Sakai Takahiro, Takagaki Hidetsugu, Yamagiwa Noriyuki, Ui Michio, Hatta Shinichi, Imai Jun
Laboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Japan.
Antioxidants (Basel). 2021 Aug 31;10(9):1398. doi: 10.3390/antiox10091398.
Lung fibrosis is the primary pathology in idiopathic pulmonary fibrosis and is considered to result from an increase in reactive oxygen species (ROS) levels in alveolar epithelial cells. However, the exact mechanism underlying lung fibrosis remains unclear and there is no effective therapy. The hydroxyl radical (OH) has the strongest oxidizing potential among ROS. Recently, OH localized to the cytoplasm (cyto OH) was reported to induce cellular senescence, while mitochondria-localized OH (mt OH) was reported to induce apoptosis. We developed the cyto OH- and mt OH-scavenging antioxidants TA293 and mitoTA293 to evaluate the effects of cyto OH and mt OH in a bleomycin (BLM)-induced pulmonary fibrosis model. Treatment of BLM-induced pulmonary fibrosis mice with TA293 suppressed the induction of cellular senescence and fibrosis, as well as inflammation in the lung, but mitoTA293 exacerbated these. Furthermore, in BLM-stimulated primary alveolar epithelial cells, TA293 suppressed the activation of the p-ATM/p-p53/p21, p-HRI/p-eIF2/ATF4/p16, NLRP3 inflammasome/caspase-1/IL-1β/IL1R/p-p38 MAPK/p16, and p21 pathways and the induction of cellular senescence. However, mitoTA293 suppressed the induction of mitophagy, enhanced the activation of the NLRP3 inflammasome/caspase-1/IL1β/IL1R/p-p38 MAPK/p16 and p21 pathways, and exacerbated cellular senescence, inflammation, and fibrosis. Our findings may help develop new strategies to treat idiopathic pulmonary fibrosis.
肺纤维化是特发性肺纤维化的主要病理表现，被认为是由肺泡上皮细胞中活性氧（ROS）水平升高所致。然而，肺纤维化的确切机制仍不清楚，且尚无有效的治疗方法。羟自由基（OH）在ROS中具有最强的氧化潜力。最近，据报道定位于细胞质的OH（细胞溶质OH）可诱导细胞衰老，而定位于线粒体的OH（线粒体OH）可诱导细胞凋亡。我们开发了清除细胞溶质OH和线粒体OH的抗氧化剂TA293和线粒体TA293，以评估细胞溶质OH和线粒体OH在博来霉素（BLM）诱导的肺纤维化模型中的作用。用TA293治疗BLM诱导的肺纤维化小鼠可抑制细胞衰老、纤维化以及肺部炎症的诱导，但线粒体TA293会加剧这些情况。此外，在BLM刺激的原代肺泡上皮细胞中，TA293可抑制p-ATM/p-p53/p21、p-HRI/p-eIF2/ATF4/p16、NLRP3炎性小体/caspase-1/IL-1β/IL1R/p-p38 MAPK/p16和p21信号通路的激活以及细胞衰老的诱导。然而，线粒体TA293可抑制线粒体自噬的诱导，增强NLRP3炎性小体/caspase-1/IL1β/IL1R/p-p38 MAPK/p16和p21信号通路的激活，并加剧细胞衰老、炎症和纤维化。我们的研究结果可能有助于开发治疗特发性肺纤维化的新策略。
