Integrin/FAK信号通路介导应力时间指数在ARDS机械通气所致肺损伤中的作用及机制研究

Ventilator-induced lung injury (VILI) is a common and serious complication during mechanical ventilation in acute respiratory distress syndrome (ARDS). Integrin（ITG）is most important adhesion molecule in interactions between cells and the extracellular matrix. The ITG/FAK signaling pathway is an important pathway during the process of translating mechanical stress into changes in cell function and causing biological lung injury, the specific mechanism is still unclear. Our previous research and reviewing literature have found that the stress time index directed APRV ventilation strategies can significantly reduce lung injury and improve outcomes in ARDS. Therefore, it is hypothesized that the cyclic mechanical stretch may cause VILI by activating the ITG /FAK signaling pathway, and the stress time index could prevent VILI in ARDS through regulating the ITG /FAK signaling pathway. In the severe ARDS animal and vitro alveolar epithelial cell experiments, this study aims to observe the effect of stress time index ventilation strategy and low tidal volume lung protective ventilation strategy on lung injury; and to explore the effect of ITG/FAK signaling pathway in VILI, and the effect and mechanism of stress time index in the process of lung inflammatory response and fibrosis response through regulating the ITG/FAK signaling pathway, clarifying its mechanism from the level of tissue, cell and molecular biology. The results of the study could provide a new theoretical basis for prevention of ARDS VILI and further improve lung protective ventilation strategy.

机械通气所致肺损伤(VILI)是ARDS机械通气过程中常见而严重的并发症。Integrin（ITG）是介导细胞与细胞外基质相互作用的主要分子，ITG/FAK信号通路是细胞感知机械应力引起肺生物性损伤的重要途径，具体机制尚不清楚。结合前期研究和查阅文献，应力时间指数优化的APRV通气能显著改善ARDS疗效，减轻肺损伤。因此提出假说：周期性机械牵张激活ITG/FAK信号通路引起VILI，应力时间指数通过调控ITG/FAK信号通路，进而预防ARDS VILI。本研究拟结合ARDS动物实验和细胞实验，观察应力时间指数通气和小潮气量肺保护性通气对肺损伤的影响；探讨ITG/FAK信号通路在VILI中的作用，以及应力时间指数通过调控ITG/FAK信号通路在肺炎症反应和纤维化反应中的作用及机制，从组织和细胞分子生物学水平阐明其作用机制。旨在为预防ARDS VILI提供理论基础和进一步完善肺保护性通气策略。

急性呼吸窘迫综合征（ARDS）发病率高，病死率高，严重威胁重症患者的生命安全。机械通气是其治疗的主要手段，ARDS治疗指南推荐应用小潮气量通气（LTV）策略，但多年的应用并未有效降低ARDS病人的病死率。气道压力释放通气（APRV）模式通过延长高压相，维持肺泡持续开放，减少肺泡塌陷，有研究证实其能有效改善ARDS患者氧合，减少机械通气时间和住ICU时间，降低病死率，且不影响血流动力学，不造成更高气压伤。但其肺保护作用的机制目前并不十分明确。大量研究表明炎性介质的释放在ARDS中发挥了重要作用。Integrin β4（ITGB4）在机械力信号传导过程中起着重要作用，且能激活FAK、p38-MAPK信号通路，而后者与炎症反应有着密切的关系。因此本研究构建巴马小型成年猪ARDS模型与体外肺上皮细胞牵张模型，探索验证APRV与LTV周期性牵张刺激通过ITGB4-p38-MAPK通路引起炎症反应的机制。. 研究结果发现APRV机械通气模式相较于LTV机械通气模式更好的改善氧合、肺顺应性以及肺通透性，从而减少肺部损伤，同时从病理学评估对肺外器官（肠道、肝脏、心脏、肾脏）无明显损伤。通过肺组织高通量测序，明确ITGB4在细胞外基质受体交互通路、黏着斑信号通路、MAPK活性激活过程中显著富集。体外实验应用细胞牵张力构建周期性机械牵张应力环境发现，与LTV牵张相比APRV牵张可以下调ITGB4，并通过p38-MAPK信号通路，减少IL-8的分泌。在发生肺泡上皮过度扩张的肺炎症性疾病中，靶向ITGB4-p38 MAPK信号通路可能是一种有前景的治疗策略。