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

Respiratory Research, Journal Year: 2024, Volume and Issue: 25(1)

Published: Oct. 30, 2024

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

Language: Английский

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Transcriptomic and proteomic profiling of young and old mice in the bleomycin model reveals high similarity

AJP Lung Cellular and Molecular Physiology, Journal Year: 2023, Volume and Issue: 324(3), P. L245 - L258

Published: Jan. 10, 2023

The most common preclinical, in vivo model to study lung fibrosis is the bleomycin-induced 2- 3-mo-old mice. Although this resembles key aspects of idiopathic pulmonary (IPF), there are limitations its predictability for human disease. One main differences juvenile age animals that commonly used experiments, resembling humans around 20 yr. Because IPF patients usually older than 60 yr, aging appears play an important role pathogenesis fibrosis. Therefore, we compared young (3 months) and old mice (21 21 days after intratracheal bleomycin instillation. Analyzing transcriptomics (mRNAs miRNAs) proteomics, found pathways be similarly regulated However, show imbalanced protein homeostasis as well increased inflammatory state fibrotic phase Comparisons with published transcriptomic data sets (GSE47460, GSE32537, GSE24206) revealed gene signature correlates significantly better patients, it also turned healthy individuals into "IPF patients" using approach based on predictive disease modeling. Both similar molecular hallmarks model, although more closely resemble several features associated comparison animals.

Language: Английский

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The Therapeutic Mechanism of Schisandrol A and Its Metabolites on Pulmonary Fibrosis Based on Plasma Metabonomics and Network Analysis

Drug Design Development and Therapy, Journal Year: 2023, Volume and Issue: Volume 17, P. 477 - 496

Published: Feb. 1, 2023

Background: Schisandrol A (Sch A) is the main active ingredient of Schisandra chinensis (Turcz.) Baill. Our previous study showed that Sch has anti-pulmonary fibrosis (PF) activity, but its metabolic-related mechanisms action are not clear. Methods: Here, we explored therapeutic on PF by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) metabolomics approach and network analysis. The metabolites in mice (bleomycin + high-dose group) plasma were identified based chromatography-quadrupole time-of-flight (UPLC-Q-TOF/MS). Results: 32 detected reversed to normal level after treating bleomycin (BLM)-induced A. biomarkers enriched energy metabolism several amino acid metabolisms, which was first report effects through rescuing disordered metabolism. UPLC-Q-TOF/MS analysis 17 possible (including isomers) plasma. Network revealed related 269 genes, 1109 disease genes PF. construction A/metabolites-target-PF a total 79 intersection TGF-β signaling pathway determined be treatment integrated involving 1-ID3-creatine pathway, 1-VIM-carnosine two pathways regulated modulate metabolic disorders, especially metabolism, metabolite M5 as most likely metabolite. Conclusion: results suggested feasibility combining reflect biological state evaluate drug efficacy mechanisms. Graphical Abstract: Keywords: schisandrol A, pulmonary fibrosis, mechanism action, analysis, metabonomics

Language: Английский

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Plasma metabolomics and quantitative interstitial abnormalities in ever-smokers

Respiratory Research, Journal Year: 2023, Volume and Issue: 24(1)

Published: Nov. 4, 2023

Abstract Background Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations QIA not well known. We sought to identify plasma metabolites in smokers. also shared differentiating metabolomics features between emphysema, another smoking-related advanced radiographic abnormality. Methods In 928 former current smokers the Genetic Epidemiology COPD cohort, we measured emphysema using local density histogram method generated metabolite profiles from samples liquid chromatography–mass spectrometry (Metabolon). assessed associations levels multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, inhaled corticosteroid use, at a Benjamini–Hochberg False Discovery Rate p-value ≤ 0.05. Using multinomial these covariates, following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, neither- predominant. Pathway enrichment analyses were performed MetaboAnalyst. Results found 85 significantly QIA, overrepresentation nicotinate nicotinamide, histidine, starch sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, sphingomyelin pathways. These included involved inflammation immune response, extracellular matrix remodeling, surfactant, muscle cachexia. There 75 different QIA-predominant emphysema-predominant phenotypes, phosphatidylethanolamine, aminoacyl-tRNA, arginine, proline, alanine, aspartate, glutamate Conclusions Metabolomic correlates may lend insight biologic pathways that underlie clinically meaningful quantitative measurements like

Language: Английский

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Lineage-tracing ofActa2+ cells in aged mice during lung fibrosis formation and resolution supports the lipofibroblast to myofibroblast reversible switch

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 22, 2024

Abstract Idiopathic pulmonary fibrosis (IPF) develops mostly in old man and is characterized by the irreversible accumulation of excessive extracellular matrix components activated myofibroblasts (aMYFs) leading to lung failure. Following bleomycin administration young mice, formation associated with efficient resolution takes place, later limiting clinical relevance this model for IPF. In we previously reported that aMYFs captured during differentiate towards a lipofibroblast (LIF)-like phenotype resolution. study, used aged mice combination trigger enhanced delayed resolution, as more relevant IPF examined heterogeneity fate at different time points. Alveolosphere assay were carried out compare alveolar resident mesenchymal niche activity AT2 stem cells versus mice. Lineage tracing Acta2+ exposed followed scRNAseq lineage-traced isolated was performed delineate their Data mining human from control datasets also decipher investigate differentiation trajectories formation. Our results show display decreased supporting cells. We report consist four subclusters displaying unique pro-alveologenic pro-fibrotic profiles. Alveolar fibroblasts high LIF-like signature largely constitute both origin respectively. The conserved humans significant proportion displays LIF signature. conclusion, our data indicate cellular molecular bases are between Importantly, work identifies subcluster potentially future management

Language: Английский

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