Differences in the Fibrogenic Response after Transfer of Active Transforming Growth Factor- β 1 Gene to Lungs of “Fibrosis-prone” and “Fibrosis-resistant” Mouse Strains
Abstract
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium, resulting in impaired lung function and respiratory failure. Investigation of the differences in individual susceptibility to the development of fibrosis may help to detect patients that are at risk to fibrosis when exposed to fibrogenic stimuli. In this study we used adenoviral gene transfer to transiently expose a fibrosis-prone (C57BL/6) and a fibrosis-resistant (Balb/c) mouse strain to high levels of active transforming growth factor (TGF)-β1, a key profibrotic cytokine. Balb/c mice developed significantly less fibrosis compared with C57BL/6 mice in response to active TGF-β1 despite higher levels of the transgene protein in the lung. This was not due to a general unresponsiveness of cells to TGF-β1, because primary fibroblasts of both strains increased collagen synthesis upon stimulation with TGF-β1 in vitro to the same degree. However, TGF-β1 induced a strong upregulation of tissue inhibitor of metalloprotease-1 gene in pulmonary fibroblasts as well as in lungs of C57BL/6 mice, in contrast to a weak induction in Balb/c mice. These findings suggest that the differences in susceptibility to pulmonary fibrosis are downstream from TGF-β1 and that fibrosis-prone individuals may have an altered collagen metabolism in the lungs that is balanced toward a “nondegrading” environment.
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For initial screening, the study used an immunocompetent C57BL/6 mouse model to ensure proper biocompatibility assessment.
“To ensure proper biocompatibility assessment in our studies we used an immunocompetent C57BL/6 mouse model for our initial screening”
From Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates (2015) · cites this paper as [31]
The C57BL/6 mouse strain mounts a strong fibrotic and foreign body response that resembles what is seen in human patients.
“this strain is known to produce a strong fibrotic and foreign body response similar to observations made in human patients31.”
From Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates (2015) · cites this paper as [31]
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- Authors
- Kolb, M., Bonniaud, P., Galt, T., Sime, P. J., Kelly, M. M., Margetts, P. J., & Gauldie, J.
- Affiliations
- Université de Bourgogne (FR)
- Corresponding author
- Gauldie, Jack
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-08-01
- Volume
- 27
- Issue
- 2
- Pages
- 141-150
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- OpenAlex
- W2145489141
- Cited by
- 168
- References
- 33
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 8 · 2018: 9 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 9 · 2012: 7
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- pulmonary fibrosis, TGF-β1, C57BL/6 mice, BALB/c mice, adenoviral gene transfer, TIMP-1, collagen synthesis, lung fibroblasts, extracellular matrix deposition
- MeSH terms
- Adenoviridae, Animals, Bronchoalveolar Lavage Fluid, Cell Line, Collagen, Female, Fibroblasts, Genetic Vectors, Humans, Hydroxyproline, Inflammation, Lung, Mice, Inbred BALB C, Mice, Inbred Strains, Protease Inhibitors, Pulmonary Fibrosis, Transforming Growth Factor beta, Gene Transfer Techniques, Tissue Inhibitor of Metalloproteinase-1, Mice, Transforming Growth Factor beta1
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