Longitudinal microcomputed tomography detects onset and progression of pulmonary fibrosis in conditional Nedd4-2 deficient mice.

IF 3.6 2区 医学 Q1 PHYSIOLOGY American journal of physiology. Lung cellular and molecular physiology Pub Date : 2024-12-01 Epub Date: 2024-10-22 DOI:10.1152/ajplung.00280.2023
Dominik H W Leitz, Philip Konietzke, Willi L Wagner, Mara Mertiny, Claudia Benke, Thomas Schneider, Rory E Morty, Christian Dullin, Wolfram Stiller, Hans-Ulrich Kauczor, Marcus A Mall, Julia Duerr, Mark O Wielpütz
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional Nedd4-2 deficiency (Nedd4-2-/-) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional Nedd4-2-/- mice by longitudinal micro-computed tomography (CT). In vivo micro-CT was performed longitudinally in control and conditional Nedd4-2-/- mice at 1, 2, 3, 4, and 5 mo after doxycycline induction. Furthermore, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. Histological assessment of lung collagen content was conducted as well. Micro-CT is sensitive to detect the onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional Nedd4-2-/- mice. Nonspecific interstitial alterations were detected from 3 mo, whereas key features such as honeycombing-like lesions were detected from 4 mo onward. Pulmonary function correlated well with in vivo (r = -0.738) and post mortem (r = -0.633) micro-CT fibrosis scores and collagen content. Longitudinal micro-CT enables in vivo monitoring of the onset and progression and detects radiological key features of IPF-like lung disease in conditional Nedd4-2-/- mice. Our data support micro-CT as a sensitive quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.NEW & NOTEWORTHY IPF diagnosis, particularly in early stages, remains challenging. In this study, micro-CT is used in conditional Nedd4-2-/- mice to closely monitor the onset and progression of progressive pulmonary fibrosis in vivo. Together with high-resolution post mortem micro-CT, this allowed us to track how nonspecific lung lesions develop into key IPF-like features. This approach offers a noninvasive method to monitor pulmonary fibrosis, providing a quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.

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纵向显微计算机断层扫描检测条件性 Nedd4-2 基因缺陷小鼠肺纤维化的发生和发展过程
目的:特发性肺纤维化(IPF)是一种致命的肺部疾病,通常在晚期才被诊断出来。人们对 IPF 的亚临床发展知之甚少。我们之前建立了一个条件性 Nedd4-2 缺乏(Nedd4-2-/-)的小鼠模型,该模型会出现类似 IPF 的肺部疾病。本研究的目的是通过纵向显微计算机断层扫描(CT)描述条件性 Nedd4-2-/- 小鼠 IPF 类肺部疾病的发生和发展过程:方法:在多西环素诱导后1、2、3、4和5个月,对对照组和条件性Nedd4-2-/-小鼠进行纵向体内显微计算机断层扫描。此外,还对年龄匹配的小鼠进行了终末体内显微 CT 扫描,随后进行了肺功能测试和死后显微 CT 扫描。使用改良的肺纤维化评分系统对显微 CT 图像进行肺纤维化评估。同时还对肺胶原含量进行了组织学评估:结果:Micro-CT能灵敏地检测体内肺纤维化的发生和进展,并能量化条件性Nedd4-2-/-小鼠疾病发展过程中明显的放射性IPF样特征。从3个月开始检测到非特异性间质改变,而从4个月开始检测到蜂窝状病变等关键特征。肺功能与体内(r=-0.738)和死后(r=-0.633)显微 CT 纤维化评分和胶原含量密切相关:纵向显微 CT 能够在体内监测发病和进展情况,并检测条件性 Nedd4-2-/- 小鼠中 IPF 类肺病的放射学关键特征。我们的数据支持将显微 CT 作为新型抗纤维化策略临床前评估的敏感定量终点。
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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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