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

可变细胞拉伸和机械通气：对新通气策略的机制和长期影响的全面研究

• 批准号: 234005084
• 负责人: Professor Dr. Marcelo Gama de Abreu
• 金额: --
• 依托单位: Department of Anesthesia, Critical Care and Pain Medicine
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234005084?language=en
• 关键词: Variable; cell; stretching; mechanical; ventilation

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.

与常规机械通气相比，可变机械通气改善了实验性肺损伤的肺功能和损伤。这种效应部分由通气和灌注重新分布到依赖性肺区来解释，这可以改善通气/灌注匹配并降低区域应力/应变。从理论上讲，在可变潮气拉伸过程中肺泡上皮细胞的分化机械转导也可能有助于可变通气过程中的肺保护机制。本项目旨在阐明长期可变通气在肺的微观和宏观结构中的肺保护机制（分别为研究A和B）。在研究A中，肺泡上皮细胞L2型，以及大鼠的原代肺泡上皮细胞II型和I型样细胞，将接受可变和不变的潮汐拉伸。将确定炎症反应、转录因子的激活和细胞膜上阳离子通道的调节。在研究B中，将通过双重打击方法在猪中诱导肺损伤，并且动物使用可变或非可变容量控制机械通气24小时。将使用正电子发射断层扫描和18F-FDG动力学的多房室模型评估静脉注射18F-氟脱氧葡萄糖（18F-FDG）的净摄取率的区域分布。我们假设可变的与不变的潮汐细胞拉伸（研究A）相比：1）降低机械敏感细胞膜蛋白双调蛋白的基因表达; 2）降低促炎细胞因子的激活和释放; 3）降低转录因子c-fos、NF-κ-B的激活和它们向细胞核的移位; 4）调节细胞膜上阳离子通道的开放不足。我们还假设，与非可变容量控制通气相比，可变容量控制通气在长期（研究B）中：a）减少并重新分布肺部的嗜酸性炎症; B）减少弥漫性肺泡损伤; c）改善气体交换; d）导致肺部通气、通气和灌注的更均匀分布。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伤的长期影响的表征。这些信息可能会激发对这种治疗策略的临床研究，这可能会影响急性呼吸窘迫综合征患者的机械通气实践。