Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication
Background: Silicosis is a chronic fibrotic pulmonary disease caused by consistent inhalation of respirable crystalline-free silica dust. The senescence of alveolar epithelial type II cells (ATII) is considered the initiation of pulmonary fibrosis. As a secreted protein, growth differentiation facto...
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Elsevier
2025-03-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325002532 |
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| author | Wenxiu Lian Demin Cheng Wenqing Sun Ting Wang Xinying Jia Zhenhua Jia Yi Liu Chunhui Ni |
| author_facet | Wenxiu Lian Demin Cheng Wenqing Sun Ting Wang Xinying Jia Zhenhua Jia Yi Liu Chunhui Ni |
| author_sort | Wenxiu Lian |
| collection | DOAJ |
| description | Background: Silicosis is a chronic fibrotic pulmonary disease caused by consistent inhalation of respirable crystalline-free silica dust. The senescence of alveolar epithelial type II cells (ATII) is considered the initiation of pulmonary fibrosis. As a secreted protein, growth differentiation factor 15 (GDF15) was found intimately associated with the severity of lung diseases via senescence. Therefore, we speculate that GDF15 may involved in silica-induced pulmonary fibrosis. Methods: Co-culture was performed to observe the pro-fibrotic effect of GDF15, which is secreted from the silica-induced senescence ATII cells, on peripheral effector cells. We further explored GDF15-related signaling pathways via ChIP and IP assays. GDF15 siRNA lipid nanoparticles, anti-aging compound β-nicotinamide mononucleotide (NMN), and the Chinese traditional drug Bazibushen (BZBS) were used individually to intervene silicosis progress. Results: SiO2 and etoposide-stimulated MLE-12 cells showed senescence phenotype and secreted substantial GDF15, which is consistent with over-expressed GDF15 in lung tissues from silica-induced pulmonary fibrosis. The results further demonstrated that senescence ATII cells could facilitate co-cultured epithelial cell epithelial-mesenchymal transition (EMT) and fibroblast activation in a GDF15-dependent manner. Mechanistically, p53 regulates GDF15 transcription and secretion in senescence ATII cells. Moreover, secreted GFD15 performed its pro-fibrotic role by directly binding to TGF-βR via autocrine and paracrine manners. Also, lipid nanoparticles targeting GDF15 or cell senescence inhibitor NMN and BZBS showed efficient anti-fibrotic effects in vivo. Conclusions: Our results elucidate that senescence ATII cell-secreted GDF15 plays a vital role in promoting silicosis by influencing surrounding cells, and provides scientific clues for the selection of potential therapeutic drugs for silicosis. |
| format | Article |
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| institution | OA Journals |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-0ced8c29ff3848beb36f7a58b9d9cfb12025-08-20T02:06:19ZengElsevierEcotoxicology and Environmental Safety0147-65132025-03-0129211791710.1016/j.ecoenv.2025.117917Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communicationWenxiu Lian0Demin Cheng1Wenqing Sun2Ting Wang3Xinying Jia4Zhenhua Jia5Yi Liu6Chunhui Ni7Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019, ChinaThe Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing medical university, Wuxi, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, ChinaDepartment of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, ChinaHebei Yiling Hospital, High-level TCM Key Disciplines of National Administration of Traditional Chinese Medicine—Luobing Theory, Shijiazhuang, Hebei 050091, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang, Hebei 050035, China; Corresponding author at: Hebei Yiling Hospital, High-level TCM Key Disciplines of National Administration of Traditional Chinese Medicine—Luobing Theory, Shijiazhuang, Hebei 050091, China.Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Corresponding author.Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of Public Health, Kangda College of Nanjing Medical University, Lianyungang 320700, China; Corresponding author at: Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.Background: Silicosis is a chronic fibrotic pulmonary disease caused by consistent inhalation of respirable crystalline-free silica dust. The senescence of alveolar epithelial type II cells (ATII) is considered the initiation of pulmonary fibrosis. As a secreted protein, growth differentiation factor 15 (GDF15) was found intimately associated with the severity of lung diseases via senescence. Therefore, we speculate that GDF15 may involved in silica-induced pulmonary fibrosis. Methods: Co-culture was performed to observe the pro-fibrotic effect of GDF15, which is secreted from the silica-induced senescence ATII cells, on peripheral effector cells. We further explored GDF15-related signaling pathways via ChIP and IP assays. GDF15 siRNA lipid nanoparticles, anti-aging compound β-nicotinamide mononucleotide (NMN), and the Chinese traditional drug Bazibushen (BZBS) were used individually to intervene silicosis progress. Results: SiO2 and etoposide-stimulated MLE-12 cells showed senescence phenotype and secreted substantial GDF15, which is consistent with over-expressed GDF15 in lung tissues from silica-induced pulmonary fibrosis. The results further demonstrated that senescence ATII cells could facilitate co-cultured epithelial cell epithelial-mesenchymal transition (EMT) and fibroblast activation in a GDF15-dependent manner. Mechanistically, p53 regulates GDF15 transcription and secretion in senescence ATII cells. Moreover, secreted GFD15 performed its pro-fibrotic role by directly binding to TGF-βR via autocrine and paracrine manners. Also, lipid nanoparticles targeting GDF15 or cell senescence inhibitor NMN and BZBS showed efficient anti-fibrotic effects in vivo. Conclusions: Our results elucidate that senescence ATII cell-secreted GDF15 plays a vital role in promoting silicosis by influencing surrounding cells, and provides scientific clues for the selection of potential therapeutic drugs for silicosis.http://www.sciencedirect.com/science/article/pii/S0147651325002532silicosisATII cellsenescenceGDF15cellular microenvironment |
| spellingShingle | Wenxiu Lian Demin Cheng Wenqing Sun Ting Wang Xinying Jia Zhenhua Jia Yi Liu Chunhui Ni Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication Ecotoxicology and Environmental Safety silicosis ATII cell senescence GDF15 cellular microenvironment |
| title | Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication |
| title_full | Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication |
| title_fullStr | Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication |
| title_full_unstemmed | Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication |
| title_short | Senescent alveolar type II epithelial cells-secreted GDF15 promotes silicosis progression via interfering intercellular communication |
| title_sort | senescent alveolar type ii epithelial cells secreted gdf15 promotes silicosis progression via interfering intercellular communication |
| topic | silicosis ATII cell senescence GDF15 cellular microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325002532 |
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