Dysregulation of metabolic pathways in pulmonary fibrosis

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 246, P. 108436 - 108436

Published: May 5, 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of unknown origin and the most common interstitial lung disease. It progresses with recruitment fibroblasts myofibroblasts that contribute to accumulation extracellular matrix (ECM) proteins, leading loss compliance alveolar integrity, compromising gas exchange capacity lung. Moreover, while there are therapeutics available, they do not offer cure. Thus, pressing need identify better therapeutic targets. With advent transcriptomics, proteomics, metabolomics, cellular mechanisms underlying disease progression understood. Metabolic homeostasis one such factor its dysregulation has been shown impact outcome IPF. Several metabolic pathways involved in metabolism lipids, protein carbohydrates have implicated While metabolites crucial for generation energy, it now appreciated several non-metabolic roles regulating processes as proliferation, signaling, death among other functions. Through this review, we succinctly elucidate role also discuss potential which target or pathways.

Language: Английский

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Nanoengineered mesenchymal stem cell therapy for pulmonary fibrosis in young and aged mice

Science Advances, Journal Year: 2023, Volume and Issue: 9(29)

Published: July 19, 2023

Pulmonary fibrosis (PF) is an age-related interstitial lung disease that results in notable morbidity and mortality. The Food Drug Administration-approved drugs can decelerate the progression of PF; however, curing aged patients with severe ineffective because insufficient accumulation these wide necrocytosis type II alveolar epithelial cells (AEC IIs). Here, we constructed a mesenchymal stem cell (MSC)-based nanoengineered platform via bioconjugation MSCs I collagenase-modified liposomes loaded nintedanib (MSCs-Lip@NCAF) for treating fibrosis. Specifically, MSCs-Lip@NCAF migrated to fibrotic lungs homing characteristic then Lip@NCAF was sensitively released. Subsequently, ablated collagen fibers, delivered into fibroblasts, inhibited fibroblast overactivation. differentiated AEC IIs repair structure ultimately promote regeneration damaged mice. Our findings indicated could be used as promising therapeutic candidate PF therapy, especially patients.

Language: Английский

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Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 17, 2022

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated progression, but response heterogeneous to date, adequate biomarkers predicting are lacking. In recent years metabolomic technology improved broadly applied in cancer research thus enabling its use other fields. Recently both aberrant metabolic lipidomic pathways have been described influence profibrotic responses. We aimed characterize the changes between IPF healthy volunteers (HV) analyze following treatment nintedanib pirfenidone. collected serial serum samples from two cohorts Germany (n = 122) Spain 21) additionally age-matched 16). Metabolomic analysis 630 metabolites covering 14 small molecule 12 different lipid classes was carried out using flow injection tandem mass spectrometry for lipids liquid chromatography molecules. Levels were correlated survival severity. identified 109 deregulated analytes compared HV cohort 1 112 2. Metabolites which up-regulated mainly triglycerides while main class down-regulated phosphatidylcholines. Only minority de-regulated Triglyceride subclasses inversely baseline severity (GAP-score) clinical compound endpoint lung function decline or death. No profiles observed Nintedanib induced up-regulation Patients whom an increase these showed trend towards better 2-years composite (HR 2.46, p 0.06). conclusion, we report major independent testing large number patients. Specific lipidic metabolite signatures may serve as progression favorable nintedanib.

Language: Английский

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Transcriptomic and Proteomic Changes Driving Pulmonary Fibrosis Resolution in Young and Old Mice

American Journal of Respiratory Cell and Molecular Biology, Journal Year: 2023, Volume and Issue: 69(4), P. 422 - 440

Published: July 6, 2023

Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic fibrosis. Yet this model, it spontaneously resolves over time. We studied molecular mechanisms resolution and lung repair, focusing on transcriptional proteomic signatures the effect aging. Old showed incomplete delayed function recovery 8 weeks after bleomycin instillation. This shift structural functional repair old bleomycin-treated was reflected a temporal gene protein expression. reveal signaling pathways that underpin process. Importantly, downregulation WNT, BMP, TGFβ antagonists Frzb, Sfrp1, Dkk2, Grem1, Fst, Fstl1, Inhba correlated with improvement. Those genes constitute network functions stem cell pathways, wound, healing. suggest insufficient those during explains impaired regenerative outcome. Together, we identified pathway molecules relevance to regeneration should be tested in-depth experimentally as potential therapeutic targets for

Language: Английский

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PPARG/SPP1/CD44 Signaling Pathway in Alveolar Macrophages: Mechanisms of Lipid Dysregulation and Therapeutic Targets in Idiopathic Pulmonary Fibrosis

Heliyon, Journal Year: 2025, Volume and Issue: 11(1), P. e41628 - e41628

Published: Jan. 1, 2025

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It characterized by inflammation in the parenchyma interstitium. Given its poor prognosis limited treatment options, understanding underlying molecular mechanisms crucial. Recent evidence suggests that lipid metabolism plays pivotal role IPF pathogenesis, however, precise remain poorly understood. To address this, we analyzed 12 bulk RNA-seq 2 single-cell datasets from GEO database using machine learning approaches. As result, identified four key lipid-related genes-PPARG, SPP1, CASP3, PECAM1-that are expressed across various cell types. Specifically, alveolar macrophages (AMs), observed PPARG was significantly downregulated, while SPP1 highly expressed. Importantly, serves as transcriptional regulator of which turn mediates intercellular signaling via CD44. Based on these findings, propose novel PPARG/SPP1/CD44 pathway AMs, modulates likely contributes to progression IPF. Moreover, network pharmacology analysis several herbal compounds target PPARG, offering potential therapeutic opportunities. In conclusion, findings highlight critical present targets for development future strategies.

Language: Английский

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Unraveling Alveolar Fibroblast and Activated Myofibroblast Heterogeneity and Differentiation Trajectories During Lung Fibrosis Development and Resolution in Young and Old Mice

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Idiopathic pulmonary fibrosis (IPF) is an age-associated disease characterized by the irreversible accumulation of excessive extracellular matrix components activated myofibroblasts (aMYFs). Following bleomycin administration in young mice, formation associated with efficient resolution takes place limiting clinical relevance this model for IPF. In study, we used aged mice combination to trigger enhanced and delayed as a more relevant Alveolosphere assays were carried out compare alveolar resident mesenchymal niche activity AT2 stem cells versus old mice. Lineage tracing Acta2+ aMYFs exposed followed scRNAseq lineage-traced isolated during was performed delineate heterogeneity their fate resolution. Integration previously published similar results using out. Our show that from display decreased supporting cells. findings suggest cellular molecular mechanisms underlying differentiation towards Lipofibroblast phenotype are mostly conserved between addition persistent fibrotic signaling aMYF resolution, also identified differences linked interleukin fibroblast populations before injury. Importantly, our work confirms subcluster potentially future management

Language: Английский

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Spatially resolved integrative analysis of transcriptomic and metabolomic changes in tissue injury studies

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

Abstract Recent developments in spatially resolved -omics have enabled studies linking gene expression and metabolite levels to tissue morphology, offering new insights into biological pathways. By capturing multiple modalities on matched sections, one can better probe how different entities interact a coordinated manner. However, such cross-modality integration presents experimental computational challenges. To align multimodal datasets shared coordinate system facilitate enhanced analysis, we propose MAGPIE ( M ulti-modal A lignment of G enes P eaks for I ntegrated E xploration ), framework co-registering transcriptomics, metabolomics, morphology from the same or consecutive sections. We illustrate generalisability scalability spatial multi-omics data tissues, combining Visium with both MALDI DESI mass spectrometry imaging. was also applied newly generated created using specialised sampling strategy characterise metabolic transcriptomic landscape an vivo model drug-induced pulmonary fibrosis, showcase small-molecule co-detection endogenous responses lung tissue. highlights refined resolution increased interpretability analyses studying injury, particularly pharmacological contexts, offers modular, accessible workflow integration.

Language: Английский

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Advances in Extracellular Matrix-Associated Diagnostics and Therapeutics

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(6), P. 1856 - 1856

Published: March 10, 2025

The extracellular matrix (ECM) is the common denominator of more than 50 chronic diseases. Some these pathologies lead to enhanced tissue formation and deposition, whereas others are associated with increased degradation, some exhibit a combination both, leading severe alterations. To develop effective therapies for diseases affecting lung, liver, kidney, skin, intestine, musculoskeletal system, heart, solid tumors, we need modulate ECM’s composition restore its organization function. Across diverse organ diseases, there denominators distinguishing factors in this fibroinflammatory axis, which may be used foster new insights into drug development across disease indications. 2nd Extracellular Matrix Pharmacology Congress took place Copenhagen, Denmark, from 17 19 June 2024 was hosted by International Society Pharmacology. event attended 450 participants 35 countries, among whom were prominent scientists who brought together state-of-the-art research on asked important questions facilitate development. We highlight key aspects ECM lungs, tumors advance our understanding central targets also advances tools technology that enable development, thereby supporting ECM.

Language: Английский

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CCTα and GVI iPLA2-induced aberrant phosphatidylcholine metabolism contributes to pulmonary inflammation and fibrosis

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 156, P. 114718 - 114718

Published: April 25, 2025

Language: Английский

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Time and phenotype-dependent transcriptome analysis in AAV-TGFβ1 and Bleomycin-induced lung fibrosis models

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 16, 2022

Abstract We have previously established a novel mouse model of lung fibrosis based on Adeno-associated virus (AAV)-mediated pulmonary overexpression TGFβ1. Here, we provide an in-depth characterization phenotypic and transcriptomic changes (mRNA miRNA) in head-to-head comparison with Bleomycin-induced injury over 4-week disease course. The analyses delineate the temporal state model-specific commonly altered pathways, thereby providing detailed insights into processes underlying development. They further guide appropriate selection as well interventional study design. Overall, resembles biphasic process acute inflammation subsequent transition (with partial resolution), whereas TGFβ1-driven is characterized by pronounced persistent concomitant equally complex phenotype observed upon Bleomycin instillation. Finally, integrative approach combining function data, mRNA/miRNA profiles, their correlation miRNA target predictions, identify putative drug targets miRNAs to be explored therapeutic candidates for fibrotic diseases. Taken together, comprehensive analysis rich data resource RNA-sequencing, along strategy transcriptome-phenotype coupling. results will value TGFβ research, discovery biomarker identification progressive fibrosing interstitial

Language: Английский

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