环氧二十碳三烯酸在肺泡II型上皮细胞衰老中的作用及机制研究

Alveolar epithelium type II cells are important cells to maintain the stability of lung function, but they are susceptible to injury to induce cellular senescence. The senescence and anti-senescence mechanism of alveolar epithelium type II cells have not been fully clarified. Recent studies have found that epoxyeicosatrienoic acids (EETs) play an important role in inhibiting cellular senescence. But EETs are easy to be degraded and inactivated by soluble epoxide hydrolase (sEH), leading to the damage of endogenous anti-cell senescence mechanism. Our previous studies and literature reports indicated that the expression of sEH in lung tissues was up-regulated during pulmonary fibrosis. We further observed that inhibition of sEH activity could reduce pulmonary fibrosis in experimental mice and reduce the expression of senescence-related proteins. Collectively, we firstly propose that EETs are new types of anti-cell senescence substance, and injury factors up-regulate sEH, reduce the content of EETs, and then accelerate the senescence of alveolar epithelium type II cells, causing the senescence of lung organs, and even pulmonary fibrosis. Therefore, the aims of this study are (1) to confirm that alveolar epithelial senescence is the initiating factor of pulmonary dysfunction; (2) to investigate the role of sEH in the senescence of alveolar epithelial type II cells; (3) to investigate the upstream and downstream molecular mechanism of sEH-EETs in cellular senescence of alveolar epithelial type II cells. Finally, we will make it clear that sEH is a new target for delaying pulmonary senescence and preventing pulmonary senescence-related diseases.

肺泡II型上皮细胞（ATII）是维持肺功能稳定的重要细胞，但易受到损伤刺激而发生衰老，目前ATII的衰老和抗衰老机制尚未完全阐明。新近研究发现环氧二十碳三烯酸（EETs）在细胞衰老中可能具有重要的负性调节作用，而EETs易被可溶性环氧化物水解酶（sEH）水解失活，导致内源性抗衰老机制受损。申请人前期研究观察到肺纤维化时肺组织sEH表达上调，抑制sEH活性可改善小鼠肺纤维化，减轻肺组织细胞衰老。因此，本项目提出EETs是一类新型抗衰老物质，而损伤因素上调sEH，降低EETs含量，加速ATII细胞衰老，参与肺脏衰老的发生发展。本项目拟：①确证ATII衰老是肺功能减退的始动环节；②探讨sEH调控EETs含量在ATII细胞衰老中的作用；③探讨sEH调控EETs诱导ATII细胞衰老的上下游分子机制。本项目将明确EETs是新型抗衰老物质，调控sEH是防治肺脏衰老性疾病的新靶点。

肺泡上皮细胞是维持肺功能稳态的重要细胞，易受到损伤刺激而发生衰老，目前肺泡上皮细胞的衰老和抗衰老机制尚未完全阐明。在本项目的资助下，课题组系统阐明环氧二十碳三烯酸（EETs）是一类新型抗衰老物质，而损伤因素上调可溶性环氧化物水解酶（sEH）的表达，加速内源性EETs的降解，导致肺泡上皮细胞衰老，参与肺脏衰老及肺衰老相关疾病的发生发展。本项目主要完成的研究有：①首次观察到EETs具有减轻衰老相关肺纤维化及慢性阻塞性肺部疾病的作用；②肺泡上皮细胞衰老时EETs含量降低，采用基因调控和药物干预等策略增加EETs含量，可减轻多种因素刺激诱导的肺泡上皮细胞衰老，其分子机制与EETs抑制内质网应激和改善线粒体功能障碍有关；③阐明EETs减轻衰老肺泡上皮细胞氧化应激的机制：EETs促进E3泛素连接酶Trim25的表达，泛素化降解keap1，促进Nrf2入核；④系统性探讨了EETs抗肺泡上皮细胞衰老与炎症反应的关系，发现EETs延缓细胞衰老的潜在机制与抑制巨噬细胞NLRP3炎症小体的活化有关；⑤提出EETs具有抗肺脏、心脏和肝脏等多器官衰老的作用；⑥揭示肺泡上皮细胞衰老新机制：线粒体柠檬酸堆积及髓样细胞表达的触发受体-1激活。本项目系统地阐明EETs是肺脏等多器官多细胞的内源性抗衰老物质，是延缓肺泡上皮细胞衰老及防治肺衰老相关疾病的新靶点，为衰老相关疾病的防治提供了新思路。