Open Access

NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis

  • Authors:
    • Hong Zhou
    • Qun Zhang
    • Chenyang Liu
    • Jiahao Fan
    • Wen Huang
    • Nan Li
    • Mingxia Yang
    • Hong Wang
    • Weiping Xie
    • Hui Kong
  • View Affiliations

  • Published online on: January 16, 2024     https://doi.org/10.3892/ijmm.2024.5349
  • Article Number: 25
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

NOD-like receptor protein 3 (NLRP3) inflammasome is closely related to silica particle‑induced chronic lung inflammation but its role in epithelial remodeling, repair and regeneration in the distal lung during development of silicosis remains to be elucidated. The present study aimed to determine the effects of the NLRP3 inflammasome on epithelial remodeling and cellular regeneration and potential mechanisms in the distal lung of silica‑treated mice at three time points. Pulmonary function assessment, inflammatory cell counting, enzyme‑linked immunosorbent assay, histological and immunological analyses, hydroxyproline assay and western blotting were used in the study. Single intratracheal instillation of a silica suspension caused sustained NLRP3 inflammasome activation in the distal lung. Moreover, a time‑dependent increase in airway resistance and a decrease in lung compliance accompanied progression of pulmonary fibrosis. In the terminal bronchiole, lung remodeling including pyroptosis (membrane‑distributed GSDMD+), excessive proliferation (Ki67+), mucus overproduction (mucin 5 subtype AC and B) and epithelial‑mesenchymal transition (decreased E‑Cadherin+ and increased Vimentin+), was observed by immunofluorescence analysis. Notably, aberrant spatiotemporal expression of the embryonic lung stem/progenitor cell markers SOX2 and SOX9 and ectopic distribution of bronchioalveolar stem cells were observed in the distal lung only on the 7th day after silica instillation (the early inflammatory phase of silicosis). Western blotting revealed that the Sonic hedgehog/Glioma‑associated oncogene (Shh/Gli) and Wnt/β‑catenin pathways were involved in NLRP3 inflammasome activation‑mediated epithelial remodeling and dysregulated regeneration during the inflammatory and fibrotic phases. Overall, sustained NLRP3 inflammasome activation led to epithelial remodeling in the distal lung of mice. Moreover, understanding the spatiotemporal profile of dysregulated epithelial repair and regeneration may provide a novel therapeutic strategy for inhalable particle‑related chronic inflammatory and fibrotic lung disease.
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March-2024
Volume 53 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Zhou H, Zhang Q, Liu C, Fan J, Huang W, Li N, Yang M, Wang H, Xie W, Kong H, Kong H, et al: NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis. Int J Mol Med 53: 25, 2024
APA
Zhou, H., Zhang, Q., Liu, C., Fan, J., Huang, W., Li, N. ... Kong, H. (2024). NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis. International Journal of Molecular Medicine, 53, 25. https://doi.org/10.3892/ijmm.2024.5349
MLA
Zhou, H., Zhang, Q., Liu, C., Fan, J., Huang, W., Li, N., Yang, M., Wang, H., Xie, W., Kong, H."NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis". International Journal of Molecular Medicine 53.3 (2024): 25.
Chicago
Zhou, H., Zhang, Q., Liu, C., Fan, J., Huang, W., Li, N., Yang, M., Wang, H., Xie, W., Kong, H."NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis". International Journal of Molecular Medicine 53, no. 3 (2024): 25. https://doi.org/10.3892/ijmm.2024.5349