Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis
Open accessAbstract
Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice ( SPC-Cre TRF1 fl/fl mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin + mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase + lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1 fl/fl mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.
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Evidence has emerged that alveolar epithelial cells can become senescent in IPF.
“In addition to lung fibroblasts, evidence has emerged that alveolar epithelial cells can become senescent in IPF [16, 20, 24].”
From Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis <i>ex vivo</i> (2017) · cites this paper as [24]
Human CX3CR1 mRNA was more highly expressed in lung microarray samples from 167 patients with lung fibrosis than in 50 healthy controls.
“Human CX3CR1 mRNA was also more highly expressed in lung microarray samples from 167 patients with lung fibrosis than in samples from 50 healthy controls”
From Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage (2019) · cites this paper as [32]
In human lung fibrosis samples, expression of genes associated with alveolar macrophages (cluster C1) was significantly decreased and expression of MHC II genes (clusters C2 and C3) was significantly increased compared to healthy controls.
“This analysis showed a significant decrease in the expression of genes associated with alveolar macrophages (cluster C1) and a significant increase in the expression of MHC II genes (cluster C2 and C3) in the human fibrosis samples compared to the healthy controls”
From Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage (2019) · cites this paper as [32]
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References 35 · Cited by 267
Research works printed but not linked: 1
- Kropski JA, et al. Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogen- esis of interstitial lung disease. Am J Respir Crit Care Med. 2015;191(4):417-426.
- Authors
- Naikawadi, R. P., Disayabutr, S., Mallavia, B., Donne, M. L., Green, G., La, J. L., Rock, J. R., Looney, M. R., & Wolters, P. J.
- Affiliations
- University of California, San Francisco (US)
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA.
- Corresponding author
- Wolters, Paul J.
- Venue
- JCI Insight
- Published
- 2016-09-08
- Volume
- 1
- Issue
- 14
- Pages
- e86704-e86704
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5033906
- OpenAlex
- W2511441887
- Cited by
- 267
- References
- 35
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 27 · 2023: 20 · 2022: 33 · 2021: 36 · 2020: 40 · 2019: 25 · 2018: 25 · 2017: 22
- FWCI
- 21.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Francisco
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Keywords
- telomere dysfunction, alveolar type II cells, idiopathic pulmonary fibrosis, TRF1, shelterin, pulmonary fibrosis, lung remodeling, cellular senescence, DNA damage, collagen deposition, mesenchymal cells, pulmonary edema
- MeSH terms
- Animals, Cells, Cultured, Epithelial Cells, Lung, Pulmonary Fibrosis, Telomere, Mice, Idiopathic Pulmonary Fibrosis, Alveolar Epithelial Cells, Telomere Shortening
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