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损伤。部分原因是通气和灌注重新分布到依赖的肺区，这可能改善通气/灌注匹配并减少区域应力/应变。从理论上讲，在可变潮汐拉伸期间肺泡上皮细胞的分化机械转导也可能有助于可变通气期间肺保护的机制。本项目旨在揭示长期可变通气在肺微观和宏观结构中的肺保护机制（研究A和研究B）。在研究A中，将大鼠L2型肺泡上皮细胞以及II型和i样原代肺泡上皮细胞进行可变和非可变潮汐拉伸。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，采用双击方法诱导猪肺损伤，动物在可变或非可变容量控制机械通气下通气24小时。静脉注射18f -氟脱氧葡萄糖（18F-FDG）净吸收率的区域分布将使用正电子发射断层扫描和18F-FDG动力学的多室模型进行评估。我们假设，与非可变潮汐细胞拉伸相比，可变潮汐细胞拉伸（研究A）： 1)降低机械敏感细胞膜蛋白双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)降低转录因子c-fos、NF-kappa-B的活化及其在细胞核内的易位；4)细胞膜上阳离子通道的打开调节不足。我们还假设，与非可变容积控制通气相比，可变容积控制通气在长期内（研究B）： a)减少并重新分配肺部的中性粒细胞炎症；B)减轻弥漫性肺泡损伤；C)改善气体交换；D)导致通气、通气和灌注在肺部的更均匀分布。本项目的研究结果可能会对了解保护的微观和宏观结构机制，以及可变机械通气对肺功能和损伤的长期影响的表征产生影响。这些信息可能会激发对这种通气策略的临床研究，这可能会影响急性呼吸窘迫综合征患者机械通气的实践。

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.