Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

Abstract

Rationale:Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD) which is a major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Objective:Our objective was to test whether telomere dysfunction contributes to pathologic changes seen in CLAD. Methods and Results:Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells (AECs), and increased expression of senescence markers (beta-galactosidase, p16, p53 and p21) in lung epithelial cells. Telomere repeat binding factor 1 flox/flox (TRF1 F/F ) mice were crossed with tamoxifen inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on micro-computed tomography, a 4fold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II AEC numbers, expression of senescenceassociated beta-galactosidase in epithelial cells and decreased SCGB1a1 expression in airway epithelial cells. Conclusions:These findings demonstrate that telomere dysfunction isolated to club cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

Telomere shortening and fibrotic remodeling in progressive fibrosing interstitial lung disease

“…This is in line with a previous study, which showed that bronchoalveolar lavage of fHP patients contained significantly higher carbonylated protein levels, a marker of ROS, compared to IPF and controls (55). However, another study showed that in mice with a Club cell-specific knock out of telomere repeat-binding factor-1 (Trf1), rapid aging of club cells by telomere dysfunction alone was sufficient to induce DNA damage and subsequent bronchiolocentric fibrosis (56). The excess DNA damage in fHP Club cells might therefore, regardless of the cause, be suggestive of an important role of these cells in fibrogenesis, and is in agreement with the localization of fibrosis in fHP.…”

“…The main function of surfactant is to prevent the collapse of alveoli by the reduction of the alveolar surface tension (52)(53)(54)(55). Furthermore, surfactant proteins are involved in innate host defense regulation through complement activation, thereby clearing away apoptotic cells and invading microorganisms (56,57). Even though all four subtypes of surfactant proteins are produced in the lung, to date only mutations in the SFTPA1/2 and SFTPC genes have been associated with FPF in adults (37,(58)(59)(60)(61)(62).…”

Telomere shortening and DNA damage in culprit cells of different types of progressive fibrosing interstitial lung disease

“…This is in line with a previous study that showed that bronchoalveolar lavage of fHP patients contained significantly higher carbonylated protein levels, a marker of ROS, compared to IPF and controls [ 47 ]. However, another study showed that in mice with a club cell-specific knockout of telomere repeat-binding factor-1 (Trf1), rapid ageing of club cells by telomere dysfunction alone was sufficient to induce DNA damage and subsequent bronchiolocentric fibrosis [ 25 ]. In addition, it was reported that in 25% of the cases with an initial diagnosis of IPF, bronchiolocentric fibrosis is indicative for a revised diagnosis of fHP [ 48 ].…”

“…However, if not fixed properly in time, the DNA damage response becomes persistent and eventually leads to cellular senescence [ 19 – 21 ], a process associated with fibrogenesis in IPF lungs and fibrotic mouse models [ 22 , 23 ]. Previous studies using mice models with a telomere repeat factor-1 (Trf1) knockout in alveolar or bronchiolar epithelial cells demonstrated telomere shortening and increased DNA damage foci in both cell types [ 24 , 25 ]. Similar results were found in TRF2-inactivated human cell lines showing an elevated amount of damage foci at uncapped telomeres [ 26 ].…”