Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury
(1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/5/728 |
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| author | Sisi Wang Xue Li Qingwen Ma Qi Wang Junping Wu Hongzhi Yu Kuan Li Yu Li Jianhai Wang Qiuyang Zhang Youwei Wang Qi Wu Huaiyong Chen |
| author_facet | Sisi Wang Xue Li Qingwen Ma Qi Wang Junping Wu Hongzhi Yu Kuan Li Yu Li Jianhai Wang Qiuyang Zhang Youwei Wang Qi Wu Huaiyong Chen |
| author_sort | Sisi Wang |
| collection | DOAJ |
| description | (1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine metabolism in the maintenance of the alveolar epithelium remains unclear. In this study, we investigated the role of glutamine metabolism in AT2 cells of patients with IPF and in mice with bleomycin-induced fibrosis. (2) Methods: Single-cell RNA sequencing (scRNA-seq), transcriptome, and metabolomics analyses were conducted to investigate the changes in the glutamine metabolic pathway during pulmonary fibrosis. Metabolic inhibitors were used to stimulate AT2 cells to block glutamine metabolism. Regeneration of AT2 cells was detected using bleomycin-induced mouse lung fibrosis and organoid models. (3) Results: Single-cell analysis showed that the expression levels of catalytic enzymes responsible for glutamine catabolism were downregulated (<i>p</i> < 0.001) in AT2 cells of patients with IPF, suggesting the accumulation of unusable glutamine. Combined analysis of the transcriptome (<i>p</i> < 0.05) and metabolome (<i>p</i> < 0.001) revealed similar changes in glutamine metabolism in bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inhibition of the key enzymes involved in glucose metabolism, glutaminase-1 (GLS1) and glutamic-pyruvate transaminase-2 (GPT2) leads to reduced proliferation (<i>p</i> < 0.01) and differentiation (<i>p</i> < 0.01) of AT2 cells. (4) Conclusions: Glutamine metabolism is required for alveolar epithelial regeneration during lung injury. |
| first_indexed | 2024-03-10T03:15:30Z |
| format | Article |
| id | doaj.art-5a08ec64fd614eba96f7c08b9ceb0b02 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T03:15:30Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-5a08ec64fd614eba96f7c08b9ceb0b022023-11-23T10:14:44ZengMDPI AGBiomolecules2218-273X2022-05-0112572810.3390/biom12050728Glutamine Metabolism Is Required for Alveolar Regeneration during Lung InjurySisi Wang0Xue Li1Qingwen Ma2Qi Wang3Junping Wu4Hongzhi Yu5Kuan Li6Yu Li7Jianhai Wang8Qiuyang Zhang9Youwei Wang10Qi Wu11Huaiyong Chen12Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Tuberculosis, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Tuberculosis, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin 300350, ChinaAcademy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, ChinaKey Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin 300350, ChinaDepartment of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin 300350, China(1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine metabolism in the maintenance of the alveolar epithelium remains unclear. In this study, we investigated the role of glutamine metabolism in AT2 cells of patients with IPF and in mice with bleomycin-induced fibrosis. (2) Methods: Single-cell RNA sequencing (scRNA-seq), transcriptome, and metabolomics analyses were conducted to investigate the changes in the glutamine metabolic pathway during pulmonary fibrosis. Metabolic inhibitors were used to stimulate AT2 cells to block glutamine metabolism. Regeneration of AT2 cells was detected using bleomycin-induced mouse lung fibrosis and organoid models. (3) Results: Single-cell analysis showed that the expression levels of catalytic enzymes responsible for glutamine catabolism were downregulated (<i>p</i> < 0.001) in AT2 cells of patients with IPF, suggesting the accumulation of unusable glutamine. Combined analysis of the transcriptome (<i>p</i> < 0.05) and metabolome (<i>p</i> < 0.001) revealed similar changes in glutamine metabolism in bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inhibition of the key enzymes involved in glucose metabolism, glutaminase-1 (GLS1) and glutamic-pyruvate transaminase-2 (GPT2) leads to reduced proliferation (<i>p</i> < 0.01) and differentiation (<i>p</i> < 0.01) of AT2 cells. (4) Conclusions: Glutamine metabolism is required for alveolar epithelial regeneration during lung injury.https://www.mdpi.com/2218-273X/12/5/728glutamine metabolismidiopathic pulmonary fibrosisalveolar progenitor cellslung regenerationomics |
| spellingShingle | Sisi Wang Xue Li Qingwen Ma Qi Wang Junping Wu Hongzhi Yu Kuan Li Yu Li Jianhai Wang Qiuyang Zhang Youwei Wang Qi Wu Huaiyong Chen Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury Biomolecules glutamine metabolism idiopathic pulmonary fibrosis alveolar progenitor cells lung regeneration omics |
| title | Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury |
| title_full | Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury |
| title_fullStr | Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury |
| title_full_unstemmed | Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury |
| title_short | Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury |
| title_sort | glutamine metabolism is required for alveolar regeneration during lung injury |
| topic | glutamine metabolism idiopathic pulmonary fibrosis alveolar progenitor cells lung regeneration omics |
| url | https://www.mdpi.com/2218-273X/12/5/728 |
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