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Abstract：
Cellular senescence is an important factor leading to pulmonary fibrosis. Deficiency of 8-oxoguanine DNA glycosylase (OGG1) in mice leads to alleviation of bleomycin (BLM)-induced mouse pulmonary fibrosis, and inhibition of the OGG1 enzyme reduces the epithelial mesenchymal transition (EMT) in lung cells. In the present study, we find decreased expression of OGG1 in aged mice and BLM-induced cell senescence. In addition, a decrease in OGG1 expression results in cell senescence, such as increases in the percentage of SA-β-gal-positive cells, and in the p21 and p-H2AX protein levels in response to BLM in lung cells. Furthermore, OGG1 promotes cell transformation in A549 cells in the presence of BLM. We also find that OGG1 siRNA impedes cell cycle progression and inhibits the levels of telomerase reverse transcriptase (TERT) and LaminB1 in BLM-treated lung cells. The increase in OGG1 expression results in the opposite phenomenon. The mRNA levels of senescence-associated secretory phenotype (SASP) components, including IL-1α, IL-1β, IL-6, IL-8, CXCL1/CXCL2, and MMP-3, in the absence of OGG1 are obviously increased in A549 cells treated with BLM. Interestingly, we demonstrate that OGG1 binds to p53 to inhibit the activation of p53 and that silencing of p53 reverses the inhibition of OGG1 on senescence in lung cells. Additionally, the augmented cell senescence is shown in vivo in OGG1-deficient mice. Overall, we provide direct evidence in vivo and in vitro that OGG1 plays an important role in protecting tissue cells against aging associated with the p53 pathway.
摘要：
细胞衰老是导致肺纤维化的重要因素。小鼠中8-氧鸟嘌呤-DNA糖基化酶（OGG1）的缺乏导致博来霉素（BLM）诱导的小鼠肺纤维化的缓解，OGG1酶的抑制减少了肺细胞中的上皮间质转化（EMT）。在本研究中,我们发现OGG1在老年小鼠和BLM诱导的细胞衰老中的表达降低。此外,OGG1表达的减少导致细胞衰老，例如SA-β-gal阳性细胞的百分比增加，在肺细胞中响应BLM的p21和p-H2AX蛋白水平。此外，在BLM存在下,OGG1促进A549细胞中的细胞转化。我们还发现OGG1siRNA阻碍细胞周期进程，并抑制BLM处理的肺细胞中端粒酶逆转录酶（TERT）和LaminB1的水平。OGG1表达的增加导致相反的现象。衰老相关分泌表型（SASP）组分的mRNA水平，包括IL-1α，IL-1β,在不存在OGG1的情况下,IL-6、IL-8、CXCL1/CXCL2和MMP-3在用BLM处理的A549细胞中明显增加。有趣的是,我们证明了OGG1与p53结合以抑制p53的激活，而p53的沉默逆转了OGG1对肺细胞衰老的抑制。此外,在OGG1缺陷小鼠体内显示出增强的细胞衰老。总的来说,我们在体内和体外提供了直接证据，证明OGG1在保护组织细胞免受与p53通路相关的衰老中起着重要作用。
