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Telomere Dysfunction in Clara Cells Leads to Airway-Centric Lung Remodeling and Fibrosis
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A4646 - Telomere Dysfunction in Clara Cells Leads to Airway-Centric Lung Remodeling and Fibrosis
Author Block: R. P. Naikawadi, G. Green, P. J. Wolters; Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA, United States.
Rationale: Telomere dysfunction has been linked to lung diseases with airway-centric remodeling and fibrosis (e.g. hypersensitivity pneumonitis and chronic lung allograft dysfunction (CLAD). CLAD is a major complication after lung transplantation. Patients who receive donor lungs with short telomeres are at increased risk for developing CLAD. It is unknown whether short telomeres are a cause or consequence of the CLAD phenotype.
Objective: We sought to investigate whether telomere dysfunction in Clara cells leads to airway-centric lung remodeling in mice.
Methods and Results: To examine the consequences of Clara cell-specific telomere dysfunction, we crossed TRF1Flox/Flox (TRF1F/F) mice with mice inducibly expressing Cre recombinase in Clara cells (SCGB1a1-creERT) to generate SCGB1a1-creTRF1F/F mice.
Tamoxifen-induced deletion of TRF1 in Clara cells resulted in death of the mice between 7-9 months after initiating tamoxifen. Histopathology of lungs harvested at the time of death showed airway-centric lung remodeling characterized by increased collagen deposition and occasional narrowing of airway lumens. Lungs of SCGB1a1-creTRF1F/F mice also show increased γH2AX DNA damage foci in Clara cells, αSMA deposition around the airways, and Type II alveolar epithelial cell hyperplasia adjacent to the airways. Differential cell count of bronchoalveolar lavage fluid (BALF) revealed more macrophages, lymphocytes and neutrophils in SCGB1a1-creTRF1F/F mice compared to TRF1F/F controls. Levels of active TGF beta and IL-6, a marker of senescence, were also increased in BALF. Importantly, telomere lengths in Clara cells of SCGB1a1-creTRF1F/F mice were approximately 4-fold shorter than in TRF1F/F mice.
Conclusions: These findings demonstrate that prolonged telomere dysfunction in Clara cells leads to age-dependent airway-centric fibrosis in the lung. These findings are similar to those found in lung transplant recipients with CLAD. Ongoing studies are designed to define the molecular mechanisms of this remodeling.
Author Block: R. P. Naikawadi, G. Green, P. J. Wolters; Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA, United States.
Rationale: Telomere dysfunction has been linked to lung diseases with airway-centric remodeling and fibrosis (e.g. hypersensitivity pneumonitis and chronic lung allograft dysfunction (CLAD). CLAD is a major complication after lung transplantation. Patients who receive donor lungs with short telomeres are at increased risk for developing CLAD. It is unknown whether short telomeres are a cause or consequence of the CLAD phenotype.
Objective: We sought to investigate whether telomere dysfunction in Clara cells leads to airway-centric lung remodeling in mice.
Methods and Results: To examine the consequences of Clara cell-specific telomere dysfunction, we crossed TRF1Flox/Flox (TRF1F/F) mice with mice inducibly expressing Cre recombinase in Clara cells (SCGB1a1-creERT) to generate SCGB1a1-creTRF1F/F mice.
Tamoxifen-induced deletion of TRF1 in Clara cells resulted in death of the mice between 7-9 months after initiating tamoxifen. Histopathology of lungs harvested at the time of death showed airway-centric lung remodeling characterized by increased collagen deposition and occasional narrowing of airway lumens. Lungs of SCGB1a1-creTRF1F/F mice also show increased γH2AX DNA damage foci in Clara cells, αSMA deposition around the airways, and Type II alveolar epithelial cell hyperplasia adjacent to the airways. Differential cell count of bronchoalveolar lavage fluid (BALF) revealed more macrophages, lymphocytes and neutrophils in SCGB1a1-creTRF1F/F mice compared to TRF1F/F controls. Levels of active TGF beta and IL-6, a marker of senescence, were also increased in BALF. Importantly, telomere lengths in Clara cells of SCGB1a1-creTRF1F/F mice were approximately 4-fold shorter than in TRF1F/F mice.
Conclusions: These findings demonstrate that prolonged telomere dysfunction in Clara cells leads to age-dependent airway-centric fibrosis in the lung. These findings are similar to those found in lung transplant recipients with CLAD. Ongoing studies are designed to define the molecular mechanisms of this remodeling.
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