NLRP3炎性体介导二氧化硅诱导的肺纤维化过程中上皮异常再生和远端肺重塑。

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
International journal of molecular medicine Pub Date : 2024-03-01 Epub Date: 2024-01-19 DOI:10.3892/ijmm.2024.5349
Hong Zhou, Qun Zhang, Chenyang Liu, Jiahao Fan, Wen Huang, Nan Li, Mingxia Yang, Hong Wang, Weiping Xie, Hui Kong
{"title":"NLRP3炎性体介导二氧化硅诱导的肺纤维化过程中上皮异常再生和远端肺重塑。","authors":"Hong Zhou, Qun Zhang, Chenyang Liu, Jiahao Fan, Wen Huang, Nan Li, Mingxia Yang, Hong Wang, Weiping Xie, Hui Kong","doi":"10.3892/ijmm.2024.5349","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>+</sup>), excessive proliferation (Ki67<sup>+</sup>), mucus overproduction (mucin 5 subtype AC and B) and epithelial‑mesenchymal transition (decreased E‑Cadherin<sup>+</sup> and increased Vimentin<sup>+</sup>), 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.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":null,"pages":null},"PeriodicalIF":5.7000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10836498/pdf/","citationCount":"0","resultStr":"{\"title\":\"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\",\"doi\":\"10.3892/ijmm.2024.5349\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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<sup>+</sup>), excessive proliferation (Ki67<sup>+</sup>), mucus overproduction (mucin 5 subtype AC and B) and epithelial‑mesenchymal transition (decreased E‑Cadherin<sup>+</sup> and increased Vimentin<sup>+</sup>), 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.</p>\",\"PeriodicalId\":14086,\"journal\":{\"name\":\"International journal of molecular medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10836498/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International journal of molecular medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3892/ijmm.2024.5349\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International journal of molecular medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3892/ijmm.2024.5349","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

摘要

NOD样受体蛋白3(NLRP3)炎性体与二氧化硅颗粒诱导的慢性肺部炎症密切相关,但它在矽肺发展过程中远端肺上皮重塑、修复和再生中的作用仍有待阐明。本研究旨在确定 NLRP3 炎性体在三个时间点对二氧化硅处理小鼠远端肺上皮重塑和细胞再生的影响及潜在机制。研究采用了肺功能评估、炎性细胞计数、酶联免疫吸附试验、组织学和免疫学分析、羟脯氨酸测定和 Western 印迹等方法。气管内单次灌入二氧化硅悬浮液可导致远端肺部 NLRP3 炎症小体持续活化。此外,气道阻力的增加和肺顺应性的降低与肺纤维化的进展呈时间依赖性。在终末支气管中,通过免疫荧光分析观察到肺部重塑,包括热变态反应(膜分布的 GSDMD+)、过度增殖(Ki67+)、粘液过度分泌(粘蛋白 5 亚型 AC 和 B)和上皮-间质转化(E-Cadherin+ 减少,Vimentin+ 增加)。值得注意的是,仅在二氧化硅灌入后第7天(矽肺早期炎症阶段),远端肺部才观察到胚胎肺干/祖细胞标志物SOX2和SOX9的时空异常表达以及支气管肺泡干细胞的异位分布。Western blotting显示,在炎症期和纤维化期,Sonic hedgehog/Glioma-associated oncogene (Shh/Gli) 和Wnt/β-catenin通路参与了NLRP3炎性体激活介导的上皮重塑和再生失调。总体而言,NLRP3炎性体的持续激活导致了小鼠远端肺上皮重塑。此外,了解上皮修复和再生失调的时空概况可能会为与可吸入颗粒相关的慢性炎症和纤维化肺病提供一种新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis.

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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
International journal of molecular medicine
International journal of molecular medicine 医学-医学:研究与实验
CiteScore
12.30
自引率
0.00%
发文量
124
审稿时长
3 months
期刊介绍: The main aim of Spandidos Publications is to facilitate scientific communication in a clear, concise and objective manner, while striving to provide prompt publication of original works of high quality. The journals largely concentrate on molecular and experimental medicine, oncology, clinical and experimental cancer treatment and biomedical research. All journals published by Spandidos Publications Ltd. maintain the highest standards of quality, and the members of their Editorial Boards are world-renowned scientists.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信