Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-30 DOI:10.1186/s12931-024-03006-7
Davide Buseghin, Andrea Grandi, Erica Ferrini, Gino Villetti, Roberta Ciccimarra, Nicola Sverzellati, Andrea Aliverti, Francesca Pennati, Franco Fabio Stellari
{"title":"Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice.","authors":"Davide Buseghin, Andrea Grandi, Erica Ferrini, Gino Villetti, Roberta Ciccimarra, Nicola Sverzellati, Andrea Aliverti, Francesca Pennati, Franco Fabio Stellari","doi":"10.1186/s12931-024-03006-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.</p><p><strong>Methods: </strong>A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.</p><p><strong>Results: </strong>Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.</p><p><strong>Conclusions: </strong>Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526612/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Respiratory Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12931-024-03006-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.

Methods: A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.

Results: Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.

Conclusions: Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
定量微计算机断层扫描生物标志物阐明了老年小鼠与年龄相关的肺纤维化。
背景:特发性肺纤维化(IPF)主要影响 60 岁以上的人群,目前主要通过年轻的小鼠模型进行研究。目前的治疗方法疗效有限,因此需要能更好地模拟老年患者群体的动物模型。为此,我们通过诱导老年小鼠肺纤维化,以纵向显微 CT 成像为主要读数,并特别关注动物福利:方法:给 18-24 个月大的雄性 C57Bl/6j 小鼠注射双倍博莱霉素,诱导肺纤维化。与幼鼠(8-12周大)的常用剂量相比,博莱霉素剂量降低至75%,从而使小鼠长期肺纤维化而不死亡,符合动物福利准则。诱导肺纤维化后,动物连续两周每天一次服用宁替达尼,并通过显微CT进行纵向监测,提供结构和功能生物标志物,然后进行死后组织学分析作为终点:结果:与年轻小鼠相比,老年小鼠的体积增大,组织密度和功能降低,炎症明显。这种脆弱性的增加迫使博莱霉素剂量减少到最低测试水平(2.5微克/只小鼠),从而诱发了较轻微但持续的纤维化,同时保护了动物福利。宁替达尼治疗可减少纤维化病变并改善肺功能:我们的数据确定了一种缩小博莱霉素剂量的治疗方法,它能在纤维化诱导和动物福利之间实现最佳权衡,而这正是在老年肺中进行抗纤维化药物试验的要求。在这种低严重程度的疾病模型中,Nintedanib显示出了显著的疗效,提示了潜在的患者分层策略。通过显微CT对肺部病理进行了定量评估,显示了临床试验中纵向终点的价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
期刊最新文献
Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats. Loss of interferon regulatory factor-1 prevents lung fibrosis by upregulation of pon1 expression. Patient-centered care in pulmonary fibrosis: access, anticipate, and act. Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3. Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice.
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1