选择性抑制JNK在线粒体上的定位对海水吸入型肺损伤保护作用的研究

With the development of offshore operations and tourism in recent years, the occurrence of maritime accidents have also increased year by year, and the seawater inhalation induced acute lung injury begin attracting more attention. The patients often have hypoxemia that conventional oxygen treatment cannot relieve. At this stage, the main treatment is mechanical ventilation, and there is no other effective treatment method. We propose that JNK transfer to the mitochondria might be a possible pathogenesis of seawater inhalation induce ALI, and selective inhibition of JNK mitochondrial location could be protective. In the previous study, we confirmed the existence of activation of JNK-mitochondrial pathway in the acute lung injury, and preliminarily explored the subcellular location of JNK. The results showed that during the ALI, JNK in the cytoplasm transfer to mitochondria, and inhibition of JNK-mitochondrial pathway by tail vein injection of Tat-SabKIM1 could reduce the autophagy and apoptosis in the lung of ALI SD rat. To elucidate the explicit mechanism, we also detected the affection of JNK-mitochondrial pathway on the homeostasis of mitochondria and endoplasmic reticulum. Here, in order to further explore the specific protection mechanism, we put forward the pathogenesis of lung injury which is related with JNK mitochondrial location, mitochondria and endoplasmic reticulum homeostasis.

随着近年海上作业和旅游等的发展，海上意外事故的发生也逐渐增多，吸入海水导致的肺损伤倍受关注。患者常有难治性呼吸困难和常规吸氧不能缓解的低氧血症，现阶段治疗主要以机械通气为主，没有探索出有效的针对性治疗方案。我们的实验研究证实急性肺损伤时存在JNK-线粒体通路活化的现象，我们也初步研究了肺损伤时JNK亚细胞定位的情况，结果显示在肺损伤时细胞质中的JNK存在着向线粒体转移的现象。我们也同时观测了通过SD大鼠尾静脉静脉注射Tat-SabKIM1选择性阻断JNK-线粒体通路后细胞自噬和凋亡的现象，并初步探索了选择性阻断JNK-线粒体通路对于线粒体及内质网稳态的影响。为了进一步探明其产生保护作用的具体机制，我们提出了以JNK向线粒体的转移为核心的涉及线粒体及内质网稳态的关于海水吸入型肺损伤的发病机制，并试图通过选择性抑制JNK在线粒体上的定位而起到保护和治疗的作用。

随着近年海上作业和旅游等的发展，海上意外事故的发生也逐渐增多，吸入海水导致的肺损伤倍受关注。而现阶段急性肺损伤的治疗主要以机械通气为主，没有探索出有效的针对性治疗方案。我们提出了以JNK向线粒体的转移为核心的涉及线粒体及内质网稳态的关于海水吸入型肺损伤的发病机制。在我们的实验研究中证实急性肺损伤时存在JNK-线粒体通路活化的现象，并明确了急性肺损伤时JNK亚细胞定位的情况，结果显示在肺损伤时细胞质中的JNK存在着向线粒体转移的现象。而通过SD大鼠尾静脉静脉注射Tat-SabKIM1选择性阻断JNK-线粒体通路后肺组织细胞凋亡减轻、线粒体膜电位稳定，探明了急性肺损伤中JNK-线粒体通路激活参与调控线粒体功能、细胞自噬、细胞凋亡。在进一步的研究中证实JNK-线粒体通路激活参与调控DNA尤其是线粒体DNA损伤及修复，其可以通过促进ROS的产生而引起线粒体DNA损伤，线粒体DNA的受损可以引起线粒体功能紊乱及ATP合成速率下降、ROS产生增多，而过表达线粒体靶向的DNA碱基切除修复酶8-oxoguanine-DNA glycosylase (OGG1)可以减轻氧化应激所致线粒体DNA损伤。最后，我们分别在海水吸入肺损伤及LPS诱导肺损伤动物模型中证实了应用特异性多肽Tat-SabKIM1抑制JNK与线粒体中Sab的结合可以起到治疗急性肺损伤的效果。