Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy
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BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy
- Date Crossref
- 31/05/2024
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Zhengzhou University Department of Geriatric Medicine pays non établi dans la noticeUniversité ou école supérieure
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Henan Provincial People's Hospital pays non établi dans la noticeÉtablissement de santé
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First Affiliated Hospital of Zhengzhou University pays non établi dans la noticeÉtablissement de santé
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Army Medical University Department of Respiratory and Critical Care Medicine pays non établi dans la noticeUniversité ou école supérieure
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Dalian Medical University pays non établi dans la noticeUniversité ou école supérieure
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Second Affiliated Hospital of Chongqing Medical University pays non établi dans la noticeÉtablissement de santé
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Chongqing Medical University pays non établi dans la noticeUniversité ou école supérieure
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Henan University of Traditional Chinese Medicine pays non établi dans la noticeUniversité ou école supérieure
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Zhengzhou Shuqing Medical College Department of Traditional Chinese Medicine pays non établi dans la noticeUniversité ou école supérieure
Department of Geriatric Medicine — Zhengzhou University, Henan Provincial People's Hospital et First Affiliated Hospital of Zhengzhou University, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.