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. 2018 May 11;19(1):95.
doi: 10.1186/s12931-018-0794-z.

The aging lung: tissue telomere shortening in health and disease

Stephanie Everaerts  1 , Elise J Lammertyn  2 , Dries S Martens  3 , Laurens J De Sadeleer  2 , Karen Maes  2 , Aernoud A van Batenburg  4 , Roel Goldschmeding  5 , Coline H M van Moorsel  4   6 , Lieven J Dupont  2   7 , Wim A Wuyts  2   7 , Robin Vos  2   7 , Ghislaine Gayan-Ramirez  2 , Naftali Kaminski  8 , James C Hogg  9 , Wim Janssens  2   7 , Geert M Verleden  2   7 , Tim S Nawrot  3   10 , Stijn E Verleden  2 , John E McDonough  2 , Bart M Vanaudenaerde  2
Affiliations

The aging lung: tissue telomere shortening in health and disease

Stephanie Everaerts et al. Respir Res. .

Abstract

Background: Telomere shortening has been associated with several lung diseases. However, telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. Consequently, telomere dynamics have not been established for the normal human lung nor for diseased lung tissue. We hypothesized an age- and disease-dependent shortening of lung tissue telomeres.

Methods: At time of (re-)transplantation or autopsy, 70 explant lungs were collected: from unused donors (normal, n = 13) and patients with cystic fibrosis (CF, n = 12), chronic obstructive pulmonary disease (COPD, n = 11), chronic hypersensitivity pneumonitis (cHP, n = 9), bronchiolitis obliterans syndrome (BOS) after prior transplantation (n = 11) and restrictive allograft syndrome (RAS) after prior transplantation (n = 14). Lungs were inflated, frozen and then scanned using CT. Four tissue cores from distinct lung regions were sampled for analysis. Disease severity was evaluated using CT and micro CT imaging. DNA was extracted from the samples and average relative telomere length (RTL) was determined using real-time qPCR.

Results: The normal lungs showed a decrease in RTL with age (p < 0.0001). Of the diseased lungs, only BOS and RAS showed significant RTL decrease with increasing lung age (p = 0.0220 and p = 0.0272 respectively). Furthermore, we found that RTL showed considerable variability between samples within both normal and diseased lungs. cHP, BOS and RAS lungs had significant shorter RTL in comparison with normal lungs, after adjustment for lung age, sex and BMI (p < 0.0001, p = 0.0051 and p = 0.0301 respectively). When investigating the relation between RTL and regional disease severity in CF, cHP and RAS, no association was found.

Conclusion: These results show a progressive decline in telomere length with age in normal, BOS and RAS lungs. cHP, BOS and RAS lungs demonstrated shorter RTL compared to normal lungs. Lung tissue RTL does not associate with regional disease severity within the lung. Therefore, tissue RTL does not seem to fully reflect peripheral blood telomere length.

Keywords: BOS; Cellular senescence; Chronic hypersensitivity pneumonitis; Chronic lung allograft dysfunction; Chronic obstructive pulmonary disease; Cystic fibrosis; RAS; Telomere length.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the local Ethics Committee (Medical Ethics Board of University Hospitals Leuven, Belgium; ML6385). According to Belgian law, organs from prospective donors, which are of insufficient quality for LTx and have been conclusively declined by the transplant surgeon, can be used for research purposes. All LTx patients gave written informed consent to use their lungs for research purposes.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
RTL decrease with age and regional difference in normal lung tissue. a: log10 RTL versus lung age in normal lungs. Log10 RTL per lung is presented as a boxplot with the grey area representing the 95% confidence interval. b and c: Paired t-test of log10 RTL in normal lungs based on spatial distribution. Every dot shows the mean log10 RTL of cores originating from the respective region per lung. b: difference in log10 RTL between cores originating from the apical (n = 26) and basal (n = 26) lung regions (p = 0.0002). c: difference in log10 RTL between upper (n = 37) and lower lobe (n = 15) cores (p = 0.0015)
Fig. 2
Fig. 2
Association of age and telomere length in AT2 cells of normal lung tissue by fluorescent in situ hybridization. Telomere length determination by FISH on normal lung tissue of (a) a 19-year old and (b) an 83-year old donor showed (c) significantly higher telomere length in AT2 cells of the youngest subject (p = 0.009). The fluorecent labelling in the a and b panel stands for green: proSPC (AT2 cells), red: telomere probe, blue: DAPI. Data are presented as boxplots and every dot represents one cell
Fig. 3
Fig. 3
Relation between RTL and age in lung disease. Log10 RTL per lung is presented as a boxplot. The grey area in each graph represents the 95% confidence interval of log10 RTL in normal lungs. a: log10 RTL versus lung age in CF lungs. b: log10 RTL versus lung age in COPD lungs. c: log10 RTL versus lung age in cHP lungs. d: log10 RTL versus lung age in BOS lungs. e: log10 RTL versus lung age in RAS lungs
Fig. 4
Fig. 4
Lack of association between RTL and local disease severity. Every dot represents an individual core log10 RTL. Horizontal lines represent means. a: RTL in normal versus abnormal CF lung tissue (both n = 24), stratified based on HRCT of the lung (p = 0.96). b: RTL in mildly versus severely affected cHP lung tissue (both n = 18), stratified based on surface density of core micro CT (p = 0.22). c: RTL in mildly versus severely affected RAS lung tissue (both n = 28), stratified based on surface density of core micro CT (p = 0.084)
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