Journal article
Adeno-Associated Virus-Mediated Dickkopf-1 Gene Transduction Reduces Silica-Induced Oxidative Stress and Silicosis in Mouse Lung
Antioxidants & redox signaling, Vol.42(10-12), pp.529-546
04/01/2025
DOI: 10.1089/ars.2024.0646
PMID: 39531217
Abstract
Aims: Silicosis is a lung disease caused by inhalation of silica particles. Both silica-induced oxidative stress and aberrant activation of the Wnt/β-catenin signaling pathway are potential targets in the treatment of pulmonary fibrosis. Dickkopf-1 (Dkk1), an inhibitor of the Wnt/β-catenin signaling pathway, plays regulatory roles in cell fate determination and immune responses. Our previous study demonstrated that adenoviral vector-mediated Dkk1 gene transfer alleviated the silica-induced mouse silicosis. However, the mechanism of therapeutic action of Dkk1 in silicosis is yet completely understood; together with the drawbacks of adenoviral vectors in gene therapy, we investigated the therapeutic effect and mechanisms of Dkk1 by employing an adeno-associated virus (AAV) vector in a silicosis mouse model.
Results: The AAV vector could efficiently transduce the Dkk1 gene in silicotic lung during both the early and the late phases of disease, resulting in an alleviation of silicotic lesions, improvement of pulmonary compliance, and radiological findings. Mechanistic studies further demonstrated that the transduction of Dkk1 inhibited the silica-activated Wnt/β-catenin signaling and reduced the silica-induced reactive oxygen species-producing enzyme NADPH oxidase 4, oxidative stress regulator nuclear factor erythroid 2-related factor 2, and signaling molecules binding immunoglobulin protein and C/EBP homologous protein. In addition, shRNA-mediated downregulation of Dkk1 exacerbated the progression of silicosis in mice, whereas the treatment of ROS scavenger n-acetylcysteine showed a comparable mitigation of silicosis that was seen in the AAV-Dkk1 treatment.
Innovation and Conclusion: This study provides an insight into the mechanism by which Dkk1 inhibits the silica-induced Wnt signaling and oxidative stress to mitigate the pathogenesis of lung silicosis and evidence of the potential of AAV-mediated Dkk1 gene transfer as an alternative approach in silicosis treatment.
Details
- Title: Subtitle
- Adeno-Associated Virus-Mediated Dickkopf-1 Gene Transduction Reduces Silica-Induced Oxidative Stress and Silicosis in Mouse Lung
- Creators
- Jia Ma - Ningxia UniversityJiaqi Wang - Ningxia Medical UniversityRuiting Sun - First Affiliated Hospital of Guangzhou Medical UniversityZheqing Hu - Ningxia UniversityZhaojun Wang - Ningxia Medical UniversityJing Xue - Ningxia UniversityShuang Wu - Ningxia UniversityWenfeng Hu - Ningxia UniversityJing Wang - Ningxia UniversityLiyuan Yang - Ningxia UniversityQian Cai - Ningxia Medical UniversityJiali Yang - The Fourth People's Hospital of Ningxia Hui Autonomous RegionJuan Chen - Ningxia Medical UniversityXiaoming Liu - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Antioxidants & redox signaling, Vol.42(10-12), pp.529-546
- DOI
- 10.1089/ars.2024.0646
- PMID
- 39531217
- NLM abbreviation
- Antioxid Redox Signal
- ISSN
- 1523-0864
- eISSN
- 1557-7716
- Publisher
- MARY ANN LIEBERT, INC
- Grant note
- National Natural Science Foundation of China: 32260174, 32070863, 81760004, 82360640 Ningxia Key Research and Development Project: 2023BEG02021
This work was financially supported by grants from National Natural Science Foundation of China (nos. 32260174, 32070863, 81760004, and 82360640) and Ningxia Key Research and Development Project (2023BEG02021). The funders had no rolein study design, data collection and analysis, decision to publish,or preparation of the article.
- Language
- English
- Electronic publication date
- 11/12/2024
- Date published
- 04/01/2025
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984748153702771
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