Short telomere length in IPF lung associates with fibrotic lesions and predicts survival

Abstract

Telomere maintenance dysfunction has been implicated in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). However, the mechanism of how telomere length is related to fibrosis in the lungs is unknown. Surgical lung biopsies of IPF patients typically show a heterogeneous pattern of non-fibrotic and fibrotic areas. Therefore, telomere length (TL) in both lung areas of patients with IPF and familial interstitial pneumonia was compared, specifically in alveolar type 2 (AT2) cells.Fluorescent in situ hybridization was used to determine TL in non-fibrotic and fibrotic areas of 35 subjects. Monochrome multiplex quantitative polymerase chain reaction (MMqPCR) was used for 51 whole lung biopsies and blood TL measurements.For sporadic IPF subjects, AT2 cell TL in non-fibrotic areas was 56% longer than in fibrotic areas. No such difference was observed in the surrounding lung cells. In subjects carrying a telomerase reverse transcriptase (TERT) mutation, AT2 cell TL was significantly shorter than in sporadic subjects. However, no difference in surrounding cell TL was observed between these subject groups. Finally, using biopsy MMqPCR TL measurements, it was determined that IPF subjects with shortest lung TL had a significantly worse survival than patients with long TL.This study shows that shortening of telomeres critically affects AT2 cells in fibrotic areas, implying TL as a cause of fibrogenesis. Furthermore, short lung telomere length is associated with decreased survival.

Telomere length and lung function in a population‐based cohort of children and mid‐life adults

“…This is congruent with the observation that, after peaking in childhood, lung size in healthy individuals plateaus with little change in FEV 1 and FVC . Others have reported stronger associations in individuals with lung pathologies such as COPD, idiopathic pulmonary fibrosis, asthma, and lung cancer . General population studies in adults have generally found weak to moderate associations between telomere length and lung function .…”

“…Telomere length may have a role in the pathways to lung diseases. As reported in other studies, our observations are likely to be of greater clinical relevance in association with more pronounced respiratory pathology, such as those with COPD, idiopathic pulmonary fibrosis, asthma, and lung cancer …”

“…35 Others have reported stronger associations in individuals with lung pathologies such as COPD, idiopathic pulmonary fibrosis, asthma, and lung cancer. 8,10,36 General population studies in adults have generally found weak to moderate associations between telomere length and lung function. 11,37 For example, two large studies in healthy adults (aged 28-73 years) reported weaker associations between telomere length and lung function (n = 44,041 controls), compared to COPD patients (n = 934) or asthmatics (n = 2834).…”

“…8,9 For instance, shortened telomeres are found in pulmonary vascular endothelial cells of COPD patients 8 and in fibrotic areas of adults with pulmonary fibrosis. 10 Further, a study of 46,396 adults aged between 43 and 73 years showed a modest association of shorter telomere length with decreased lung function. 11 However, the generalizability of these findings across the lifecourse is uncertain as most studies were conducted in older patients already exhibiting lung disease.…”

“…Increasing evidence in adults suggests that shortened telomeres are associated with reduced lung health . For instance, shortened telomeres are found in pulmonary vascular endothelial cells of COPD patients and in fibrotic areas of adults with pulmonary fibrosis . Further, a study of 46,396 adults aged between 43 and 73 years showed a modest association of shorter telomere length with decreased lung function .…”