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

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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.

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          Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.

          M. Selman, T E King, A. Pardo (2001)
          Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast-myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies.
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            Telomerase mutations in families with idiopathic pulmonary fibrosis.

            Mary Armanios, Julian J L Chen, Joy Cogan … (2007)
            Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis. To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR. Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families. Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease. Copyright 2007 Massachusetts Medical Society.
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              Short telomeres are a risk factor for idiopathic pulmonary fibrosis.

              Jonathan Alder, Julian J L Chen, Lisa H. Lancaster … (2008)
              Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.
              Article 0 comments Cited 233 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Reinier Snetselaar: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Aernoud A. van Batenburg:
                ORCID: http://orcid.org/0000-0002-2841-7911
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Matthijs F. M. van Oosterhout: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Karin M. Kazemier: Role: MethodologyRole: Writing – review & editing
                Suzan M. Roothaan: Role: Data curation
                Ton Peeters: Role: MethodologyRole: Writing – review & editing
                Joanne J. van der Vis: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – review & editing
                Roel Goldschmeding: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Jan C. Grutters: Role: SupervisionRole: Writing – review & editing
                Coline H. M. van Moorsel: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Gernot Zissel: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 27 December 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 12
                Electronic Location Identifier: e0189467
                Affiliations
                [1 ] Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands
                [2 ] Department of Pathology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands
                [3 ] Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
                [4 ] Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
                [5 ] Department of Clinical Chemistry, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands
                Universitatsklinikum Freiburg, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-2841-7911
                Article
                Publisher ID: PONE-D-17-01649
                DOI: 10.1371/journal.pone.0189467
                PMC ID: 5744955
                PubMed ID: 29281671
                SO-VID: 4776c8b0-3128-4c26-ba94-6c00452abb44
                Copyright © © 2017 Snetselaar et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 13 January 2017
                Date accepted : 28 November 2017
                Page count
                Figures: 7, Tables: 3, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001826, ZonMw;
                Award ID: 842002003
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004854, St. Antonius Ziekenhuis;
                Award Recipient :
                This research was enabled by ZonMW-TopZorg St Antonius Science Corner grant (grant number 842002003; www.zonmw.nl; JCG CHMvM JJvdV) and 'Pendersfonds' of the lungfibrosis patient association (CHMvM).
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Chromosome Biology
                Subject: Chromosomes
                Subject: Chromosome Structure and Function
                Subject: Telomeres
                Subject: Telomere Length
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Chromosome Biology
                Subject: Chromosomes
                Subject: Chromosome Structure and Function
                Subject: Telomeres
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Fibrosis
                Subject: Pulmonary Fibrosis
                Subject: Medicine and Health Sciences
                Subject: Surgical and Invasive Medical Procedures
                Subject: Biopsy
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Fibrosis
                Subject: Medicine and Health Sciences
                Subject: Pulmonology
                Subject: Pneumonia
                Subject: Research and Analysis Methods
                Subject: Cytogenetic Techniques
                Subject: Fluorescent in Situ Hybridization
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Molecular Probe Techniques
                Subject: Probe Hybridization
                Subject: Fluorescent in Situ Hybridization
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Molecular Probe Techniques
                Subject: Probe Hybridization
                Subject: Fluorescent in Situ Hybridization
                Custom metadata
                Data Availability Data restricted because they contain potentially identifying or sensitive patient information. Restrictions are imposed by the Medical Research Ethics Committees United (MEC-U). All anonymized data are available from: ILD Center of Excellence Biobank, M. Struik, MSc, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands, m.struik@ 123456antoniusziekenhuis.nl . Raw telomere data was uploaded in a separate excel file ( S1 Dataset).

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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