Variable cell stretching and mechanical ventilation: A comprehensive investigation on the mechanisms and long-term effects of a new ventilatory strategy

与常规机械通气相比，可变机械通气可改善实验性肺损伤的肺功能和肺损伤。这种影响的部分原因是通气量和灌注量重新分配到依赖肺区，这可能会改善通风/灌注量匹配，减少局部应力/应变。理论上，在可变潮气拉伸过程中，肺泡上皮细胞中的一种分化的机械转导也可能在可变通气期的肺保护机制中发挥作用。本项目旨在从肺的微观和宏观结构(研究A和研究B)方面阐明长期可变通风对肺的保护机制。在研究A中，来自大鼠的L2型肺泡上皮细胞以及原代肺泡上皮细胞II和I型样细胞将接受可变和不可变的潮汐拉伸。炎症反应、转录因子的激活和细胞膜上阳离子通道的调节将被确定。在研究B中，采用两次打击的方法造成猪肺损伤，并对动物进行24小时的可变或非可变容量控制机械通气。18F-脱氧葡萄糖(18F-FDG)静脉注射的净摄取率的区域分布将用正电子发射断层扫描和18F-FDG动力学的多室模型来评估。我们假设变量与非变量潮汐细胞拉伸相比(研究A)：1)减少机械敏感的细胞膜蛋白两性调节蛋白的基因表达；2)减少促炎细胞因子的激活和释放；3)减少转录因子c-fos、核因子-kappa-B的激活和移位到细胞核中；4)下调细胞膜上阳离子通道的开放。我们还假设，与非可变容量控制的呼吸机相比，从长远来看(研究B)：a)减少和重新分布中性粒细胞炎症；b)减少弥漫性肺泡损伤；c)改善气体交换；d)在整个肺部导致更均匀的通风、通风和灌流。该项目的结果可能会影响对保护的微观和宏观结构机制的理解，以及对可变机械通气对肺功能和损害的长期影响的表征。这些信息可能会推动对这种呼吸策略的临床研究，这可能会影响患有急性呼吸窘迫综合征患者的机械通气实践。

Variable mechanical ventilation improves lung function and damage in experimental lung injury, as compared to conventional mechanical ventilation. Such effects are partially explained by redistribution of aeration and perfusion to dependent lung zones, which may improve ventilation/perfusion matching and reduce regional stress/strain. Theoretically, a differentiated mechanotransduction in alveolar epithelial cells during variable tidal stretching could also contribute to the mechanisms of lung protection during variable ventilation. This project aims at shedding light onto the mechanisms of lung protection of long-term variable ventilation in the micro and macro-structure of lungs (studies A and B, respectively). In study A, alveolar epithelial cells type L2, as well as primary alveolar epithelial cells type II and type I-like from rats, will be submitted to variable and non-variable tidal stretching. The inflammatory response, activation of transcriptional factors and the regulation of cation channels on the cell membrane will be determined. In study B, lung injury will be induced in pigs by a double-hit approach, and animals ventilated for 24 h with either variable, or non-variable volume controlled mechanical ventilation. The regional distribution of the net uptake rate of the intravenous injection of 18F-fluorodeoxyglucose (18F-FDG) will be assessed using positron emission tomography and a multicompartmental model of 18F-FDG kinetics. We hypothesize that variable compared to non-variable tidal cell stretching (study A): 1) decreases the gene expression of the mechano-sensitive cell membrane protein amphiregulin; 2) decreases the activation and release of pro-inflammatory cytokines; 3) decreases the activation of transcriptional factors c-fos, NF-kappa-B and their translocation into the cell nucleus and; 4) under-regulates the opening of cation channels on the cell membrane. We also hypothesize that variable compared to non-variable volume controlled ventilation, in the long-term (study B): a) reduces and redistributes neutrophilic inflammation across the lungs; b) reduces diffuse alveolar damage; c) improves gas exchange and; d) results in more homogeneous distribution of aeration, ventilation and perfusion across the lungs. The results from this project may have impact on the understanding of the micro- and macro-structural mechanisms of protection, as well as on characterization of the long-term effects of variable mechanical ventilation on lung function and damage. Such information will likely motivate clinical investigations on this ventilatory strategy, which may influence the practice of mechanical ventilation in patients suffering from the acute respiratory distress syndrome.