Joelsson Jon Petur, Asbjarnarson Arni, Sigurdsson Snaevar, Kricker Jennifer, Valdimarsdottir Bryndis, Thorarinsdottir Holmfridur, Starradottir Eir, Gudjonsson Thorarinn, Ingthorsson Saevar, Karason Sigurbergur
University of Iceland, Reykjavík, Iceland.
EpiEndo Pharmaceuticals, Reykjavik, Iceland.
Lab Anim Res. 2022 Jul 22;38(1):23. doi: 10.1186/s42826-022-00133-4.
Mechanical ventilation is a life-saving therapy for critically ill patients, providing rest to the respiratory muscles and facilitating gas exchange in the lungs. Ventilator-induced lung injury (VILI) is an unfortunate side effect of mechanical ventilation that may lead to serious consequences for the patient and increase mortality. The four main injury mechanisms associated with VILI are: baro/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; oxygen toxicity due to use of high ratio of oxygen in inspired air, causing formation of free radicals; and biotrauma, the resulting biological response to tissue injury, that leads to a cascade of events due to excessive inflammatory reactions and may cause multi-organ failure. An often-overlooked part of the inflammatory reaction is oxidative stress. In this research, a mouse model of VILI was set up with three tidal volume settings (10, 20 and 30 mL/kg) at atmospheric oxygen level. Airway pressures and heart rate were monitored and bronchoalveolar lavage fluid (BALF) and lung tissue samples were taken.
We show a correlation between increased inflammation and barrier failure, and higher tidal volumes, evidenced by increased IL-6 expression, high concentration of proteins in BALF along with changes in expression of adhesion molecules. Furthermore, swelling of mitochondria in alveolar type II cells was seen indicating their dysfunction and senescence-like state. RNA sequencing data present clear increases in inflammation, mitochondrial biogenesis and oxidative stress as tidal volume is increased, supported by degradation of Keap1, a redox-regulated substrate adaptor protein.
Oxidative stress seems to be a more prominent mechanism of VILI than previously considered, indicating that possible treatment methods against VILI might be identified by impeding oxidative pathways.
机械通气是危重症患者的一种挽救生命的治疗方法，可为呼吸肌提供休息并促进肺部气体交换。呼吸机相关性肺损伤（VILI）是机械通气的一种不良副作用，可能给患者带来严重后果并增加死亡率。与VILI相关的四种主要损伤机制为：肺组织过度拉伸导致的气压/容积伤；肺泡反复开闭导致剪切应力而引起的肺不张伤；吸入空气中高氧比例使用导致的氧中毒，引起自由基形成；以及生物伤，即对组织损伤产生的生物学反应，由于过度炎症反应导致一系列事件，并可能引起多器官功能衰竭。炎症反应中一个常被忽视的部分是氧化应激。在本研究中，在常压氧水平下设置了三种潮气量设置（10、20和30 mL/kg）建立VILI小鼠模型。监测气道压力和心率，并采集支气管肺泡灌洗液（BALF）和肺组织样本。
我们发现炎症增加与屏障功能障碍以及更高的潮气量之间存在相关性，这通过IL-6表达增加、BALF中蛋白质浓度升高以及黏附分子表达变化得以证明。此外，观察到II型肺泡细胞中线粒体肿胀，表明其功能障碍和类似衰老的状态。RNA测序数据显示，随着潮气量增加，炎症、线粒体生物发生和氧化应激明显增加，这得到了氧化还原调节的底物衔接蛋白Keap1降解的支持。
氧化应激似乎是VILI比先前认为更为突出的机制，这表明可能通过阻碍氧化途径来确定针对VILI的治疗方法。
