Abstract
BackgroundTelomere 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.MethodsAt 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.ResultsThe 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.ConclusionThese 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.
Highlights
Telomere shortening has been associated with several lung diseases
Patients with cystic fibrosis (CF), bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) had a significantly lower Body mass index (BMI) compared to donors of unused normal lungs
Estimates are presented as percentage change in average RTL for each 1-year increase in lung age RTL relative telomere length, 95% CI 95% confidence interval, CF cystic fibrosis, COPD chronic obstructive pulmonary disease, cHP chronic hypersensitivity pneumonitis, BOS bronchiolitis obliterans syndrome, RAS restrictive allograft syndrome p-value < 0.05 is captured in bold not different from normal lung tissue in the same model (Table 4)
Summary
Telomere shortening has been associated with several lung diseases. telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. The respiratory system undergoes structural remodelling, including rearrangement of extracellular matrix, dilatation of alveoli and enlargement of airspaces leading to lung function decline This process of structural aging together with immunosenescence leads to an increased susceptibility to acute and chronic pulmonary disease, which can be influenced by individual factors, such as genetic background and exposure [3, 4]. Shortened peripheral blood leukocyte telomeres have been associated with various age-related diseases, such as atherosclerosis [7] and type 2 diabetes mellitus [8], and an increased risk for some cancers [9]. This suggests that the increased turnover and replication of circulating leukocytes during chronic inflammation accelerates the rate of leukocyte telomere shortening [7, 10]
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