Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice
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 hydr...
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MDPI AG
2021-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/9/1398 |
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| author | Takahiro Sakai Hidetsugu Takagaki Noriyuki Yamagiwa Michio Ui Shinichi Hatta Jun Imai |
| author_facet | Takahiro Sakai Hidetsugu Takagaki Noriyuki Yamagiwa Michio Ui Shinichi Hatta Jun Imai |
| author_sort | Takahiro Sakai |
| collection | DOAJ |
| description | 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 (<sup>•</sup>OH) has the strongest oxidizing potential among ROS. Recently, <sup>•</sup>OH localized to the cytoplasm (cyto <sup>•</sup>OH) was reported to induce cellular senescence, while mitochondria-localized <sup>•</sup>OH (mt <sup>•</sup>OH) was reported to induce apoptosis. We developed the cyto <sup>•</sup>OH- and mt <sup>•</sup>OH-scavenging antioxidants TA293 and mitoTA293 to evaluate the effects of cyto <sup>•</sup>OH and mt <sup>•</sup>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<sup>ser1981</sup>/p-p53<sup>ser15</sup>/p21, p-HRI/p-eIF2<sup>ser51</sup>/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. |
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| language | English |
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| publishDate | 2021-08-01 |
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| series | Antioxidants |
| spelling | doaj.art-5549e55c491b444fbc1da67da170be0a2023-11-22T11:48:09ZengMDPI AGAntioxidants2076-39212021-08-01109139810.3390/antiox10091398Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model MiceTakahiro Sakai0Hidetsugu Takagaki1Noriyuki Yamagiwa2Michio Ui3Shinichi Hatta4Jun Imai5Laboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, JapanLaboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, JapanLaboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, JapanLaboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, JapanLaboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, JapanLaboratory of Physiological Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, JapanLung 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 (<sup>•</sup>OH) has the strongest oxidizing potential among ROS. Recently, <sup>•</sup>OH localized to the cytoplasm (cyto <sup>•</sup>OH) was reported to induce cellular senescence, while mitochondria-localized <sup>•</sup>OH (mt <sup>•</sup>OH) was reported to induce apoptosis. We developed the cyto <sup>•</sup>OH- and mt <sup>•</sup>OH-scavenging antioxidants TA293 and mitoTA293 to evaluate the effects of cyto <sup>•</sup>OH and mt <sup>•</sup>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<sup>ser1981</sup>/p-p53<sup>ser15</sup>/p21, p-HRI/p-eIF2<sup>ser51</sup>/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.https://www.mdpi.com/2076-3921/10/9/1398hydroxyl radicalcytoplasmic hydroxyl radicalmitochondrial hydroxyl radicalcellular senescencepulmonary fibrosisinflammation |
| spellingShingle | Takahiro Sakai Hidetsugu Takagaki Noriyuki Yamagiwa Michio Ui Shinichi Hatta Jun Imai Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice Antioxidants hydroxyl radical cytoplasmic hydroxyl radical mitochondrial hydroxyl radical cellular senescence pulmonary fibrosis inflammation |
| title | Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice |
| title_full | Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice |
| title_fullStr | Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice |
| title_full_unstemmed | Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice |
| title_short | Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice |
| title_sort | effects of the cytoplasm and mitochondrial specific hydroxyl radical scavengers ta293 and mitota293 in bleomycin induced pulmonary fibrosis model mice |
| topic | hydroxyl radical cytoplasmic hydroxyl radical mitochondrial hydroxyl radical cellular senescence pulmonary fibrosis inflammation |
| url | https://www.mdpi.com/2076-3921/10/9/1398 |
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