Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis
Ram P. Naikawadi, Supparerk Disayabutr, Benat Mallavia, Matthew L. Donne, Gary Green, Janet L. La, Jason R. Rock, Mark R. Looney, Paul J. Wolters
Ram P. Naikawadi, Supparerk Disayabutr, Benat Mallavia, Matthew L. Donne, Gary Green, Janet L. La, Jason R. Rock, Mark R. Looney, Paul J. Wolters
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Resource and Technical Advance Pulmonology

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

Abstract

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 TRF1fl/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 TRF1fl/fl mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.

Authors

Ram P. Naikawadi, Supparerk Disayabutr, Benat Mallavia, Matthew L. Donne, Gary Green, Janet L. La, Jason R. Rock, Mark R. Looney, Paul J. Wolters

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Figure 1

Telomere dysfunction in type II AECs results in DNA damage and increased susceptibility to influenza virus, spontaneous lung remodeling, and death.

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Telomere dysfunction in type II AECs results in DNA damage and increased...
(A) Immunoblot showing TRF1 deletion in type II AECs isolated from tamoxifen-treated TRF1fl/fl and SPC-Cre TRF1fl/fl mice. (B) Survival of TRF1fl/fl and SPC-Cre TRF1fl/fl mice following influenza virus infection (A/PR/8/34). Mice were treated with tamoxifen (250 mg/kg body weight) weekly for 4 weeks prior to infection. n =10 mice/group, **P = 0.001, log-rank test. (C) Survival of TRF1fl/fl and SPC-Cre TRF1fl/fl mice treated with weekly injections of tamoxifen (250 mg/kg body weight). n= 10 mice per group, ***P < 0.0001, log-rank test. (D) γH2AX immunostaining of lung sections from TRF1fl/fl and SPC-Cre TRF1fl/fl mice treated with tamoxifen (250 mg/kg body weight) for 2 weeks. Note the γH2AX foci (green immunofluorescence, white arrows) in the nuclei of SPC-Cre TRF1fl/fl mice. SPC, surfactant protein C (red immunostain). Nuclei were stained with DAPI (blue). Scale bars: 10 μm. (E) Quantification of percentage of γH2AX-positive nuclei in SPC-positive cells. n = 3–5 mice/group, ***P = 0.0002, 2-tailed Student’s t test.