Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milano, Italy.
ANTHEM (AdvaNced Technologies for Human-centrEd Medicine), Spoke 3, Milan, Italy.
Respir Res. 2024 Oct 30;25(1):393. doi: 10.1186/s12931-024-03006-7.
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.
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.
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.
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.
特发性肺纤维化（IPF）主要影响 60 岁以上的个体，主要在年轻的小鼠模型中进行研究。目前治疗方法的疗效有限，突出表明需要更好地模拟老年患者人群的动物模型。我们通过在老年小鼠中诱导肺纤维化来解决这个问题，使用纵向微 CT 成像作为主要读数，并特别关注动物福利。
对 18-24 个月大的雄性 C57Bl/6j 小鼠给予双博来霉素剂量以诱导肺纤维化。与通常给予年轻（8-12 周龄）小鼠的剂量相比，博来霉素剂量减少了低至 75%，从而在不导致死亡率的情况下实现了长期肺纤维化，符合动物福利指南。纤维化诱导后，动物每天接受一次尼达尼布治疗两周，并通过微 CT 进行纵向监测，提供结构和功能生物标志物，然后作为终末终点进行死后组织学分析。
与年轻小鼠相比，老年动物显示出体积增加、组织密度和功能降低以及明显的炎症。这种增加的脆弱性将博来霉素剂量降低到测试的最低水平（2.5µg/只），诱导出更温和但持续的纤维化，同时保持动物福利。尼达尼布治疗减少了纤维化病变并改善了肺功能。
我们的数据确定了一种缩小的博来霉素治疗方法，该方法在纤维化诱导和动物福利之间实现了最佳平衡，这是老年肺部抗纤维化药物测试的要求。尼达尼布在这种较低严重程度的疾病模型中显示出显著疗效，表明可能存在患者分层策略。肺部病理学通过微 CT 进行定量评估，指出纵向终点在临床试验中的价值。
