Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling
Abstract Background Acute lung injury (ALI) caused by intestinal ischemia–reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor that participates in the initiation of the inflammatory response. This study aims to establish whether C-176 (STING inhi...
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | European Journal of Medical Research |
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| Online Access: | https://doi.org/10.1186/s40001-022-00703-1 |
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| author | Mei Yang Yu-Xia Ma Ying Zhi Hai-Bin Wang Li Zhao Peng-Sheng Wang Jie-Ting Niu |
| author_facet | Mei Yang Yu-Xia Ma Ying Zhi Hai-Bin Wang Li Zhao Peng-Sheng Wang Jie-Ting Niu |
| author_sort | Mei Yang |
| collection | DOAJ |
| description | Abstract Background Acute lung injury (ALI) caused by intestinal ischemia–reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor that participates in the initiation of the inflammatory response. This study aims to establish whether C-176 (STING inhibitor) improves ALI under intestinal ischemia–reperfusion conditions. Methods To induce ALI, 72 male C57BL/6 mice were subjected to intestinal ischemia for 60 min and reperfusion for 3 h. Through intraperitoneal injection, C-176, a selective STING inhibitor, was injected 30 min before surgical treatment; meanwhile, compound C, an antagonist of adenosine monophosphate-activated protein kinase (AMPK), was administered 30 min after surgery. Based on immunofluorescence and Western blot assays, post-ALI assessments included lung water content (TLW), bronchoalveolar lavage fluid (BALF) protein, H&E staining, Masson staining, pulmonary pyroptosis [Gasdermin-D (GSDMD), cleaved caspase-1], and apoptosis (TUNEL, cleaved caspase-3). Results C-176 administration significantly attenuated intestinal ischemia–reperfusion-mediated ALI; this effect was reflected by exacerbated TLW and BALF protein, aggravated lung injury score, elevated degree of pulmonary fibrosis, increased TUNEL- and GSDMD-positive cells, and upregulated phospho-AMPK, cleaved caspase-1, cleaved caspase-3 and IFNβ mRNA expression. Moreover, C-176 increased phospho-AMPK under ALI conditions. Nonetheless, compound C partially reversed these beneficial effects. Conclusion C-176, a selective STING inhibitor, improves intestinal ischemia–reperfusion-mediated ALI, and its underlying mechanism may be associated with AMPK signal activation. |
| first_indexed | 2024-12-12T03:16:07Z |
| format | Article |
| id | doaj.art-e871bbf8ed064b4e86e09415742dc658 |
| institution | Directory Open Access Journal |
| issn | 2047-783X |
| language | English |
| last_indexed | 2024-12-12T03:16:07Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj.art-e871bbf8ed064b4e86e09415742dc6582022-12-22T00:40:17ZengBMCEuropean Journal of Medical Research2047-783X2022-05-0127111110.1186/s40001-022-00703-1Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signalingMei Yang0Yu-Xia Ma1Ying Zhi2Hai-Bin Wang3Li Zhao4Peng-Sheng Wang5Jie-Ting Niu6Department of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityDepartment of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityDepartment of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityDepartment of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityDepartment of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityDepartment of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityDepartment of Gerontology, Cangzhou Central Hospital, Hebei Medical UniversityAbstract Background Acute lung injury (ALI) caused by intestinal ischemia–reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor that participates in the initiation of the inflammatory response. This study aims to establish whether C-176 (STING inhibitor) improves ALI under intestinal ischemia–reperfusion conditions. Methods To induce ALI, 72 male C57BL/6 mice were subjected to intestinal ischemia for 60 min and reperfusion for 3 h. Through intraperitoneal injection, C-176, a selective STING inhibitor, was injected 30 min before surgical treatment; meanwhile, compound C, an antagonist of adenosine monophosphate-activated protein kinase (AMPK), was administered 30 min after surgery. Based on immunofluorescence and Western blot assays, post-ALI assessments included lung water content (TLW), bronchoalveolar lavage fluid (BALF) protein, H&E staining, Masson staining, pulmonary pyroptosis [Gasdermin-D (GSDMD), cleaved caspase-1], and apoptosis (TUNEL, cleaved caspase-3). Results C-176 administration significantly attenuated intestinal ischemia–reperfusion-mediated ALI; this effect was reflected by exacerbated TLW and BALF protein, aggravated lung injury score, elevated degree of pulmonary fibrosis, increased TUNEL- and GSDMD-positive cells, and upregulated phospho-AMPK, cleaved caspase-1, cleaved caspase-3 and IFNβ mRNA expression. Moreover, C-176 increased phospho-AMPK under ALI conditions. Nonetheless, compound C partially reversed these beneficial effects. Conclusion C-176, a selective STING inhibitor, improves intestinal ischemia–reperfusion-mediated ALI, and its underlying mechanism may be associated with AMPK signal activation.https://doi.org/10.1186/s40001-022-00703-1Acute lung injuryIntestinal ischemia–reperfusionSTINGAMPKInflammation |
| spellingShingle | Mei Yang Yu-Xia Ma Ying Zhi Hai-Bin Wang Li Zhao Peng-Sheng Wang Jie-Ting Niu Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling European Journal of Medical Research Acute lung injury Intestinal ischemia–reperfusion STING AMPK Inflammation |
| title | Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling |
| title_full | Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling |
| title_fullStr | Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling |
| title_full_unstemmed | Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling |
| title_short | Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling |
| title_sort | inhibitors of ifn gene stimulators sting improve intestinal ischemia reperfusion induced acute lung injury by activating ampk signaling |
| topic | Acute lung injury Intestinal ischemia–reperfusion STING AMPK Inflammation |
| url | https://doi.org/10.1186/s40001-022-00703-1 |
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