羊膜腔内注射肺表面活性物质对宫内感染致肺损伤胎兔肺表面活性相关蛋白A表达的影响

目的 探讨羊膜腔内注射肺表面活性物质(PS)对宫内感染致肺损伤胎兔肺组织肺表面活性相关蛋白A(SP-A)表达的影响.方法 选取健康成年育龄日本大耳白兔 19只,成功受孕后随机分为对照组、细菌组、细菌+ PS组.建立宫内感染模型.对照组和细菌组按胎龄又分为 21、22、23、24、26 d 5个亚组,细菌+ PS组分为24 d、26 d 2个亚组.细菌组宫内注射大肠埃希杆菌(E.coli)菌株,细菌+ PS组宫内注射E.coli菌株,同时胎兔羊膜腔内注射PS 200 mg/kg,对照组宫内注射生理盐水.模型建成后分别在各时间点对孕兔行剖宫产,杀取胎兔后取肺组织,以TGF-β1兔多克隆抗体为一抗,用免疫组织化学方法 检测其肺组织内SP-A表达;用RT-PCR检测其SP-A mRNA表达;用Western blotting方法 检测其SP-A蛋白表达;应用SPSS13.0软件进行统计学处理.结果 免疫组化结果 显示不同组间SP-A表达差异有统计学意义(F=237.865,P=0.000),细菌组SP-A 表达明显低于对照组及细菌+PS组.SP-A mRNA、蛋白表达则在细菌感染后明显下降,差异具有统计学意义(F=1 101.741,P=0.000).注射PS后SP-A表达增强,高于细菌组(P=0.000),与对照组比较差异无统计学意义(P>0.05).结论 羊膜腔内感染可导致SP-A异常低表达,与新生儿呼吸窘迫综合征(RDS)发生密切相关;羊膜腔内注射PS后SP-A表达上调,表明羊膜腔内注射PS可做为一种安全、有效的预防治疗手段,对降低新生儿发生呼吸窘迫综合征等肺疾病具有重要意义.     

Biomarkers in acute lung injury: insights into the pathogenesis of acute lung injury

Studies of potential biomarkers of acute lung injury (ALI) have provided information relating to the pathophysiology of the mechanisms of lung injury and repair. The utility of biomarkers remains solely among research tools to investigate lung injury and repair mechanisms. Because of lack of sensitivity and specificity, they cannot be used in decision making in patients with ALI or acute respiratory distress syndrome. The authors reviewed known biomarkers in context of their major biologic activity. The continued interest in identifying and studying biomarkers is relevant, as it provides information regarding the mechanisms involved in lung injury and repair and how this may be helpful in identifying and designing future therapeutic targets and strategies and possibly identifying a sensitive and specific biomarker.     

Mesenchymal stem cells and acute lung injury

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute respiratory failure presenting with hypoxemia and bilateral pulmonary infiltrates, most often in the setting of pneumonia, sepsis, or major trauma. The pathogenesis of ARDS involves lung endothelial injury, alveolar epithelial injury, and the accumulation of protein-rich fluid and cellular debris in the alveolar space. No pharmacologic therapy has so far proved effective. A potential strategy involves cell-based therapies, including mesenchymal stem cells (MSCs). Herein we review basic properties of MSCs, their use in preclinical models of lung injury and ARDS, and potential therapeutic mechanisms.     

促红细胞生成素在急性肺损伤与急性呼吸窘迫综合征中作用的研究进展

急性肺损伤（ALI）或急性呼吸窘迫综合征（ARDS）是临床常见急危重症。各种病因包括严重感染、创伤、休克、急性胰腺炎、肺炎等肺内或肺外因素均可导致ALI/ARDS,发病机制主要包括炎症反应、细胞凋亡、氧化应激和肺泡毛细血管膜的损害等,目前尚无特殊有效的治疗方法,临床上也无修复肺损伤的有效药物。促红细胞生成素（EPO）作为一种多功能的内源性调节因子对各种组织损伤有一定的细胞保护作用,尤其是肺组织〔1〕,成为治疗ALI/ARDS的研究热点,     

Aspirin effect on early and late changes in acute lung injury in sheep

Objective There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B₂ (TxB₂) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep.Design 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i. v.) 30 min before OA, the others saline as placebo.Measurements and results Pulmonary and tissue gas exchange, pulmonary and systemic hemodynamics, respiratory system mechanics, TxB₂ and 6-keto-PGF1, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB₂ generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at 1 in ASA-group compared to its fall to 0.7 in controls.Conclusion Our findings suggest that ASA: 1) is only effective to treat the very transient TxB₂-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB₂; 2) has a transient protective effect on the TxB₂-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO₂.     

氯氮平中毒继发急性肺损伤/急性呼吸窘迫综合征的抢救体会

目的:探讨氯氮平中毒继发急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)有效的治疗方法。方法:总结分析16例氯氮平中毒继发ALI/ARDS患者的临床表现和治疗方法。患者在中毒后6～144h出现ALI/ARDS表现,予气管插管、机械通气,抗胆碱药物治疗及血液灌流等综合治疗。结果:本组患者均治愈,平均住院时间(14±1.6)d;机械通气时间平均(134±12)h,中毒后(48～96)h意识转清。结论:氯氮平中毒继发的急性肺损伤/急性呼吸窘迫综合征主要与肺水肿、吸入性肺炎及氯氮平对肺组织的直接损伤作用有关。早期进行机械通气联合血液灌流和合理抗胆碱药物的,是治疗重度氯氮平重度并发急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)的有效方法。     

Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury

Purpose  Preclinical studies suggest that HMG-CoA reductase inhibitors (statins) may attenuate organ dysfunction. We evaluated whether statins are associated with attenuation of lung injury and prevention of associated organ failure in patients with ALI/ARDS. Methods  From a database of patients with ALI/ARDS, we determined the presence and timing of statin administration. Main outcome measures were the development and progression of pulmonary and nonpulmonary organ failures as assessed by changes in PaO₂/FiO₂ ratio and Sequential Organ Failure Assessment score (SOFA) between days 1 and 7 after the onset of ALI/ARDS. Secondary outcomes included ventilator free days, ICU and hospital mortality, and lengths of ICU and hospital stay. Results  From 178 patients with ALI/ARDS, 45 (25%) received statin therapy. From day 1 to day 7, the statin group showed less improvement in their PaO₂/FiO₂ ratio (27 vs. 55, P = 0.042). Ventilator free days (median 21 vs. 16 days, P = 0.158), development or progression of organ failures (median ΔSOFA 1 vs. 2, P = 0.275), ICU mortality (20% vs. 23%, P = 0.643), and hospital mortality (27 vs. 37%, P = 0.207) were not significantly different in the statin and non-statin groups. After adjustment for baseline characteristics and propensity for statin administration, there were no differences in ICU or hospital lengths of stay. Conclusion  In this retrospective cohort study, statin use was not associated with improved outcome in patients with ALI/ARDS. We were unable to find evidence for protection against pulmonary or nonpulmonary organ dysfunction. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

俯卧位通气对急性肺损伤和急性呼吸窘迫综合征临床疗效影响的Meta分析

目的 系统评价俯卧位通气(PPV)对我国急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)患者的短期临床疗效.方法 利用Cochrane系统评价法,全面检索2000年至2009年国内公开发表的所有ALI与ARDS患者PPV的临床研究资料.对纳入研究独立进行质量评价、资料提取、交叉核对后行Meta分析.结果 纳入研究8项共184例患者,PPV时患者动脉血氧分压(PaO2)、氧合指数(PaO2/FiO2)、呼吸系统总顺应性(C)均显著升高;动脉血二氧化碳分压(PaCO2)、中心静脉压(CVP)、呼吸道峰压(PIP)和呼吸系统总阻力(Raw)无显著的变化;心率(HR)与平均动脉压(MAP)显著升高. 结论 ALI与ARDS患者行PPV可增加呼吸系统总顺应性,改善患者低氧血症,相关临床研究结果基本一致.但因Meta分析的自身局限性,我们仍急需开展设计严谨的高质量大样本临床研究,明确PPV临床疗效、作用机制、科学的操作流程及PPV对患者血流动力学的影响等临床实际问题,改善国内ALI与ARDS患者的临床护理水平.     

急性肺损伤患者血清肺表面活性物质蛋白A的变化及其意义

目的;动态观测急性肺损伤虱血清肺表面活性物质蛋白Ａ（ＳＰ－Ａ）的变化,并探讨其临床意义。方法：选择符合ＡＬＩ诊断标准并已给予机械通气治疗的患者２０例,于入组时和出组时抽取静脉血,多数患者在观察期间病情有明显变化时重复抽血,共收集静脉血标本７１例次;并同时记录动脉血气测值和呼吸机参数,计算动脉血氧分压与吸入气氧浓度比值和静态总呼吸顺应性。     

外源性肺表面活性物质治疗脓毒性急性肺损伤的机制研究

目的;观察外源性肺表面活性物质早期治疗对脓毒性急性肺损伤的疗铲及对内源性ＰＳ的影响。方法：实验动物在机械通气下建立脓毒性ＡＬＩ模型,早期气管内稍许主有机提取的ＰＳ１００ｍｇ／ｋｇ,连续治疗６小时,观察氧合指数,肺内分流,肺动脉顺应性的变化;并对支气管肺泡灌洗液磷脂含量和表面张力进行分析。用Ｗｅｓｔｅｒｎ ｄｏｔ ｂｌｏｔ法测定ＰＳ特异性结合蛋白含量,用Ｎｏｒｔｈｅｒｎ ｂｌｏｔ法测定ＳＰ－ＡｍＲＮ     

Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome

Summary. Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho‐alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator‐induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor‐mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator‐mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti‐inflammatory effects of these therapies in ARDS and pneumonia.     

The effect of aspirin in preventing the acute respiratory distress syndrome/acute lung injury: A meta-analysis

Background

The effects of aspirin in preventing the occurrence of acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) among adult patients are controversial. We aimed to further determine the effectiveness of aspirin in reducing the rate of ARDS/ALI.

Pulmonary endothelium in acute lung injury: from basic science to the critically ill

Background Pulmonary endothelium is an active organ possessing numerous physiological, immunological, and metabolic functions. These functions may be altered early in acute lung injury (ALI) and further contribute to the development of acute respiratory distress syndrome (ARDS). Pulmonary endothelium is strategically located to filter the entire blood before it enters the systemic circulation; consequently its integrity is essential for the maintenance of adequate homeostasis in both the pulmonary and systemic circulations. Noxious agents that affect pulmonary endothelium induce alterations in hemodynamics and hemofluidity, promote interactions with circulating blood cells, and lead to increased vascular permeability and pulmonary edema formation.Objective We highlight pathogenic mechanisms of pulmonary endothelial injury and their clinical implications in ALI/ARDS patients.     

急性肺损伤炎症反应失控所致的系统代谢紊乱及其发生机制

目的 探讨炎症反应失控致肺损伤患者的代谢改变情况。方法 采用核磁共振波谱仪（NMR）检测创伤致全身性炎症反应综合征（SIRS）、急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）患者的血清NMR氢谱,进行整体代谢组分析。结果 NMR谱的偏最小二乘法-判别分析（PLS-DA）可区分SIRS患者在发生ALI、甚至ARDS后的代谢模式迁移过程。SIRS患者以低化学位移区段的信号增强为主,主要包含酪氨酸、赖氨酸等生酮氨基酸谱峰;ALI/ARDS患者则以δ1.02～2.50和δ3.02～4.14积分区段信号增强为主,主要包含乳酸、缬氨酸、精氨酸、谷氨酸等多种生糖氨基酸,以及丙酮酸、肌酸、脂质的脂肪酸、甘油等谱峰。代谢通路富集显示,ALI/ARDS的发生主要与糖酵解、糖异生、丙酮酸代谢、甘油酯代谢、精氨酸代谢、初级胆汁酸合成等通路的激活有关,提示ALI炎症反应失控所致的系统代谢紊乱以缺氧状态下高分解代谢为特征。结论 血清整体代谢组能够反映肺损伤后患者的代谢改变,进而有助于监测炎症反应失控导致肺损伤的进程,以及阐明肺损伤代谢紊乱发生的分子机制。     

Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis

AIM: To investigate the efficacy and safety of ulinastatin for patients with acute lung injury (ALI) and those with acute respiratory distress syndrome (ARDS).METHODS: A systematic review of randomized controlled trials (RCTs) of ulinastatin for ALI/ARDS was conducted. Oxygenation index, mortality rate [intensive care unit (ICU) mortality rate, 28-d mortality rate] and length of ICU stay were compared between ulinastatin group and conventional therapy group. Meta-analysis was performed by using Rev Man 5.1.RESULTS: Twenty-nine RCTs with 1726 participants were totally included, the basic conditions of which were similar. No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies (1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference (SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I² = 92%]. ICU mortality and 28-d mortality were respectively reported in eighteen studies (987 patients) and three studies (196 patients). We found that ulinastatin significantly decreased the ICU mortality [I² = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat (NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected (I² = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay (six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I² = 86%).CONCLUSION: Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided.     

Monitoring alveolar epithelial function in acute lung injury

Objective.Identification of humoral markers of acute lung injury may lead to insights into pathologic mechanisms. In addition, specific markers may be useful for predicting development of acute respiratory distress syndrome (ARDS) or for assessing prognosis. Ultimately, studies of lung injury markers may help define interventions that prevent or moderate ARDS. The alveolar epithelium is important both for the integrity of the blood-gas barrier and for repair of the barrier after lung injury. This article reviews markers that derive from or relate to the alveolar epithelium and that might be used for monitoring alveolar epithelial function in acute lung injury. Surfactant apoproteins may be important markers of injury or for prognosis. Levels of surfactant apoprotein A (SP-A) fall 50–75% in patients with severe lung injury compared to normal patients. Serum levels of SP-A in patients dying of acute respiratory distress syndrome are double serum levels of survivors. This revised version was published online in July 2006 with corrections to the Cover Date.     

间充质干细胞在急性肺损伤治疗中的研究进展

急性肺损伤(acute lung injure, ALI)是在ICU中常见的危重症,通常是由多种直接或者间接损伤因素所导致的,具有较高的死亡率,而急性呼吸窘迫综合征(acute respiratory distress syndrome, ARDS)通常认为是ALI的严重阶段。目前临床上对于ALI/ARDS的治疗主要是通过呼吸末正压通气的方式,但是这种方式仍然需要通过不断优化来提高存活率。间充质干细胞(mesenchymal stem cells, MSCs)治疗作为一种非侵入式的、新型的治疗方法,在动物实验中已经取得了很好的疗效,并且已经开始研究MSCs在临床实际治疗时的细节。因此,本文将对阐述MSCs在ALI治疗机制等方面的研究,以期为临床治疗奠定基础。     

白细胞介素-10对急性肺损伤炎症/抗炎介质表达的影响

目的探讨白细胞介素-10(IL—10)对急性肺损伤(ALI)大鼠炎症介质／抗炎介质表达的影响。方法向气道内滴注内毒素(LPS，10mg／kg)建立大鼠ALI模型。54只雄性SD大鼠随机分为对照组、LPS损伤组、LPS加IL-10组，每组18只，各组又分为2、6和24h3个亚组，每个亚组各6只。按各时间点观察大鼠动脉血氧分压(PaO2)、支气管肺泡灌洗液(BALF)中细胞总数及分类计数、肺系数、BALF总蛋白水平及肺病理，同时用逆转录-聚合酶链反应(RT—PCR)方法检测肺组织中炎症介质／抗炎介质的表达。结果①LPS损伤组大鼠PaO2呈进行性降低；肺系数、BALF总蛋白水平及BALF中细胞总数均明显增加，分类以中性粒细胞为主；肺病理示肺内中性粒细胞大量浸润，伴出血、透明膜形成。LPS加IL-10组的各项指标均较LPS损伤组减轻。②LPS损伤组肺组织肿瘤坏死因子-α(TNF—α)mRNA表达于2h达高峰，随后迅速下降；白细胞介素-1β(IL—1β)mRNA表达于2h显著升高，6h达高峰，随后迅速下降；IL-1受体拮抗剂(IL—1ra)mRNA表达6h开始升高，且为峰值。24h仍高于对照组。LPS加IL-10组肺组织TNF—αmRNA、IL-1βmRNA表达受抑，而IL—1ra mRNA表达不受影响。结论①ALI早期TNF—αmRNA、IL-1βmRNA表达明显增加，而IL—1ra mRNA表达滞后，提示在无外来干预情况下，ALI早期存在炎症介质／抗炎介质的失衡。②IL-10可明显抑制炎症介质表达，不影响抗炎介质表达，有利于重建炎症介质／抗炎介质平衡，减轻LPS所致ALI。     

Increased plasma levels of heparin-binding protein in patients with acute respiratory distress syndrome

Introduction

Heparin-binding protein (HBP) is an antimicrobial protein stored in neutrophil granules and plays a role in endothelial permeability regulation. The aim was to assess the diagnostic and prognostic value of measuring HBP in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).

Methods

Plasma HBP was collected from 78 patients with ALI/ARDS, 28 patients with cardiogenic pulmonary edema (CPE) and 20 healthy volunteers at enrollment. Levels of HBP were measured by ELISA.

Results

Patients with ALI/ARDS had significantly higher median levels of HBP compared with patients with CPE (17.15 (11.95 to 24.07) ng/ml vs. 9.50 (7.98 to 12.18) ng/ml, P <0.001) at enrollment. There was no significant difference between CPE patients and healthy subjects in terms of HBP value (P = 0.372). The HBP levels of nonsurvivors was significantly higher than that of survivors (23.90 (14.81 to 32.45) ng/ml vs. 16.01 (10.97 to 21.06) ng/ml, P = 0.012) and multivariate logistic regression showed HBP (odds ratio =1.52, P = 0.034) was the independent predictor for 30-day mortality in patients with ALI/ARDS.

Conclusions

Plasma HBP levels of ALI/ARDS patients were significantly higher than that of CPE patients. HBP was a strong prognostic marker for short-term mortality in ALI/ARDS.     

肺表面活性物质联合布地奈德对急性脑损伤并发呼吸窘迫综合征患者脑血流的影响

目的探讨肺表面活性物质(PS)与布地奈德(BUD)联合治疗对急性脑损伤并发呼吸窘迫综合征(ARDS)患者脑血流及肺功能的影响。方法 64例急性脑损伤合并ARDS患者随机分为观察组及对照组,每组32例。2组患者均行机械通气辅助治疗,对照组在入ICU后30~60 min内给予70 mg/kg的肺表面活性物质,观察组在对照组基础上给予0.25 mg/kg布地奈德联合治疗。比较2组治疗前,治疗后1、3、5、7 d患者搏动指数(PI)、平均血流速度(Vm)、血流阻力指数(RI)、收缩期峰值流速(Vs)、舒张末期血流速度(Vd)。记录2组患者潮气量(VT)、胸肺总顺应性(Crs)、连续呼吸阻力(Raw)。观察2组患者死亡率、脑室周围白质软化(PVL)、脑室周围-脑室内出血(PVH-IVH)发生率。结果观察组治疗3、5、7 d的PI、Vm、RI、Vs、Vd值显著高于对照组(P0.05)。观察组治疗3、5、7 d的VT、Crs显著高于对照组,而Raw显著低于对照组(P0.05)。观察组死亡率、PVL、PVH-IVH发生率显著低于对照组,机械通气时间显著短于对照组(P0.05)。结论 PS联合BUD能有效改善急性脑损伤并发ARDS患者脑血流及肺功能,降低脑损伤发生率,降低患者死亡率。