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
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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.

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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。
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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.
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