC[J].JbiolChem.1982,257(2):859-864
[58]Takeda N, Maemurak, Horie S,et al.Thrombomodulin is a clock controlled gene invascular endothelial cells[J]. J Biol Chem.2007,282(45):32561-32567
[59]Takahashi H, Ito S,Hanana M, et al. Circulating thrombomodulin asa novelendothelial cell marker comparison of its behavior with von willebrand factor andtissue type plasm inogen activator[J].Am J Hematol.1992,41(1):32-39
[60]Takano S,Kimura S,Ohdama S.Plasma thrombomodulin in health anddiseases[J].Blood.1990,76(10):2024
[61]Iba T, Nakarai E, Takayama T, et al.Combination effect of antithrombin andrecombinant human soluble thrombomodulin in a lippolysaccharide induced rat sepsis model[J].Crit care.2009,13(6):R203
[62]Olson N C, Joyce PB, Fleisher LN, et al. Role of platelet-activating factor andeicosanoids during endotoxin-induced lung injury in pigs[J].AmJPhysiol.1990,258(5):H1674-1686
[63]Robert A, Parker K, Siflinger-Birnboim A, et al. Increased endothelialpermeabilityafterneutrophilactivationoccursbyadiffusion-dependentmechanism[J].MicrovascularResearch.1995,49(2):227-232
[64]Laurindo F R, Goldstein RE, Davenport NJ, et al.Mechanisms of hypotensionproduced by platelet-activating factor[J].J Appl Physiol.1989,66(6):2681-2690
[65]Shin-Wen Chang.TNF potentiates PAF-induced pulmonary vasoconstriction in therat: role of neutrophils and thromboxane A2[J].J ApplPhysiol.1994,77(6):2817-2826
[66]Parvez S, Tabassum H, Banerjee BD, et al. Taurine prevents tamoxifen-inducedmitochondrial oxidative damage in mice[J].Basic Clin PharmacolToxicol.2008,102(4):382-387
[67]Abreu SC, Antunes MA, Pelosi P, et al. Mechanisms of cellular therapy inrespiratory diseases[J]. Intensive Care Med.2011,37(9):1421-1431
[68]Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme2in lungdiseases[J].Curr Opin Pharmacol.2006,6(3):271-6
[69]Yang LX. Role of TRPC1and NF-kappa B in mediating angiotensin II-inducedCa2+entry and endothelial hyperpermeability[J].Peptides.2009,30(7):1368-1373
[70]Zhang H,Schmeisser A, Garlichs CD, etal. AngiotensinII-induced superoxide aniongeneration in human vascular endothelial cells:role ofmembrane-boundNADH-/NADPH-oxidases[J].CardiovascRes.1999,44(1):215-222
[71]Oriji GK.Angiotensin II-induced ET and PGI2release in rat aorticendothelialcells is mediated by PKC[J].Prostaglandins Leukot Essent Fatty Acids.1999,61(2):113-117
[72]刚宏林，苏云明.血管紧张素转换酶抑制剂药理研究进展[J].中医药信息.2005.22（1）：22-23
[73]Ghazi-Khansari M, Nasiri G, Honarjoo M. Decreasing the oxidant stress fromparaquat in isolated perfused rat lung using captopril and niacin[J]. Arch Toxicol.2005,79(6):341-345
[1][Rubenfeld GD,Herridge MS. Epidemiolog and Outcomes of Acute Lung Injury [J].Chest.2007.131(2):554-562
[2] Lu Y, Song Z, Zhou X, et al. A12-month clinical survey of incidence and outcomeof acute respiratory distress syndrome in Shanghai intensive care units [J].IntensiveCare Med.2004,30(12):2197-2203
[3]北京市科委重大项目MODS课题组.1998-2003年北京地区重症加强治疗病房急性呼吸窘迫综合征的临床流行病学调查[J].中国危重病急救医学.2007,19(4):201-204
[4] Luhr OR, Antonsen K, Karls son M, et al，and the ARF s tudy group. Incidenceandmortality after acute respiratory failure and acute respiratory dirtress syndromein Sweden, Denmark, and Iceland[J]. Am J Respir Cri t Care Med.1999,159:1849-1861
[5] Bernard GR, Artigas A, Brigham KL, et aland the consensus committee. TheAmerican-European Consensus Conference on ARDS,definitions, mechanisms,relevant outcomes,and clinical trial coordination[J]. Am J Respir Crit Care Med.1994,149:818-824
[6]北京市科委重大项目“MODS中西医结合诊治/降低病死率研究课”组:多器官功能障碍综合佂诊断标准、病情严重度评分及预后评估系统和中西医结合证型诊断[J].中国危重病急救医学.2008,20(1):1-3
[7] Murray JF, Matthay M A, Luce J M, et al. An expanded definition of the adultrespirratory distress syndrome [J]. Am Rev Respir Dis.1988,138:720-723
[8] Artigas A, Bernard GR, Carlet J, et al.The American-European Consens usConference on ARDS, part2: ventilatory, pharmacologic,supportive therapy, studydesign strategies,and issues related to recovery and remodeling[J]. Am J Respir CritCare Med.1998,157:1332-1347.
[9] Ferguson N D,Davis A M,Slutsky AS,et al.Development of aclinincal definition foracute respiratory distress syndrome using the Delphi technique [J].J Crit Care.2005,20:147-154
[10]Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratorydistresssyndrome (ARDS).The Berlin Definition[J]. JAMA.2012，307:2526-2533
[11]The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidalvolumes as compared with traditional tidal volumes for acute lung injury and theacute respiratory distress syndrome[J]. N Engl J Med.2000，342:1301–1308.
[12]Ferguson ND, et al. Acute respiratory distress syndrome: underrecognition byclinicians and diagnostic accuracy of three clinical definitions[J].Crit Care Med.2005，33:2228–2234
[13]Cedeno A, et al. Acute lung injury/acute respiratory distress syndrome: a need foreducation[J].P R Health Sci J.2002，21:305–308
[14]Howard AE, et al. Comparison of3methods of detecting acute respiratory distresssyndrome: clinical screening, chart review, and diagnostic coding[J]. Am J CritCare.2004,13:59–64
[15]曾因明.麻醉学第2版［M］．北京:人民卫生出版社，2010,1.38
[16]Jerng J S, Yu CJ, Liaw YS, et al. Clinical spectrum of acute resperatory distres ssyndrome in a tertiary referral hospital: etiology,severity, clinical course, andhospital outcome[J]. J Formos Med Assoc.2000，99:538-543
[17]Brun-Bris son C, Mi nelli C, Brazzi L, et al.The European survey (alive) of acutelung injury and ARDS[J]. Am J Res pir Crit Care Med.2001,163:956-959
[18]陈学华.宁夏交通事故规律分析及预防对策研究[D].长安大学，2006:3
[19]赵雪生.应重视创伤后的急性肺损伤与ARDS[J].第八届全国中西医结合灾害急救危重病医学学术会议.2012，4（18）:168-172
[20]黄显凯.做好严重创伤早期救治的几个关键环节[J].创伤外科杂志.2012，3:196-198
[21]徐金富.肺部感染相关急性肺损伤发病机制研究进展[J].国外医学.呼吸系统分册.2004，02:72-75.
[22]宋振举,白春学.我国急性肺损伤/急性呼吸窘迫综合征临床和实验研究进展[J].内科理论与实践.2010，6：496-499
[23]赖军华,莫小源.影响ARDS患者预后的危险因素分析[J].中国医药导报.2012，12：82-84
[24]Brun-Bris son C, Mi nelli C, Brazzi L, et al.The European survey (alive) of acutelung injury and ARDS[J]. Am J Res pir Crit Care Med.2001,163: A956
[25]Angus DC, et al. Epidemiology of severe sepsis in the United States: analysis ofincidence, outcome, and associated costs of care[J]. Crit Care Med.2001；29:1303–1310
[26]GordonD.Rubenfeld,MD,MSc,MargaretS.Herridge,MD,MPH,FCCP.Epidemiologand Outcomes of Acute Lung Injury[J].2007，131(2):554-562
[27]葛庆岗，赵建娟，吕旌乔等.重症监护病房中急性呼吸窘迫综合征的预后危险因素分析[J].解放军医学杂志.2010，6:82-84
[28]陆月明,孙波.急性肺损伤和急性呼吸窘迫综合征临床流行病学研究进展[J].中华急诊医学杂志.2003,1:65-66
[29]刘大为.实用重症医学［M］．北京:人民卫生出版社，2010.381-387
[30]李文元,丁士芳.急性呼吸窘迫综合征患者预后的危险因素分析[J].山东大学学报(医学版).2012,3:93-95
[31]谢才德,秦蓁,邹华兰等.急性呼吸窘迫综合征临床治疗观察及预后影响因素分析[J].现代生物医学进展.2012,25:4921-4923
[32]Est enssoro E, Dubin A, Laffaire E. Impact of positive end-expiratory pressure onthe def inition of acute respiratory distress syndrome [J].Intensive Care Med.2003,29(11):1936-1942
[33]Dicker RA, Morabito DJ, Pittet JF, et a1. Acute respiratory distress syndromecriteria in trauma patients: why the definitions do not work[J].J Trauma.2004,57(3):522-528
[34]李昂,王海曼,阴赪宏等.多器官功能障碍综合征患者急性呼吸窘迫综合征流行病学调查[J].中国实用内科杂志.2009，11:1036-1038
[1]钱桂生.急性肺损伤和急性呼吸窘迫综合征研究现状与展望[J].解放军医学杂.2003，28（2）：97-101
[2] The ACCP/SCCM Consensus Conference Committee. Chest.1992；101：1644-1655
[3] Ranieri V M, Rubenfeld G D, Thoposon B T, et al.Acute respiratory distresssyndrome(ARDS): The Belin Definition[J].Jama.2012,307:2526-2533
[4] Lu Y,Song Z, Zhou X,et al. A12-month clinical survey of incidence and outcomeof acute respiratory distress syndrome in Shanghai intensive care units[J]. IntensiveCare Med.2004,30(12):2197-2203
[5]北京市科委重大项目MODS课题组.1998-2003年北京地区重症加强治疗病房急性呼吸窘迫综合征的临床流行病学调查[J].中国危重病急救医学.2007,19(4):201-204
[6] Narasaraju T, Yang E, Samy RP, et al.Excessive neutrophils and neutrophilextraacellular traps contribute to acute lung injury of influenza pneumonitis[J].AmJ Pathol.2011,179(1):199-210
[7] Soehnlein O,Oehmcke S,Ma X,et al.Neutrophil degranulation mediates severe lungdamage triggered by streptococcal M1protein[J].Eur Respir J.2008,32(2):405-12
[8] Ware LB, Bastarche JA, Wang L.Coagulation and fibrinolysis in human acutelung injury–new therapeutic targets?[J].Keio J Med.2005,54(3):142-149
[9]叶玲，金美玲，徐晓波，等.急性肺损伤/急性呼吸窘迫综合征患者凝血纤溶系统的变化[J].复旦学报（医学版）.2008，35（5）：671-674，680
[10]钱桂生.急性肺损伤和急性呼吸窘迫综合征的诊断与治疗[J].解放军医学杂志.2009，34（4）：371-373
[11]Moraes TJ,Zurawska JH, Doweny GP. Neutrophil granule contents in thepathogenesis of lung injury[J].Curr Opin Hematol.2006,13(1):21-27
[12]Lucas R,Verin AD, Black SM, et al.Regulators of endothelial and epithelialbarrier integrity and function in acute lung injury[J].Biochem Pharmacol.2009,77(12):1763-1772
[13]Su X, Song Y, Jiang J, et al. The role of aquaporin-1(AQP1) expression in amurine model of lipopolysaccharide-induced acute lung injury[J]. Respir Physiol Neurobilo.2004,142(1):1-11
[14]Rocco PR,Dos Santos C, Pelosi P.lung parenchyma remodeling in acute respiratorydistress syndrome[J]. Minerva Anestesiol.2009,75(12):730-740
[15]Chopra M, Reuben JS, Sharma AC, et al. Acute lung injury: apoptosis and signalingmechanisms[J]. Exp Biol Med.2009,234(4):361-371
[16]Galani V, Tataski E,Bai M,et al.The role of apoptosis in the pathophysiology ofacute respiratory distress syndrome(ARDS): an up-to-date cell-specificreview[J].Pathol Res Pract.2010,206(30)：145-150
[17]Perl M, Lomas-Neira J, Chung CS, et al.Epithelial cell apoptosis and neutrophilrecruitment in acute lung injury-a unifying hypothesis? What we have learned fromsmall interfering RNAs[J]. Mol Med.2008,14(7-8):465-475
[18]Calfee CS, Matthay MA. Nonventilatory treatment for acute lung injury andARDS[J].Chest.2007,13(3):913-920[19]中华医学会重症医学分会.机械通气临床应用指南（2006）[J].中国危重病急救医学.2007，19（2）：65-72
[19]张翔宇.肺保护性机械通气策略的进展与临床评价[J].同济大学学报.2008,29(3):4-6
[20]蔡映云.呼吸重症监护和治疗[M].北京：科学技术出版社.2006,377-392
[21]Bream-Roww enhorst HR. Beltz EA, Ross M B, et al Recentdevelopments in themanagement of acute respiratiory distress syndrome in adults[J]. Am J H ealth SystPham.2008,65(1):29-36
[22]张波，高和.实用机械通气治疗手册[M].2版.北京:人民军医出版社.2006,195-200
[23]邱海波，许红阳，杨毅，等.呼气末正压对急性呼吸窘迫综合征肺复张容积及氧合影响的临床研究[J].中国危重病急救医学.2004,16(7):399-402
[24]邱海波，陈永铭，杨毅.急性呼吸窘迫综合征犬肺牵张指数与肺复张及氧合的关系[J].中华结核和呼吸杂志.2006，29（8）：554-557
[25]Lamm W JE, Graham MM, Albert RK, et al Mechzanism by which the proneposieion in proves oxygenation in acute lung injury[J]. Am Jrespir Crit CareMed.2005,150,184-193
[26]刘笑雷张国强.俯卧位通气治疗急性呼吸窘迫综合征研究进展.[J].实用医院临床杂志.2012,9(1),15-17
[27]刘又宁，解立新.急性肺损伤/急性呼吸窘迫综合征近年来国内研究进展[J].中华呼吸和结核杂志.2004，27（1）：8-10
[28]刘宏，姚尚龙，曾邦雄.体外膜肺氧和治疗ARDS的实验研究[J].内科急危重症杂志2008,14(1):19-22
[29]Anon. Ventilation with lower tidal volumes as compared with traditional tidalvolumes for acute lung injury and the acute respiratory distress syndrome.The acuteRespiratory Distress Syndrome Network.[J]. N Engl JMed.2000,342(18):1301-1308
[30]Phua J, Badia JR,Adhikari NK, et al.Has motality from acute respiratory distresssyndrome decreased over time?[J].Am J Respir Crit CareMed.2009,179(3):220-227
[31]Bao Z,Ye Q, Gong W,et al.Humanized monoclonal antibody anainst the chemokineCXCL-8(IL-8) effectively prevents acute lung injury [J]. IntlImmunopharmacol.2010,10(2)：259-263
[32]Sun J, Yang D,Li S, et al.Effects of curcumin or dexamethasone on lungischaemia-reperfusion injury in rats[J]. Eur Respir J.2009,33(2):398-404
[33]Sun J,Yang D, Li S,et al.Effects of curcumin or dexamethasone on lungischaemia-reperfusio Spragg RG,Lewis JF, Walmrath HD,et al. Effect ofrecombinant surfactant protein C-based surfactant on the acute respiratory distresssyndrome[J].N Engl J Med.2004,351(9):884-892
[34]Taylor RW,Zimmerman JL, Dellinger RP, et al.Low-dose inhaled nitric oxide inpatients with acute lung injury: a randomized controlledtrial[J].JAMA.2004,291(13):1603-1609
[35]Liu KD, Levitt J,Zhuo H,et al.Randomized clinical trial of activated protein Cfor the treatment of acute lung injury[J].Am J Respir Crit Care Med.2008,178(6):618-623
[36]Ware LB,Matthay MA. Alveolar fluid clearance is impaired in the majority ofpatients with acute lung injury and the acute respiratory distress syndrom e[J].Am J Respir Crit Care Med.2001,163(6):1376-1383
[37]Gupta N,Su X, Popov B,et al.Intrapulmonary delivery of bone marrow-derivedmesenchymal stem cells improves survival and attenuates edotoxin-induced acutelung injury in mice[J]. J Immunol.2007,179(30:1855-1863
[38]Abraham E, Albert R,Amato M,et al. Round table conference: Acute lunginjury.Am J Respir Crit Care Med.1998,158:675-679
[39]Kim S M, Kim H k, Yang W B. et al. Protective effect of taurine onindomethacin-induced gasric mucosal injury[M]. In: Huxtable R J,Azuma J,Kuriyama K,Kakagawa M, Baba A.(Eds.),Taurine.New York: Plenum Press,1996.147-155
[40]李金芳，周萌庄，屠淑洁.牛磺酸对细胞的保护功能[J].首都师范大学学报（自然科学版）.2006，27（1）：63-66
[41]Finnegan N M,Redmond H P,Bouchier-Haves DJ,et al. Taurine attenuatesrecombinant interleukin-2activated Lymphocyte-mediated endothelial cell injury[J]. Cancer.1998,82(1):186-199
[42]Maher S G, Condron C E M, Bouchier-Hayes D J,et al.Taurine attenuatesCD3/interleukin-2-induced T cell apoptosis in an in vitro model ofactivation-induced cell death(AICD)[J].Clinical and experimental immunology.2005,139(2):279-286
[43]Cetiner M, Sener G,Sehirli A O,et al.Taurine protects against methotrexate-inducedtoxicity and inhibits leukocyte death[J].Toxicology and appliedpharmacology.2005,209(1):39-50
[44]Wang JH, Redmond HP, Waston RW, et al.Royal College of Surgeons in Ireland,Department of Surgery, Beaumont Hospital, DuBLIN, Ireland[J].Shock.1996,6(5):331-338
[45]何芳，邓峰美，李悦山等.牛磺酸对家兔油酸肺损伤的防治作用[J].中国病理生理杂志.1999,15(7):666-668
[46]Abdih H, Kelly CJ,Bouchier-Hayes D, et al.Taurine prevents interleukin-2-inducedacute lung injury in rats[J].Eur Surg Res.2000,32(6):347-52
[47]Effect of intravenous taurine on endotoxin-induced acute lung injury in sheep EganBM, Abdih H, Kelly CJ, Condron C, Bouchier-Hayes DJ. Eur J Surg.2001,167(8):575-80
[48]门秀丽,张连元,董淑云等.牛磺酸对大鼠肢体缺血再灌注后肺损伤时细胞凋亡的影响[J].中国病理生理杂志.2004,20(3):421-424
[49]李锁严,高义.牛磺酸对大鼠内毒素性肺损伤保护作用的研究[J].内蒙古医学杂志.2008,40(4):414-416
[50]Bhavsar TM, Cantor JO, Patel SN, et al.Attenuating effect of taurine onlipopolysaccharide-induced acute ling injury in hamsters.Pharmacol Res[J].2009,
[Epub ahead of print]
[51]Wang JH, Redmond HP, Watson RW,et al.The beneficial effect of taurine on theprevention of human endothelial cell death[J]. Shock.1996,6(5):331-8
[52]Egan BM, Abdih H, Kelly CJ,et al.Effect of intravenous taurine onendotoxin-induced acute lung injury in sheep[J].Eur J Surg.2001,167(8):575-80
[53]吴素芳，杨少辉，于晓静.血管紧张素转化酶抑制剂的应用与评价[J].中国医刊.2007,42(1):65
[54]刚宏林，苏云明.血管紧张素转换酶抑制剂药理研究进展[J].中医药信息.2005，22（1）：22-23
[55]Da Cunha V, Tham DM, Martin-McNulty B, et al. Enalapril attenuates angiotensinII induced atherosclerosis and vascular inflammation[J].Atherosclerosis.2005,178(1):9-17
[56]Luno J, Prage M. De Vinusesa SG, et al. The reno-protective effect of the dualblockade of the renin angiotensin system(RAS)[J]. Curr Pharm Jes.2005,11(10):1291
[57]唐杨章，许庆源，赵凤兰，等.雷米普利对急性心肌梗死患者的长期抗缺血作用[J].中国综合临床.2004，20（1）：17-18
[58]Manning J, Vehaskari VM. Postnatal modulation of prenatally programmedhypertension by dietary Na and ACE inhibition[J]. Am J Physiol Regul IntegrComp Physiol.2005,288(1): R80
[59]Hele D J, Birre IIMA, W ebber SE, et al.Effect of endothelin, antagonista,including the novel ET(A) receptor antagonist LBL031, on endothelin-1andlipopolysaccharide-induced microvascular leakage in rat airways[J].Br Jphamacol.2000,31(6):146-149
[60]Marshall RP,W ebb S, Bellingan G J, et al. Angiotensin converting enzymeinsertion/deletion polymorphism is associaed with susceptibility and outcomein acute respiratory distress syndrome. Am J Respir Crit Care Med.2002,166:646-650
[61]Yam am oto T, Wang L,Shinakura K, et al. Angiotensin II-induced pulmonaryedema in a rabbit model[J]. Jpn J Phamacol.1997,73(1):33-40
[62]I mai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme2protects fromsevere acute lung failure[J]. Nature.2005,436:112-116
[63]沈利汉，莫红缨，蔡立华等。肾素-血管紧张素系统与ALI/ARDS的关系探讨[J].中国呼吸与危重监护杂志.2010，9：310-314
[64]Ruiz-Ortega M, Esteban V, Ruprez M, et al. Renal and vascular hypertension-induced inflammation: role of angiotensin II[J].Curr Opin Nephro1Hypertens.2006,15(2):159-166
[65]Grafe M, Auch-Schwelk W, Zakrewicz A, et al. AngiotensinII induced leukocyteadhesion on human coronary endothelial cells is mediaed by E selectin [J]. CircRes.1997,81(5)：804-811
[66]Kranzhofer R, Schmidt J, Pferffer CAH,et al. Angiotensin induces inflammatoryactivation of human vascular smooth muscle cells[J]. Arterioscler Thromb VascBiol.1999,19(7):623-629
[67]刘和亮,赵金垣.血管紧张素转换酶抑制剂对化学性急性呼吸窘迫综合征治疗作用的实验研究[J].中华预防医学杂志.2002,36(2).93-96
[68]李玖军,俞志凌,薛辛东.卡托普利在高氧致新生大鼠肺损伤模型中的保护作用[J].中国当代儿科杂志.2006,8(1):41-44
[69]XiaoLin He, Bing Han, Marco Mura, et al. Angiotensin-converting enzymeinhibitor captopril prevents oleic acid-induced severe acute lung injury inrats[J].Proceedings of the American Thoracic Society.2006,vol3:A839
[70]白慧颖译。血管紧张素转换酶抑制剂对炎症反应的影响[J].中国中西医结合急救杂志.2009,16(2)：126
[71]李顺乐,陈熹,张心武等.卡托普利在大鼠重症急性胰腺炎肺损伤中的保护作用[J].南方医科大学学报.2010,30(12):2742-2745
[72]韩鹏凯，张婷，王导新.卡托普利对急性肺损伤血凝素样氧化低密度血浆脂蛋白受体-1蛋白表达的影响[J].第三军医大学学报.2010，2（10）：1047-1050
[73]Konrad R, Ole B, Frank B, et al. Markers of endothelial damage in organdysfunction and sepsis[J].Crit Care Med.2002,30: S302-S312
[2] Beasley MB. The pathologist′s approach to acute lung injury[J].Arch Pathol LabMed.2010,134(5):719-27
[3] Moraes TJ,Zurawska JH, Doweny GP. Neutrophil granule contents in thepathogenesis of lung injury[J].Curr Opin Hematol.2006,13(1):21-27
[4]钱桂生.急性肺损伤和急性呼吸窘迫综合征的诊断与治疗[J].解放军医学杂志.2009,34（4）：371-373
[5] Lucas R, Verin AD, Black SM, et al. Regulators of endothelial and epithelial barrierintegrity and function in acute lung injury[J].BiochemPharmacol.2009,77(12):1763-1772
[6] Calfee CS, Matthay MA. Nonventilatory treatment for acute lung injury andARDS[J].Chest.2007,13(3):913-920
[7] Anon. Ventilation with lower tidal volumes as compared with traditionaltidalvolumes for acute lung injury and the acute respiratory distress syndrome.Theacute Respiratory Distress Syndrome Network [J].N Engl J Med.2000,342(18):1301-1308
[8] Phua J, Badia JR,Adhikari NK, et al.Has motality from acute respiratory distresssyndrome decreased over time?[J].Am J Respir Crit CareMed.2009,179(3):220-227
[9] Bhargava M, Wendt CH. Biomarkers in acute lung injury[J]. Transl Res.2012,159(4):205-17
[10]Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophilextraacellular traps contribute to acute lung injury of influenza pneumonitis[J].Am J Pathol.2011,179(1):199-210
[11]Abraham E, Albert R,Amato M,et al. Round table conference: Acute lunginjury[J].Am J Respir Crit Care Med.1998,158:675-679
[12]Bhavsar TM, Cantor JO, Patel SN, et al. Attenuating effect of taurine onlipopolysaccharide-induced acute lung injury in hamsters[J].PharmacolRes.2009,60(5):418-428
[13]Neyrinck AP, Matthay MA. The role of angiotensin-converting enzyme inhibitionin endotoxin-induced lung injury in rats[J].Crit Care Med.2009,37(2):776-777
[14]中华医学会重症医学分会.急性肺损伤/急性呼吸窘迫综合征诊断与治疗指南（2006）[J].中华内科杂志.2007,46（5）:430-435
[15]白涛,田阿勇,王俊科.谷氨酰胺对内毒素性急性肺损伤大鼠肺组织肿瘤坏死因子-a表达的影响[J].中华麻醉学杂志,2006,26(11),1013-1015
[16]Smith KM, Mrozek JD, Sim ont on SC, et al. Prolonged partical liquid ventilationusing convent ional and hing frequency ventilatory techniques: gasexchange andlung pathology in an animal model of respiratory distress syndrome[J].Crit CareMed.1997,25(11):1888-1897
[17]钱桂生.急性肺损伤和急性呼吸窘迫综合征研究现状与展望[J].解放军医学杂志.2003，28（2）：97-101
[18]The ACCP/SCCM Consensus Conference Committee[J].Chest.1992,101：1644-1655
[19]Ranieri V M, Rubenfeld G D, Thoposon B T, et al.Acute respiratory distresssyndrome(ARDS):The Belin Definition[J].Jama.2012,307:2526-2533
[20]Hough CL, Herridge MS. Long-term outcome after acute lung injury. Curr OpinCrit Care.2012,18(1):8-15
[21]Lu Y, Song Z, Zhou X,et al.A12-month clinical survey of incidence and outcome ofacute respiratory distress syndrome in Shanghai intensive care units[J].IntensiveCare Med.2004,30(12):2197-2203
[22]北京市科委重大项目MODS课题组.1998-2003年北京地区重症加强治疗病房急性呼吸窘迫综合征的临床流行病学调查[J].中国危重病急救学.2007,19(4):201-204
[23]Carmen SV. Acute lung injury and acute respiratory distress syndrome: diagnostichurdles[J].J Bras Pneumo.2007,33(4):338-9
[24]Ferguson ND, Frutos-Vivar F, Esteban A, et al.Acute respiratory distresssyndrome:under recognition by clinicians and diagnostic accuracy of three clinicaldefinitions[J].Critical Care Med.2005,33(10):2228-2234
[25]Gordon DR, Ellen C.Incidence and Outcomes ofAcute Lung Injury[J].N Engl JMed.2005,3(53):1685-93
[26]Claude AP, David AS. The Acute Respiratory Distress Syndrome[J].Ann InternMed.2004,14(1):460-70
[27]Lorraine B. Pathophysiology of acute lung injury and the acute respiratory distresssyndrome[J].Semin Respiratory Critical Care Med.2006,27(4):337-349
[28]Wheeler AP, Bernard GR. Acute lung injury and the acute respirato-ry distresssyndrome,A Clinical Review[J].Lancet.2007,369:1553-1564
[29]侯一峰，周艳春，周永双.全身炎症反应综合征一急性肺损伤大鼠模型的研究[J].中国实验动物学报.2003,11(3):147-150
[30]白春学，孙波.急性呼吸窘迫综合征[M].上海：复旦大学出版社.2005,p331
[31]徐涛,曾邦雄,李兴旺.中性粒细胞胶原酶在内毒素性急性肺损伤中的作用[J].中华麻醉学杂志.2004,24(1):29-32
[32]Xu T，Zeng BX，Li XW. The role of neutrophil collagenase in endotoxic acute lunginjury[J].Hua zhong Univ Sci Technolog Med Sci.2004,24(2):196-198
[33]Shen Y, Wang D, Wang X. Role of CCR2and IL-8in acute lung injury: a newmechanism and therapeutic target[J]. Expert Rev Respir Med.2011,5(1):107-14
[34]Pugin J, Schurer MC, Leturcq D, et al. Lipopolyscchride-binding protein andsoluble CD14[J].Proc Natl Acad Sci USA.1993,90:2744-2748
[35]Bevilacqua MP, Pober JS, Wheeler ME, et al.Interleukin1acts on cultures hamanvascular endothelium to increse the adhesion of polymorphnuclear leukocytes,monocytes and related leukocyte cell lines[J]. JClin Invest.1985,76:2003
[36]Nieuwenhuijzen GA, Knapen MF, Oyen WJ, et al. Organ damages is preceded bychanges in protein extravasation in an experimental model ofmultiple organdusfunction syndrome[J].Shock.1997,7:98-104
[37]Garcia JG, Schaphorst KM. Regulation of endothelial cell gap formation andparacellular permeability[J].J Invest Med.1995,43:117-126
[38]Louise CB, Tran MC, Obrig TG.Sensitazation of human umbilical vein endothelialcells to Shiga toxin: invovelment of protein kinase C and NF-kB[J].InfectImmun.1997,65:3337-3344
[39]Banneman DD, Goldblum SE.Endotoxin induces endothelial barrier dysfunctionthrough protein tyrosine phosphorylation[J].Am J Physiol.1997,273(1):217-226
[40]Blann AD, Lip GYH.The endothelium in atherothrombotic dis-eases:assessment offunction, mechanisms and clinical implications[J].Blood Coag Fibrinolys.1998,9:297-306
[41]Odanos S E, Mavrommati I, Korovesi I, et a1.Pulmonary endotheliumin acute lunginjury from basic science to the critically ill[J].Intensive CareMed.2004,30(9):1702-1714
[42]Ware LB, Eisner MD, Taylor Thampson B, et al.Significance of von willebrandfactor in septic and nonseptic patients with acute lung injury[J].Am J Respir CritCare Med.2004,170(7):766-772
[43]Heidi R, Flori MD, Lorraine B, Ware MD,et al.Early elevation of plasma vonwillebrand factor antigen in pediatric acute lung injury is associated withanincreased risk of death and prolonged mechanical ventilation[J].Pediatr Crit CareMed.2007,8(2),96-101
[44]Rubin DB, Wiener K, Murray JF,et al.Elevated yon Willebrand factor antigen is anearly plasma predictor of acute lung injury in nonpulmonary sepsissyndrome[J].JClin Invest.1990,86(2):474-480
[45]Comellas AP,Briva A.Role of endothelin-1in acute lung injury [J].TranslRes.2009,153(6):263-271
[46]Motte S,Mc Entee K,Naeije R.Endothelin receptor antagonists [J].PharmacolTherapeutics.2006,110(3):386-414
[47]Habre W,Petá k F,Ruchonnet Met railler I,et al.The role of endothelin-1inhyperoxia-induced lung injury in mice [J].Respir Res.2006,7:45-51
[48]Berger MM,Rozendal CS,Schieber C,et al.The effect of endothelin-1on alveolarfluid clearance and pulmonary edema formation in the rat[J].AnesthAanalg.2009,108(1):225-231
[49]Blackwell TS, Debelak JP, VenkatakrishnanA, et al. Acute lung injury afterhepatic cryoablation: Correlation with NF-kappaB activeation and cytokineproduction[J].Surgery.1999,1263:518-526
[50]Drllm lW, StelterRL, WaldhauslW, et al. Endothelin-1in adult respirstory distresssyndrome[J].Am Rev Respir Dis.1993,1487:1169-1173
[51]Mc Clintock D, Zhuo H, Wickersham N, et al.Biomarkers ofinflammation,coagulation and fibrinolysis pridict mortality in adute lunginjury[J].Crit Care.2008,12(2):R41
[52]Calfee CS,Eisner MD, Parsons PE, et al.Soluble intercellular adhesion molecule-1and clinical outcomes in patients with acute lung injury[J].Intensive CareMed.2009,35(2):248-257
[53]ChenKH,Reece LM,Leary JF.Mitochondrial glutathione modulates TNFα-inducedendothelial cell dysfunction[J].Fre Rad Bio Mled.1999,27(1):100-109
[54]Boyle EM,Kovacich JC,Cant TG,etal.Inhibition of nuclear factor-KBnuclearlocation reduces human E-selectin expression and the systemicin-flammatoryresponse[J].Circulation.1998,98(19supple):282-288.
[55]KacimiR,KarlinerJS,KoudssiF,etal.Expression and regulation ofadhesionmoleculesinCardiac cellsby cytokines response to acute hypoxia [J].Circ Res.1998,82(5):576-586
[56]Esmon CT,Owen WG.Identification of an endothelial cell cofactor for thrombincatalyzed activation of protein C[J].Proc Natl Acad Sci USA.1981,78(4):2249
[57]Esmon NL,OwenWG,Esmon CT.Isolation of a membrane-bound co factor forthrombin catalyzedactivationofproteinC[J].JbiolChem.1982,257(2):859-864
[58]Takeda N, Maemurak, Horie S,et al.Thrombomodulin is a clock controlled gene invascular endothelial cells[J]. J Biol Chem.2007,282(45):32561-32567
[59]Takahashi H, Ito S,Hanana M, et al. Circulating thrombomodulin asa novelendothelial cell marker comparison of its behavior with von willebrand factor andtissue type plasm inogen activator[J].Am J Hematol.1992,41(1):32-39
[60]Takano S,Kimura S,Ohdama S.Plasma thrombomodulin in health anddiseases[J].Blood.1990,76(10):2024
[61]Iba T, Nakarai E, Takayama T, et al.Combination effect of antithrombin andrecombinant human soluble thrombomodulin in a lippolysaccharide induced rat sepsis model[J].Crit care.2009,13(6):R203
[62]Olson N C, Joyce PB, Fleisher LN, et al. Role of platelet-activating factor andeicosanoids during endotoxin-induced lung injury in pigs[J].AmJPhysiol.1990,258(5):H1674-1686
[63]Robert A, Parker K, Siflinger-Birnboim A, et al. Increased endothelialpermeabilityafterneutrophilactivationoccursbyadiffusion-dependentmechanism[J].MicrovascularResearch.1995,49(2):227-232
[64]Laurindo F R, Goldstein RE, Davenport NJ, et al.Mechanisms of hypotensionproduced by platelet-activating factor[J].J Appl Physiol.1989,66(6):2681-2690
[65]Shin-Wen Chang.TNF potentiates PAF-induced pulmonary vasoconstriction in therat: role of neutrophils and thromboxane A2[J].J ApplPhysiol.1994,77(6):2817-2826
[66]Parvez S, Tabassum H, Banerjee BD, et al. Taurine prevents tamoxifen-inducedmitochondrial oxidative damage in mice[J].Basic Clin PharmacolToxicol.2008,102(4):382-387
[67]Abreu SC, Antunes MA, Pelosi P, et al. Mechanisms of cellular therapy inrespiratory diseases[J]. Intensive Care Med.2011,37(9):1421-1431
[68]Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme2in lungdiseases[J].Curr Opin Pharmacol.2006,6(3):271-6
[69]Yang LX. Role of TRPC1and NF-kappa B in mediating angiotensin II-inducedCa2+entry and endothelial hyperpermeability[J].Peptides.2009,30(7):1368-1373
[70]Zhang H,Schmeisser A, Garlichs CD, etal. AngiotensinII-induced superoxide aniongeneration in human vascular endothelial cells:role ofmembrane-boundNADH-/NADPH-oxidases[J].CardiovascRes.1999,44(1):215-222
[71]Oriji GK.Angiotensin II-induced ET and PGI2release in rat aorticendothelialcells is mediated by PKC[J].Prostaglandins Leukot Essent Fatty Acids.1999,61(2):113-117
[72]刚宏林，苏云明.血管紧张素转换酶抑制剂药理研究进展[J].中医药信息.2005.22（1）：22-23
[73]Ghazi-Khansari M, Nasiri G, Honarjoo M. Decreasing the oxidant stress fromparaquat in isolated perfused rat lung using captopril and niacin[J]. Arch Toxicol.2005,79(6):341-345
[1][Rubenfeld GD,Herridge MS. Epidemiolog and Outcomes of Acute Lung Injury [J].Chest.2007.131(2):554-562
[2] Lu Y, Song Z, Zhou X, et al. A12-month clinical survey of incidence and outcomeof acute respiratory distress syndrome in Shanghai intensive care units [J].IntensiveCare Med.2004,30(12):2197-2203
[3]北京市科委重大项目MODS课题组.1998-2003年北京地区重症加强治疗病房急性呼吸窘迫综合征的临床流行病学调查[J].中国危重病急救医学.2007,19(4):201-204
[4] Luhr OR, Antonsen K, Karls son M, et al，and the ARF s tudy group. Incidenceandmortality after acute respiratory failure and acute respiratory dirtress syndromein Sweden, Denmark, and Iceland[J]. Am J Respir Cri t Care Med.1999,159:1849-1861
[5] Bernard GR, Artigas A, Brigham KL, et aland the consensus committee. TheAmerican-European Consensus Conference on ARDS,definitions, mechanisms,relevant outcomes,and clinical trial coordination[J]. Am J Respir Crit Care Med.1994,149:818-824
[6]北京市科委重大项目“MODS中西医结合诊治/降低病死率研究课”组:多器官功能障碍综合佂诊断标准、病情严重度评分及预后评估系统和中西医结合证型诊断[J].中国危重病急救医学.2008,20(1):1-3
[7] Murray JF, Matthay M A, Luce J M, et al. An expanded definition of the adultrespirratory distress syndrome [J]. Am Rev Respir Dis.1988,138:720-723
[8] Artigas A, Bernard GR, Carlet J, et al.The American-European Consens usConference on ARDS, part2: ventilatory, pharmacologic,supportive therapy, studydesign strategies,and issues related to recovery and remodeling[J]. Am J Respir CritCare Med.1998,157:1332-1347.
[9] Ferguson N D,Davis A M,Slutsky AS,et al.Development of aclinincal definition foracute respiratory distress syndrome using the Delphi technique [J].J Crit Care.2005,20:147-154
[10]Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratorydistresssyndrome (ARDS).The Berlin Definition[J]. JAMA.2012，307:2526-2533
[11]The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidalvolumes as compared with traditional tidal volumes for acute lung injury and theacute respiratory distress syndrome[J]. N Engl J Med.2000，342:1301–1308.
[12]Ferguson ND, et al. Acute respiratory distress syndrome: underrecognition byclinicians and diagnostic accuracy of three clinical definitions[J].Crit Care Med.2005，33:2228–2234
[13]Cedeno A, et al. Acute lung injury/acute respiratory distress syndrome: a need foreducation[J].P R Health Sci J.2002，21:305–308
[14]Howard AE, et al. Comparison of3methods of detecting acute respiratory distresssyndrome: clinical screening, chart review, and diagnostic coding[J]. Am J CritCare.2004,13:59–64
[15]曾因明.麻醉学第2版［M］．北京:人民卫生出版社，2010,1.38
[16]Jerng J S, Yu CJ, Liaw YS, et al. Clinical spectrum of acute resperatory distres ssyndrome in a tertiary referral hospital: etiology,severity, clinical course, andhospital outcome[J]. J Formos Med Assoc.2000，99:538-543
[17]Brun-Bris son C, Mi nelli C, Brazzi L, et al.The European survey (alive) of acutelung injury and ARDS[J]. Am J Res pir Crit Care Med.2001,163:956-959
[18]陈学华.宁夏交通事故规律分析及预防对策研究[D].长安大学，2006:3
[19]赵雪生.应重视创伤后的急性肺损伤与ARDS[J].第八届全国中西医结合灾害急救危重病医学学术会议.2012，4（18）:168-172
[20]黄显凯.做好严重创伤早期救治的几个关键环节[J].创伤外科杂志.2012，3:196-198
[21]徐金富.肺部感染相关急性肺损伤发病机制研究进展[J].国外医学.呼吸系统分册.2004，02:72-75.
[22]宋振举,白春学.我国急性肺损伤/急性呼吸窘迫综合征临床和实验研究进展[J].内科理论与实践.2010，6：496-499
[23]赖军华,莫小源.影响ARDS患者预后的危险因素分析[J].中国医药导报.2012，12：82-84
[24]Brun-Bris son C, Mi nelli C, Brazzi L, et al.The European survey (alive) of acutelung injury and ARDS[J]. Am J Res pir Crit Care Med.2001,163: A956
[25]Angus DC, et al. Epidemiology of severe sepsis in the United States: analysis ofincidence, outcome, and associated costs of care[J]. Crit Care Med.2001；29:1303–1310
[26]GordonD.Rubenfeld,MD,MSc,MargaretS.Herridge,MD,MPH,FCCP.Epidemiologand Outcomes of Acute Lung Injury[J].2007，131(2):554-562
[27]葛庆岗，赵建娟，吕旌乔等.重症监护病房中急性呼吸窘迫综合征的预后危险因素分析[J].解放军医学杂志.2010，6:82-84
[28]陆月明,孙波.急性肺损伤和急性呼吸窘迫综合征临床流行病学研究进展[J].中华急诊医学杂志.2003,1:65-66
[29]刘大为.实用重症医学［M］．北京:人民卫生出版社，2010.381-387
[30]李文元,丁士芳.急性呼吸窘迫综合征患者预后的危险因素分析[J].山东大学学报(医学版).2012,3:93-95
[31]谢才德,秦蓁,邹华兰等.急性呼吸窘迫综合征临床治疗观察及预后影响因素分析[J].现代生物医学进展.2012,25:4921-4923
[32]Est enssoro E, Dubin A, Laffaire E. Impact of positive end-expiratory pressure onthe def inition of acute respiratory distress syndrome [J].Intensive Care Med.2003,29(11):1936-1942
[33]Dicker RA, Morabito DJ, Pittet JF, et a1. Acute respiratory distress syndromecriteria in trauma patients: why the definitions do not work[J].J Trauma.2004,57(3):522-528
[34]李昂,王海曼,阴赪宏等.多器官功能障碍综合征患者急性呼吸窘迫综合征流行病学调查[J].中国实用内科杂志.2009，11:1036-1038
[1]钱桂生.急性肺损伤和急性呼吸窘迫综合征研究现状与展望[J].解放军医学杂.2003，28（2）：97-101
[2] The ACCP/SCCM Consensus Conference Committee. Chest.1992；101：1644-1655
[3] Ranieri V M, Rubenfeld G D, Thoposon B T, et al.Acute respiratory distresssyndrome(ARDS): The Belin Definition[J].Jama.2012,307:2526-2533
[4] Lu Y,Song Z, Zhou X,et al. A12-month clinical survey of incidence and outcomeof acute respiratory distress syndrome in Shanghai intensive care units[J]. IntensiveCare Med.2004,30(12):2197-2203
[5]北京市科委重大项目MODS课题组.1998-2003年北京地区重症加强治疗病房急性呼吸窘迫综合征的临床流行病学调查[J].中国危重病急救医学.2007,19(4):201-204
[6] Narasaraju T, Yang E, Samy RP, et al.Excessive neutrophils and neutrophilextraacellular traps contribute to acute lung injury of influenza pneumonitis[J].AmJ Pathol.2011,179(1):199-210
[7] Soehnlein O,Oehmcke S,Ma X,et al.Neutrophil degranulation mediates severe lungdamage triggered by streptococcal M1protein[J].Eur Respir J.2008,32(2):405-12
[8] Ware LB, Bastarche JA, Wang L.Coagulation and fibrinolysis in human acutelung injury–new therapeutic targets?[J].Keio J Med.2005,54(3):142-149
[9]叶玲，金美玲，徐晓波，等.急性肺损伤/急性呼吸窘迫综合征患者凝血纤溶系统的变化[J].复旦学报（医学版）.2008，35（5）：671-674，680
[10]钱桂生.急性肺损伤和急性呼吸窘迫综合征的诊断与治疗[J].解放军医学杂志.2009，34（4）：371-373
[11]Moraes TJ,Zurawska JH, Doweny GP. Neutrophil granule contents in thepathogenesis of lung injury[J].Curr Opin Hematol.2006,13(1):21-27
[12]Lucas R,Verin AD, Black SM, et al.Regulators of endothelial and epithelialbarrier integrity and function in acute lung injury[J].Biochem Pharmacol.2009,77(12):1763-1772
[13]Su X, Song Y, Jiang J, et al. The role of aquaporin-1(AQP1) expression in amurine model of lipopolysaccharide-induced acute lung injury[J]. Respir Physiol Neurobilo.2004,142(1):1-11
[14]Rocco PR,Dos Santos C, Pelosi P.lung parenchyma remodeling in acute respiratorydistress syndrome[J]. Minerva Anestesiol.2009,75(12):730-740
[15]Chopra M, Reuben JS, Sharma AC, et al. Acute lung injury: apoptosis and signalingmechanisms[J]. Exp Biol Med.2009,234(4):361-371
[16]Galani V, Tataski E,Bai M,et al.The role of apoptosis in the pathophysiology ofacute respiratory distress syndrome(ARDS): an up-to-date cell-specificreview[J].Pathol Res Pract.2010,206(30)：145-150
[17]Perl M, Lomas-Neira J, Chung CS, et al.Epithelial cell apoptosis and neutrophilrecruitment in acute lung injury-a unifying hypothesis? What we have learned fromsmall interfering RNAs[J]. Mol Med.2008,14(7-8):465-475
[18]Calfee CS, Matthay MA. Nonventilatory treatment for acute lung injury andARDS[J].Chest.2007,13(3):913-920[19]中华医学会重症医学分会.机械通气临床应用指南（2006）[J].中国危重病急救医学.2007，19（2）：65-72
[19]张翔宇.肺保护性机械通气策略的进展与临床评价[J].同济大学学报.2008,29(3):4-6
[20]蔡映云.呼吸重症监护和治疗[M].北京：科学技术出版社.2006,377-392
[21]Bream-Roww enhorst HR. Beltz EA, Ross M B, et al Recentdevelopments in themanagement of acute respiratiory distress syndrome in adults[J]. Am J H ealth SystPham.2008,65(1):29-36
[22]张波，高和.实用机械通气治疗手册[M].2版.北京:人民军医出版社.2006,195-200
[23]邱海波，许红阳，杨毅，等.呼气末正压对急性呼吸窘迫综合征肺复张容积及氧合影响的临床研究[J].中国危重病急救医学.2004,16(7):399-402
[24]邱海波，陈永铭，杨毅.急性呼吸窘迫综合征犬肺牵张指数与肺复张及氧合的关系[J].中华结核和呼吸杂志.2006，29（8）：554-557
[25]Lamm W JE, Graham MM, Albert RK, et al Mechzanism by which the proneposieion in proves oxygenation in acute lung injury[J]. Am Jrespir Crit CareMed.2005,150,184-193
[26]刘笑雷张国强.俯卧位通气治疗急性呼吸窘迫综合征研究进展.[J].实用医院临床杂志.2012,9(1),15-17
[27]刘又宁，解立新.急性肺损伤/急性呼吸窘迫综合征近年来国内研究进展[J].中华呼吸和结核杂志.2004，27（1）：8-10
[28]刘宏，姚尚龙，曾邦雄.体外膜肺氧和治疗ARDS的实验研究[J].内科急危重症杂志2008,14(1):19-22
[29]Anon. Ventilation with lower tidal volumes as compared with traditional tidalvolumes for acute lung injury and the acute respiratory distress syndrome.The acuteRespiratory Distress Syndrome Network.[J]. N Engl JMed.2000,342(18):1301-1308
[30]Phua J, Badia JR,Adhikari NK, et al.Has motality from acute respiratory distresssyndrome decreased over time?[J].Am J Respir Crit CareMed.2009,179(3):220-227
[31]Bao Z,Ye Q, Gong W,et al.Humanized monoclonal antibody anainst the chemokineCXCL-8(IL-8) effectively prevents acute lung injury [J]. IntlImmunopharmacol.2010,10(2)：259-263
[32]Sun J, Yang D,Li S, et al.Effects of curcumin or dexamethasone on lungischaemia-reperfusion injury in rats[J]. Eur Respir J.2009,33(2):398-404
[33]Sun J,Yang D, Li S,et al.Effects of curcumin or dexamethasone on lungischaemia-reperfusio Spragg RG,Lewis JF, Walmrath HD,et al. Effect ofrecombinant surfactant protein C-based surfactant on the acute respiratory distresssyndrome[J].N Engl J Med.2004,351(9):884-892
[34]Taylor RW,Zimmerman JL, Dellinger RP, et al.Low-dose inhaled nitric oxide inpatients with acute lung injury: a randomized controlledtrial[J].JAMA.2004,291(13):1603-1609
[35]Liu KD, Levitt J,Zhuo H,et al.Randomized clinical trial of activated protein Cfor the treatment of acute lung injury[J].Am J Respir Crit Care Med.2008,178(6):618-623
[36]Ware LB,Matthay MA. Alveolar fluid clearance is impaired in the majority ofpatients with acute lung injury and the acute respiratory distress syndrom e[J].Am J Respir Crit Care Med.2001,163(6):1376-1383
[37]Gupta N,Su X, Popov B,et al.Intrapulmonary delivery of bone marrow-derivedmesenchymal stem cells improves survival and attenuates edotoxin-induced acutelung injury in mice[J]. J Immunol.2007,179(30:1855-1863
[38]Abraham E, Albert R,Amato M,et al. Round table conference: Acute lunginjury.Am J Respir Crit Care Med.1998,158:675-679
[39]Kim S M, Kim H k, Yang W B. et al. Protective effect of taurine onindomethacin-induced gasric mucosal injury[M]. In: Huxtable R J,Azuma J,Kuriyama K,Kakagawa M, Baba A.(Eds.),Taurine.New York: Plenum Press,1996.147-155
[40]李金芳，周萌庄，屠淑洁.牛磺酸对细胞的保护功能[J].首都师范大学学报（自然科学版）.2006，27（1）：63-66
[41]Finnegan N M,Redmond H P,Bouchier-Haves DJ,et al. Taurine attenuatesrecombinant interleukin-2activated Lymphocyte-mediated endothelial cell injury[J]. Cancer.1998,82(1):186-199
[42]Maher S G, Condron C E M, Bouchier-Hayes D J,et al.Taurine attenuatesCD3/interleukin-2-induced T cell apoptosis in an in vitro model ofactivation-induced cell death(AICD)[J].Clinical and experimental immunology.2005,139(2):279-286
[43]Cetiner M, Sener G,Sehirli A O,et al.Taurine protects against methotrexate-inducedtoxicity and inhibits leukocyte death[J].Toxicology and appliedpharmacology.2005,209(1):39-50
[44]Wang JH, Redmond HP, Waston RW, et al.Royal College of Surgeons in Ireland,Department of Surgery, Beaumont Hospital, DuBLIN, Ireland[J].Shock.1996,6(5):331-338
[45]何芳，邓峰美，李悦山等.牛磺酸对家兔油酸肺损伤的防治作用[J].中国病理生理杂志.1999,15(7):666-668
[46]Abdih H, Kelly CJ,Bouchier-Hayes D, et al.Taurine prevents interleukin-2-inducedacute lung injury in rats[J].Eur Surg Res.2000,32(6):347-52
[47]Effect of intravenous taurine on endotoxin-induced acute lung injury in sheep EganBM, Abdih H, Kelly CJ, Condron C, Bouchier-Hayes DJ. Eur J Surg.2001,167(8):575-80
[48]门秀丽,张连元,董淑云等.牛磺酸对大鼠肢体缺血再灌注后肺损伤时细胞凋亡的影响[J].中国病理生理杂志.2004,20(3):421-424
[49]李锁严,高义.牛磺酸对大鼠内毒素性肺损伤保护作用的研究[J].内蒙古医学杂志.2008,40(4):414-416
[50]Bhavsar TM, Cantor JO, Patel SN, et al.Attenuating effect of taurine onlipopolysaccharide-induced acute ling injury in hamsters.Pharmacol Res[J].2009,
[Epub ahead of print]
[51]Wang JH, Redmond HP, Watson RW,et al.The beneficial effect of taurine on theprevention of human endothelial cell death[J]. Shock.1996,6(5):331-8
[52]Egan BM, Abdih H, Kelly CJ,et al.Effect of intravenous taurine onendotoxin-induced acute lung injury in sheep[J].Eur J Surg.2001,167(8):575-80
[53]吴素芳，杨少辉，于晓静.血管紧张素转化酶抑制剂的应用与评价[J].中国医刊.2007,42(1):65
[54]刚宏林，苏云明.血管紧张素转换酶抑制剂药理研究进展[J].中医药信息.2005，22（1）：22-23
[55]Da Cunha V, Tham DM, Martin-McNulty B, et al. Enalapril attenuates angiotensinII induced atherosclerosis and vascular inflammation[J].Atherosclerosis.2005,178(1):9-17
[56]Luno J, Prage M. De Vinusesa SG, et al. The reno-protective effect of the dualblockade of the renin angiotensin system(RAS)[J]. Curr Pharm Jes.2005,11(10):1291
[57]唐杨章，许庆源，赵凤兰，等.雷米普利对急性心肌梗死患者的长期抗缺血作用[J].中国综合临床.2004，20（1）：17-18
[58]Manning J, Vehaskari VM. Postnatal modulation of prenatally programmedhypertension by dietary Na and ACE inhibition[J]. Am J Physiol Regul IntegrComp Physiol.2005,288(1): R80
[59]Hele D J, Birre IIMA, W ebber SE, et al.Effect of endothelin, antagonista,including the novel ET(A) receptor antagonist LBL031, on endothelin-1andlipopolysaccharide-induced microvascular leakage in rat airways[J].Br Jphamacol.2000,31(6):146-149
[60]Marshall RP,W ebb S, Bellingan G J, et al. Angiotensin converting enzymeinsertion/deletion polymorphism is associaed with susceptibility and outcomein acute respiratory distress syndrome. Am J Respir Crit Care Med.2002,166:646-650
[61]Yam am oto T, Wang L,Shinakura K, et al. Angiotensin II-induced pulmonaryedema in a rabbit model[J]. Jpn J Phamacol.1997,73(1):33-40
[62]I mai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme2protects fromsevere acute lung failure[J]. Nature.2005,436:112-116
[63]沈利汉，莫红缨，蔡立华等。肾素-血管紧张素系统与ALI/ARDS的关系探讨[J].中国呼吸与危重监护杂志.2010，9：310-314
[64]Ruiz-Ortega M, Esteban V, Ruprez M, et al. Renal and vascular hypertension-induced inflammation: role of angiotensin II[J].Curr Opin Nephro1Hypertens.2006,15(2):159-166
[65]Grafe M, Auch-Schwelk W, Zakrewicz A, et al. AngiotensinII induced leukocyteadhesion on human coronary endothelial cells is mediaed by E selectin [J]. CircRes.1997,81(5)：804-811
[66]Kranzhofer R, Schmidt J, Pferffer CAH,et al. Angiotensin induces inflammatoryactivation of human vascular smooth muscle cells[J]. Arterioscler Thromb VascBiol.1999,19(7):623-629
[67]刘和亮,赵金垣.血管紧张素转换酶抑制剂对化学性急性呼吸窘迫综合征治疗作用的实验研究[J].中华预防医学杂志.2002,36(2).93-96
[68]李玖军,俞志凌,薛辛东.卡托普利在高氧致新生大鼠肺损伤模型中的保护作用[J].中国当代儿科杂志.2006,8(1):41-44
[69]XiaoLin He, Bing Han, Marco Mura, et al. Angiotensin-converting enzymeinhibitor captopril prevents oleic acid-induced severe acute lung injury inrats[J].Proceedings of the American Thoracic Society.2006,vol3:A839
[70]白慧颖译。血管紧张素转换酶抑制剂对炎症反应的影响[J].中国中西医结合急救杂志.2009,16(2)：126
[71]李顺乐,陈熹,张心武等.卡托普利在大鼠重症急性胰腺炎肺损伤中的保护作用[J].南方医科大学学报.2010,30(12):2742-2745
[72]韩鹏凯，张婷，王导新.卡托普利对急性肺损伤血凝素样氧化低密度血浆脂蛋白受体-1蛋白表达的影响[J].第三军医大学学报.2010，2（10）：1047-1050
[73]Konrad R, Ole B, Frank B, et al. Markers of endothelial damage in organdysfunction and sepsis[J].Crit Care Med.2002,30: S302-S312