Mouse Models of Lung Fibrosis

Preclinical MRI to Quantify Pulmonary Disease Severity and Trajectories in Poorly Characterized Mouse Models: A Pedagogical Example Using Data from Novel Transgenic Models of Lung Fibrosis

Journal of Magnetic Resonance Open ◽

10.1016/j.jmro.2021.100013 ◽

2021 ◽

pp. 100013

Author(s):

Ian R. Stecker ◽

Matthew S. Freeman ◽

Sneha Sitaraman ◽

Chase S. Hall ◽

Peter J. Niedbalski ◽

...

Keyword(s):

Pulmonary Disease ◽

Disease Severity ◽

Mouse Models ◽

Lung Fibrosis ◽

Transgenic Models ◽

Preclinical Mri ◽

Using Data

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Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis

10.1101/2020.03.04.960179 ◽

2020 ◽

Author(s):

Steven L. Brody ◽

Sean P. Gunsten ◽

Hannah P. Luehmann ◽

Debbie H. Sultan ◽

Michelle Hoelscher ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Disease ◽

Mouse Models ◽

Chemokine Receptor ◽

Pet Imaging ◽

Lung Fibrosis ◽

Ex Vivo ◽

Inflammatory Monocytes ◽

Fibrotic Process ◽

Fibrotic Lung Disease

AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive, inflammatory lung disease that is monitored clinically by measures of lung function, without effective molecular markers of disease activity or therapeutic efficacy. Lung immune cells active in the pro-fibrotic process include inflammatory monocyte and interstitial macrophages that express the C-C motif chemokine receptor 2 (CCR2). CCR2+ monocyte lung influx is essential for disease phenotypes in models of fibrosis and identified in lungs from subjects with IPF. Here, we show that our peptide-based radiotracer 64Cu-DOTA-ECL1i identifies CCR2+ inflammatory monocytes and interstitial macrophages in multiple preclinical mouse models of lung fibrosis, using positron emission tomography (PET) imaging. Mice with bleomycin-induced fibrosis treated with blocking antibodies to interleukin-1β, a mediator of fibrosis associated with CCR2+ cell inflammation, or with pirfenidone, an approved anti-fibrotic agent, demonstrated decreased CCR2-dependent interstitial macrophage accumulation and reduced 64Cu-DOTA-ECL1i PET uptake, compared to controls. Lung tissues from patients with fibrotic lung disease demonstrated abundant CCR2+ cells surrounding regions of fibrosis, and an ex vivo tissue-binding assay showed correlation between radiotracer localization and CCR2+ cells. In a phase 0/1 clinical study of 64Cu-DOTA-ECL1i PET, healthy volunteers showed little lung uptake, while subjects with pulmonary fibrosis exhibited increased uptake, notably in zones of subpleural fibrosis, reflecting the distribution of CCR2+ cells in the profibrotic niche. These findings support a pathologic role of inflammatory lung monocytes/macrophages in fibrotic lung disease and the translational use of 64Cu-DOTA-ECL1i PET to track CCR2-specific inflammation for image-guided therapy.One Sentence SummaryPET imaging of CCR2+ cells in lung fibrosis identifies a therapeutic response in mouse models and displays a perifibrotic signal in subjects with IPF.

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Use of human amniotic epithelial cells in mouse models of bleomycin-induced lung fibrosis: A systematic review and meta-analysis

PLoS ONE ◽

10.1371/journal.pone.0197658 ◽

2018 ◽

Vol 13 (5) ◽

pp. e0197658 ◽

Cited By ~ 6

Author(s):

Fang He ◽

Aiting Zhou ◽

Shuo Feng

Keyword(s):

Systematic Review ◽

Epithelial Cells ◽

Mouse Models ◽

Lung Fibrosis ◽

Meta Analysis ◽

Amniotic Epithelial Cells ◽

Human Amniotic Epithelial Cells

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Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-210821 ◽

2017 ◽

Vol 76 (11) ◽

pp. 1931-1940 ◽

Cited By ~ 32

Author(s):

Jerome Avouac ◽

Irena Konstantinova ◽

Christophe Guignabert ◽

Sonia Pezet ◽

Jeremy Sadoine ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Fibrosis ◽

Mouse Model ◽

Transgenic Mice ◽

Mouse Models ◽

Lung Fibrosis ◽

Lung Fibroblasts ◽

Dependent Manner ◽

Vascular Remodelling ◽

Ppar Agonist

ObjectiveTo evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH).MethodsIVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks.ResultsIVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF.ConclusionWe demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements.

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