Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice

Introduction  

Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis.     

单肺通气肺损伤机制及保护策略研究进展

单肺通气作为麻醉领域内一个比较特殊的通气方式,在为胸外科手术提供便利条件的同时也不可避免地会产生一定程度的肺损伤.为减轻或避免围术期肺损伤,通常采用下列措施,如选择合适麻醉方式、麻醉药物、呼吸参数、通气模式及非通气侧肺持续低压给氧、应用药物改善氧合、通气侧肺的保护、浅低温以及其他相关肺保护措施.本文就近年来单肺通气期间肺损伤的机制及保护策略的研究进展作一综述.     

Mechanical ventilation aggravates transfusion-related acute lung injury induced by MHC-I class antibodies

Purpose  

Transfusion-related acute lung injury (TRALI) occurs more often in critically ill patients than in a general hospital population, possibly due to the presence of underlying inflammatory conditions that may prime pulmonary neutrophils. Mechanical ventilation may be a risk factor for developing TRALI. We examined the influence of mechanical ventilation (MV) on the development of TRALI, combining a murine MV model causing ventilator-induced lung injury with a model of antibody-induced TRALl.     

Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia

OBJECTIVE: Acute respiratory failure is a significant complication of severe pneumococcal pneumonia. In a mouse model, we observed early-onset lung microvascular leakage after pulmonary infection with Streptococcus pneumoniae, and we hypothesized that the important virulence factor pneumolysin may be the direct causative agent. DESIGN: Controlled, in vivo, ex vivo, and in vitro laboratory study. SETTING: Laboratory. SUBJECTS: Female mice, 8-12 wks old. INTERVENTIONS: Ventilated and blood-free perfused murine lungs were challenged with recombinant pneumolysin via the airways as well as via the vascular bed. In addition, we analyzed the impact of pneumolysin on electrical cell impedance and hydraulic conductivity of human umbilical vein endothelial cell (HUVEC) and alveolar epithelial cell (A549) monolayers. MEASUREMENTS AND MAIN RESULTS: Aerosolized pneumolysin dose-dependently increased capillary permeability with formation of severe lung edema but did not affect pulmonary vascular resistance. Intravascular pneumolysin caused an impressive dose-dependent increase in pulmonary vascular resistance and in lung microvascular permeability. By immunohistochemistry, pneumolysin was detected mainly in endothelial cells of pulmonary arterial vessels, which concomitantly displayed strong vasoconstriction. Moreover, pneumolysin increased permeability of HUVEC and A549 monolayers. Interestingly, immunofluorescence of endothelial cell monolayers exposed to pneumolysin showed gap formation and moderate stress fiber generation. CONCLUSIONS: Pneumolysin may play a central role for early-onset acute lung injury due to severe pneumococcal pneumonia by causing impairment of pulmonary microvascular barrier function and severe pulmonary hypertension.     

Mechanical ventilation in acute lung injury and ARDS. Tidal volume reduction

Traditional mechanical ventilation practices used generous tidal volumes in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). This approach may have caused overdistention of aerated lung units, thus exacerbating lung injury in some patients. Several recent clinical trials of traditional versus lower tidal volume strategies in ALI/ARDS yielded disparate results. In the largest study, the lower tidal volume approach was associated with lower mortality and more ventilator-free days. This article reviews the rationale for tidal volume reduction in ALI/ARDS and the differences between the studies. Several different interpretations of the recent clinical trial results are addressed.     

脓毒症相关性肺损伤治疗进展

近年来,随着药物治疗学及生物细胞学的快速发展,有关脓毒症相关性肺损伤治疗的新方法也相应出现,并且在动物模型中的相关干预效果令人鼓舞,临床试验有待进一步证实.临床上急性肺损伤定义的更新和发展及共识的达成,对指导相应机械通气策略的应用有帮助.     

单肺通气中肺保护策略研究进展

目的 通过对单肺通气中肺保护策略研究进展的分析,为临床工作提供理论指导,减少单肺通气术中低氧血症和术后肺部并发症的发生.方法 应用计算机在Pubmed上检索2007年1月～ 2012年5月有关单肺通气的文章,检索词为:one lung ventilation,hypoxemia,lungprotection,限定文章语言种类为English.对资料进行初审,并查找全文.纳入标准:①有关单肺通气的实验及临床研究;②有关肺保护的试验研究.排除标准:①综述文献;②重复研究.共收集到200多篇有关单肺通气方面的文献,纳入14篇.结果 纳入的14篇文章中有关单肺通气术中管理方面的文献12篇,有关单肺通气时低氧血症方面的文献2篇.通过对入选文献进行分析、整理,将单肺通气术中管理从通气模式选择、潮气量与呼吸频率的设置、PEEP及CPAP的运用、吸入氧浓度及液体管理等5方面进行分析,归纳总结出目前在单肺通气时的肺保护策略和麻醉管理进展.结论 随着对单肺通气中肺保护的深入研究,单肺通气的麻醉管理将更加有效、合理.     

Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Background  

Experimental and clinical studies on sepsis have demonstrated activation of the innate immune response following the initial host–bacterial interaction. In addition, mechanical ventilation (MV) can induce a pulmonary inflammatory response. How these two responses interact when present simultaneously remains to be elucidated. We hypothesized that MV modulates innate host response during sepsis by influencing Toll-like receptor (TLR) signaling.     

Liquid ventilation with perflubron in the treatment of rats with pneumococcal pneumonia

OBJECTIVE: To determine the efficacy of liquid ventilation using a medical-grade perfluorocarbon (perflubron) combined with parenteral or intratracheal antibiotics in a rat model of pneumonia. DESIGN: Prospective, laboratory investigation. SETTING: Experimental laboratory in a university medical center. SUBJECTS: Wistar rats (n = 112). INTERVENTIONS: One day after intratracheal inoculation with Streptococcus pneumoniae, rats received one of five experimental treatments or no treatment (control): modified liquid ventilation (MLV), intramuscular ampicillin, MLV plus intramuscular ampicillin, MLV with intratracheal ampicillin, or MLV plus ampicillin PulmoSpheres. MEASUREMENTS AND MAIN RESULTS: Animals receiving MLV plus intramuscular ampicillin, MLV with intratracheal ampicillin, or MLV plus ampicillin PulmoSpheres had significantly improved 10-day survival rates (85%, 72%, and 72%, respectively) compared with all other groups (0% to 25%). CONCLUSIONS: MLV in combination with either intramuscular, intratracheal, or PulmoSpheres ampicillin improved survival as compared with MLV alone or the same dose of antibiotics delivered intramuscularly.     

盐酸戊乙奎醚对腹腔感染脓毒症小鼠肺损伤的保护作用

脓毒症／感染性休克是造成多器官功能障碍乃至死亡的重要原因。在脓毒症并发的多器官损伤中，肺脏往往是受累最早也是最严重的器官。抗胆碱药用于治疗微循环障碍性疾病取得了很好的效果，文献报道山莨菪碱（654—2）能将脓毒症的病死率降至14％，但其具体机制还不十分清楚。盐酸戊乙奎醚（PHC）为新型选择性抗胆碱药，但其用于脓毒症／感染性休克治疗的研究尚未见报道。本研究利用盲肠结扎穿孔术（CLP）复制脓毒症／感染性休克动物模型，观察PHC对肺组织超氧化物歧化酶（SOD）活性、丙二醛（MDA）含量和诱生型一氧化氮合酶（iNOS）mRNA表达的影响，并探讨其可能的机制。     

右美托咪定通过调节线粒体分裂和耗氧量减轻细支气管肺炎小鼠肺损伤的机制

目的 探讨右美托咪定通过调节线粒体分裂和耗氧量减轻细支气管肺炎小鼠肺损伤的机制.方法 50只无特定病原体级雄性白化小鼠为研究对象,将所有小鼠按照实验设置分为5组:对照组、阴性对照组、低剂量右美托咪定组、中剂量右美托咪定组和高剂量右美托咪定组,各10只.除对照组外,其余4组通过人工感染铜绿假单胞菌的方法构造小鼠细支气管肺...     

鞭毛蛋白与盲肠结扎穿孔脓毒症致大鼠肺损伤的对比观察

目的 观察鞭毛蛋白与盲肠结扎穿孔脓毒症致大鼠肺损伤的差异。方法 鞭毛蛋白经颈静脉注射以复制大鼠急性肺损伤(ALI)模型。ELISA法检测大鼠外周血血清中TNF-α含量,并观察动脉血气分析、肺组织湿干比值(W/D)和肺病理变化程度。结果 用鞭毛蛋白成功建立了大鼠肺损伤模型。鞭毛蛋白致肺损伤大鼠的动脉氧分压(PaO2)、TNF-α、W/D和肺病理变化程度较脓毒症致肺损伤大鼠有显著性差别。结论 鞭毛蛋白可用于急性肺损伤模型的建立。     

Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice

IntroductionLung-protective ventilation reduced acute respiratory distress syndrome (ARDS) mortality. To minimize ventilator-induced lung injury (VILI), tidal volume is limited, high plateau pressures are avoided, and positive end-expiratory pressure (PEEP) is applied. However, the impact of specific ventilatory patterns on VILI is not well defined. Increasing inspiratory time and thereby the inspiratory/expiratory ratio (I:E ratio) may improve oxygenation, but may also be harmful as the absolute stress and strain over time increase. We thus hypothesized that increasing inspiratory time and I:E ratio aggravates VILI.MethodsVILI was induced in mice by high tidal-volume ventilation (HV_T 34 ml/kg). Low tidal-volume ventilation (LV_T 9 ml/kg) was used in control groups. PEEP was set to 2 cm H₂O, FiO₂ was 0.5 in all groups. HV_T and LV_T mice were ventilated with either I:E of 1:2 (LV_T 1:2, HV_T 1:2) or 1:1 (LV_T 1:1, HV_T 1:1) for 4 hours or until an alternative end point, defined as mean arterial blood pressure below 40 mm Hg. Dynamic hyperinflation due to the increased I:E ratio was excluded in a separate group of animals. Survival, lung compliance, oxygenation, pulmonary permeability, markers of pulmonary and systemic inflammation (leukocyte differentiation in lung and blood, analyses of pulmonary interleukin-6, interleukin-1β, keratinocyte-derived chemokine, monocyte chemoattractant protein-1), and histopathologic pulmonary changes were analyzed.ResultsLV_T 1:2 or LV_T 1:1 did not result in VILI, and all individuals survived the ventilation period. HV_T 1:2 decreased lung compliance, increased pulmonary neutrophils and cytokine expression, and evoked marked histologic signs of lung injury. All animals survived. HV_T 1:1 caused further significant worsening of oxygenation, compliance and increased pulmonary proinflammatory cytokine expression, and pulmonary and blood neutrophils. In the HV_T 1:1 group, significant mortality during mechanical ventilation was observed.ConclusionAccording to the “baby lung” concept, mechanical ventilation-associated stress and strain in overinflated regions of ARDS lungs was simulated by using high tidal-volume ventilation. Increase of inspiratory time and I:E ratio significantly aggravated VILI in mice, suggesting an impact of a “stress/strain × time product” for the pathogenesis of VILI. Thus increasing the inspiratory time and I:E ratio should be critically considered.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0759-2) contains supplementary material, which is available to authorized users.     

脓毒症急性肺损伤大鼠肺组织细胞凋亡的研究

目的观察脓毒症急性肺损伤（ALI）大鼠肺组织的细胞凋亡情况。方法24只SPF级SD大鼠采用盲肠结扎穿孔术（CLP）复制脓毒症模型,分别于CLP后0、12、36和72h颈椎脱臼法处死大鼠,取肺组织。行肺组织HE染色,观察病理变化,以透射电镜、TUNEL法检测细胞凋亡。结果HE染色可见,CLP后12、36、72h肺泡间隔增宽,间质充血水肿,肺泡腔变窄,炎症细胞渗出。TUNEL法检测发现,CLP后12、36、72h肺组织内细胞凋亡指数（Al）增加,其中36hAl值最高（P〈0．01）。透射电镜证实细胞凋亡的特征性改变。结论脓毒症大鼠肺组织的Al明显增加,细胞凋亡可能在脓毒症ALI发生、发展中起着重要作用。     

机械通气致肺损伤的防护

[目的]通过研究大潮气量机械通气引起的肺损伤（VILI），提出机械通气时通气机所致VELI的护理防护。[方法]将24只健康绎巨SD大鼠随机等分为对照组与实验组，对照组小潮气量通气（VT=8mL／kg）；实验组为致伤组大潮气量通气（VT=40mL／kg）。通气时间均为4h，每小时行1次动脉血气分析。通气后行支气管肺泡灌洗液（BALF）中性粒细胞计数，血清和BALF中TNF—α、IL-1β含量测定。[结果]实验组大鼠氧合指数较对照组显著下降，BALF中性粒细胞计数、血清和BALF中TNF—α、IL-1β水平较对照组显著增加。[结论]大潮气量机械通气能引起明显的VILI，临床上对于机械通气的病人，应尽量避免大潮气量通气。加强对通气机所致VILI的护理防护。     

《2004严重感染和感染性休克治疗指南》系列讲座(6)严重感染和感染性休克所致急性呼吸窘迫综合征的机械通气治疗

急性肺损伤(ALI)是急性呼吸衰竭最常见的原因和表现,急性呼吸窘迫综合征(ARDS)是其病情进展的结果。ARDS的发病原因复杂多样,但最常见的为严重感染,25％-42％的ARDS由严重感染引起,其中以肺部和腹腔感染最为多见。顽固性低氧血症是ARDS最突出的临床特征,机械通气是纠正低氧血症的主要治疗手段。ARDS患者大量肺泡塌陷,肺容积显著减少,肺顺应性明显降低,决定了机械通气中必须采用特殊的通气模式和通气条件。     

Murine in vivo myocardial contractile dysfunction after burn injury is exacerbated by pneumonia sepsis

We evaluated hemodynamic and cardiac contractile dysfunction in a murine model of 40% contact burn complicated by Streptococcus pneumoniae (1 x 10(5) CFU) sepsis. Male, 9- to 10-week-old C57/BL6 mice were divided into the following groups: sham burn, sham sepsis; 24 h after burn alone; 24 h after sepsis alone; 7 days after burn alone; and 7 days after burn followed by pneumonia sepsis. Hemodynamic and cardiac contractile function was assessed with carotid artery cannulation and left ventricular pressure-volume analysis. At 24 h after burn, there were significant decreases in all load-insensitive contractility variables including the end-systolic pressure volume relationship, preload-recruitable stroke work, and maximum elastance, but there were no changes in global hemodynamics. Twenty-four hours after sepsis, there was similar cardiac contractile dysfunction, along with a decrease in cardiac output, but mean arterial pressure was maintained with an increase in systemic vascular resistance. Late burn (7 days) was associated with a recovery of all contractility variables except the end-systolic pressure volume relationship. However, sepsis induced during the late burn period was associated with a significant decrease in heart rate and cardiac output, but mean arterial pressure was still maintained with increased systemic vascular resistance. With burn complicated by sepsis, all cardiac contractility variables showed profound contractile dysfunction. Our data indicate that burn complicated by sepsis is associated with more pronounced cardiac contractile dysfunction than burn alone or sepsis alone.