OGG1通过mtDAMP/TLR-9通路调控中性粒细胞胞外杀菌网NETs生成在急性呼吸窘迫综合征中的作用和机制

Acute respiratory distress syndrome (ARDS) is a critical disease in clinic. Due to lack of detailed research, its treatment is mainly limited to mechanical ventilation, and there are no effective and specific treatments. So, it is difficult to achieve satisfactory effect. For this reason, we explored the injury of mitochondrial DNA (mtDNA) and the expression of mtDNA repair molecule OGG1 during ARDS by experiments. However, the mechanism of overexpression OGG1 alleviating ARDS by repairing mtDNA is still unknown. We further found that lung cells of ARDS patients produce large amounts of mitochondrial damage associated molecular patterns (mtDAMP), followed by neutrophil extracellular traps (NETs) generation. These NETs contain high concentrations of inflammatory cytokines and cell killing substances, and can cause damage to lung cells. In order to explore the new mechanisms of the development of lung injury and find effective protection strategy, we plan to explore whether over expression DNA repair protein OGG1 in mitochondria could reduce the mtDNA damage induced by oxidative stress, so as to alleviate ARDS, and whether it could regulate the mtDAMP/TLR-9 pathway and inhibit the release of mtDNA and NETs generation.

急性呼吸窘迫综合征（ARDS）是临床常见的危重症，因缺乏详实的研究，其治疗仅限于以机械通气为主的对症支持治疗，缺乏有效的特异性治疗方案，难以达到令人满意的疗效。对此，我们在预实验中探索了ARDS时线粒体DNA（mtDNA）损伤情况以及mtDNA修复分子OGG1表达变化；但是OGG1通过修复mtDNA起到减轻ARDS的具体机制仍然不明。为此我们进一步研究了ARDS时损伤性刺激肺组织细胞产生大量的线粒体损伤相关分子模式（mtDAMP），继而引起中性粒细胞胞外杀菌网络（NETs）生成，这些NETs中存在着高浓度的炎症因子及细胞杀伤物质，可以对肺组织细胞造成损害。为探索ARDS发生发展的新机制及保护策略，本课题拟通过在线粒体中过表达DNA修复蛋白OGG1，减轻氧化应激所致mtDNA损伤，从而达到减轻ARDS的作用，并证实其可以通过调控mtDAMP/TLR-9通路抑制mtDNA释放和NETs生成。

急性呼吸窘迫综合征（ARDS）是临床常见的危重症，因缺乏详实的研究，其治疗仅限于以机械通气为主的对症支持治疗，缺乏有效的特异性治疗方案，难以达到令人满意的疗效。对此，我们提出通过在线粒体中过表达DNA修复蛋白OGG1，减轻氧化应激所致mtDNA损伤，从而达到减轻ARDS的作用，并设想其可以通过调控mtDAMP/TLR-9通路抑制mtDNA释放和NETs生成。在实验中我们发现肺损伤时存在mtDNA的损伤以及修复蛋白OGG1表达的升高，并证实海水吸入型肺损伤时存在着mtDAMP的产生和释放，而释放到细胞外的mtDAMP（尤其是mtDNA）可以产生损伤肺组织细胞的作用。释放到细胞外的mtDNA可以通过中性粒细胞上的TLR-9受体，从而激活大量的中性粒细胞，促进中性粒细胞的黏附、渗出和迁移趋化，促进中性粒细胞的细胞因子释放。激活中性粒细胞上的TLR-9受体也可以引起SD大鼠肺脏或是分离的中性粒细胞产生无菌性的NETs。产生的NETs可以引起肺泡上皮细胞单层细胞通透性的升高，以及肺损伤的加重。通过过表达OGG1在海水吸入型肺损伤时可以起到保护性作用，并且这种保护作用是通过降低mtDNA的释放实现的。