GABA信号通路在机械通气所致“肺-脑交互”损伤中的作用及其机制研究

Mechanical ventilation (MV) is essential for patients with acute respiratory failure.However,ventilator induced not only lung injury but also brain dysfunction. The mechanism of mechanical ventilation-induced lung-brain crosstalk injury has not been identified. Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in central nervous system. Recent studies have found that GABA is related to not only cognition impairment and brain dysfunction but also NF-κB、p38MAPK signaling pathway involved in lung injury. Our preliminary experiment showed that GABA expression of lung and brain was up-regulated in the model of ventilator induced lung injury in rat. Based on our preliminary experiment, we propose hypothesis that GABA is the key signaling pathway of mechanical ventilation-induced lung-brain crosstalk injury. Our project intends to use pathology, molecular biology, RNA gene interference detection technology to discuss the effect of GABA signaling pathways in mechanical ventilation-induced lung-brain crosstalk njury and on activation of NF-κB、p38MAPK STAT3 signaling pathway.Fuethermore, we explore the molecular mechanism of GABA signaling pathways, with a view to provide new ideas for clinical prevention of lung-brain crosstalk injury.

机械通气是一把双刃剑，不仅引起机械通气肺损伤，还可以诱发脑损伤。但机械通气所致“肺-脑交互”损伤发生机制迄今远未阐明。γ-氨基丁酸(GABA)作为中枢神经系统中最重要的抑制性神经递质，近年发现其不但参与脑损伤及认知功能障碍的发生，而且成为加剧肺脏损伤的重要介质，并与参与肺损伤 NF-κB、p38MAPK等炎性通路激活密切相关。尤其近期我们发现机械通气所致肺损伤模型大鼠肺、脑组织中GABA表达均明显增高。结合前期研究结果，我们推测GABA系统激活可能是机械通气所致“肺-脑交互”损伤的关键信号分子。本项目拟采用病理学、分子生物学、RNA基因干扰等技术，重点研究 GABA 系统激活对肺-脑损伤程度以及下游NF-κB、p38MAPK和STAT3信号通路的影响，探究激活的GABAR亚型，阐明GABA通路在机械通气所致肺-脑损伤的分子效应和调控机制。为临床机械通气肺、脑损伤的防治提供新思路。

机械通气是一把双刃剑，不仅引起机械通气肺损伤(VILI)，还可以诱发脑损伤。积极探索预防VILI诱发脑损伤的措施，对于改善需行机械通气的危重患者预后具有重要意义。γ氨基丁酸受体(GABAR)在炎症反应和肺部抗损伤过程中起重要作用，其参与气道重塑程序，肺动态平衡调节和哮喘发病机制。我们推测GABA信号通路的激活可能在减轻VILI，进而参与到脑损伤的发生发展过程中扮演着重要角色。因此我们提出：通过各种途径阻断或者激活GABA信号通路，将有可能改善机械通气肺脑交互损伤(VILBI)。本研究通过体外和体内实验观察GABA信号通路对机械通气肺脑交互损伤的影响及相关机制。主要研究结果显示：(1) 大潮气量通气大鼠海马组织GABA信号通路活化水平明显升高，脑组织炎性介质释放水平增加，大鼠短期学习记忆能力下降，提示大潮气量机械通气可引起远隔部位的脑损伤；(2) GABA信号通路的激活能够改善大潮气量通气引起的VILI，减轻肺泡上皮细胞骨架的破坏以及凋亡，抑制GABA信号通路则恶化原有损伤；(3) GABA信号通路的激活可减轻VILI引起的血清S100β、NSE以及炎症介质的增加，改善VILI大鼠的空间学习和记忆能力，并降低海马神经元细胞的凋亡。该研究结果无疑为“干预GABA信号通路”肺脑保护策略预防VILBI的发生提供科学理论依据。