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An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices
Open accessAbstract
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic interstitial lung disease (ILD) characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression, but the exact molecular mechanisms behind IPF remain unclear. Several drugs have been shown to slow disease progression, but treatments that halt or reverse IPF progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices (PCLS). Although PCLS production from IPF explants is possible, IPF explants are rare and typically represent end-stage disease. Here we present a novel model of early fibrosis-like changes in human PCLS derived from patients without ILD/IPF using a combination of profibrotic growth factors and signaling molecules (transforming growth factor-β, tumor necrosis factor-α, platelet-derived growth factor-AB, and lysophosphatidic acid). Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by water-soluble tetrazolium-1, RT-qPCR, Western blot analysis, and ELISA. PCLS remained viable after 5 days of treatment, and fibrotic gene expression ( FN1, SERPINE1, COL1A1, CTGF, MMP7, and ACTA2) increased as early as 24 h of treatment, with increases in protein levels at 48 h and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in surfactant protein C and loss of HOPX. In summary, using human-derived PCLS, we established a novel ex vivo model that displays characteristics of early fibrosis and could be used to evaluate novel therapies and study early-stage IPF pathomechanisms.
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“it is now possible to induce several features which mimic the fibrogenic response by applying a profibrotic cytokine cocktail (e.g. TGFβ1, lysophosphatidic acid receptor (LPA), and interleukin-1 (IL-1)), in PCLS obtained from control tissue over the course of a few days (Alsafadi et al., 2017).”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Alsafadi et al., 2017
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Metadata
- Authors
- Alsafadi, H. N., Staab-Weijnitz, C. A., Lehmann, M., Lindner, M., Peschel, B., Königshoff, M., & Wagner, D. E.
- Affiliations
- Helmholtz Munich (DE)
- Asklepios Fachkliniken München-Gauting (DE)
- Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany;
- Corresponding author
- Wagner, Darcy E.
- ORCID
- Venue
- American Journal of Physiology-Lung Cellular and Molecular Physiology
- Publisher
- American Physiological Society
- Published
- 2017-06-01
- Volume
- 312
- Issue
- 6
- Pages
- L896-L902
- ISSN
- 1040-0605 (ISSN-L)
- 1522-1504
- OpenAlex
- W2595866898
- Cited by
- 263
- References
- 21
- Citations by year
- 2026: 25 · 2025: 52 · 2024: 39 · 2023: 41 · 2022: 25 · 2021: 24 · 2020: 19 · 2019: 21 · 2018: 14 · 2017: 3
- FWCI
- 12.79
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- American Journal of Physiology-Lung Cellular and Molecular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- Funders
- American Thoracic Society (ATS)
- Helmholtz Zentrum München GmbH
- Whitaker International Fellows and Scholars Program
- Helmholtz Association
- EC | European Research Council (ERC) (ERC-2010-StG 261302)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- idiopathic pulmonary fibrosis, precision-cut lung slices, ex vivo model, fibrosis, TGF-beta, TNF-α, PDGF-AB, lysophosphatidic acid, myofibroblast activation, extracellular matrix deposition, surfactant protein C, HOPX, interstitial lung disease
- MeSH terms
- Aged, Extracellular Matrix, Female, Humans, Lung, Male, Models, Biological, Tissue Survival, Biomarkers, Up-Regulation, Inflammation Mediators, Collagen Type I, Idiopathic Pulmonary Fibrosis, Alveolar Epithelial Cells
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