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

Reinier Snetselaar,Jan C Grutters,Matthijs F M Van Oosterhout,Suzan M Roothaan,Aernoud A Van Batenburg,Joanne J Van Der Vis,Roel Goldschmeding,Coline H M Van Moorsel,Ton Peeters,Karin M Kazemier,Gernot Zissel

doi:10.1371/journal.pone.0189467

Reinier Snetselaar, Jan C Grutters + Show 9 more

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https://doi.org/10.1371/journal.pone.0189467

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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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterized by progressive fibrosis of lung parenchyma [1]
In order to investigate whether alveolar type 2 (AT2) telomere shortening is related to fibrosis, we performed a fluorescence in situ hybridization (FISH) staining on FFPE material in a group of 16 sporadic IPF subjects
We found that telomere shortening is predominantly observed in AT2 cells and associates with fibrotic lesions in IPF lung biopsies (Figs 2 and 3)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterized by progressive fibrosis of lung parenchyma [1]. It was shown that TL of the lung alveolar type 2 (AT2) cells of IPF patients was shorter compared to controls [11] Together, these findings indicate that telomere related pathology plays a role in both familial and sporadic IPF. A contemporary view on the pathogenesis of IPF focuses on the role of AT2 cell during disease development [9,14,15,16] Evidence for this can be found in patients diagnosed with a surfactant-related familial interstitial pneumonia (FIP). It has been demonstrated that mice with telomere repeat binding factor 1 (TRF1)-deleted AT2 cells develop lung fibrosis and showed short telomeres in AT2 cells [20,21] This might explain the human AT2 cell TL shortening in IPF, which could result in a similar response characterized by progressive fibrosis [22]. Short whole biopsy telomere length in sporadic IPF patients is associated with worse survival

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