From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis

English version

Autoři: Aernoud A. van Batenburg ^aff001; Karin M. Kazemier ^aff002; Matthijs F. M. van Oosterhout ^aff004; Joanne J. van der Vis ^aff001; Hendrik W. van Es ^aff006; Jan C. Grutters ^aff001; Roel Goldschmeding ^aff008; Coline H. M. van Moorsel ^aff001
Působiště autorů: Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands ^aff001; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands ^aff002; Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, the Netherlands ^aff003; Pathology–DNA, Department of Pathology, St Antonius ILD Center of Excellence St Antonius Hospital, Nieuwegein, The Netherlands ^aff004; Department of Clinical Chemistry, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands ^aff005; Department of Radiology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands ^aff006; Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands ^aff007; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands ^aff008
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0226785

Souhrn

Rationale

A subset of patients with idiopathic pulmonary fibrosis (IPF) contains short leukocyte telomeres or telomere related mutations. We previously showed that alveolar type 2 cells have short telomeres in fibrotic lesions. Our objectives were to better understand how telomere shortening associates with fibrosis in IPF lung and identify a subset of patients with telomere-related disease.

Methods

Average telomere length was determined in multiple organs, basal and apical lung, and diagnostic and end-stage fibrotic lung biopsies. Alveolar type 2 cells telomere length was determined in different areas of IPF lungs.

Results

In IPF but not in controls, telomere length in lung was shorter than in other organs, providing rationale to focus on telomere length in lung. Telomere length did not correlate with age and no difference in telomere length was found between diagnostic and explant lung or between basal and apical lung, irrespective of the presence of a radiological apicobasal gradient or fibrosis. Fifteen out of 28 IPF patients had average lung telomere length in the range of patients with a telomerase (TERT) mutation, and formed the IPF_short group. Only in this IPF_short and TERT group telomeres of alveolar type 2 cells were extremely short in fibrotic areas. Additionally, whole exome sequencing of IPF patients revealed two genetic variations in RTEL1 and one in PARN in the IPF_short group.

Conclusions

Average lung tissue telomere shortening does not associated with fibrotic patterns in IPF, however, approximately half of IPF patients show excessive lung telomere shortening that is associated with pulmonary fibrosis driven by telomere attrition.

Klíčová slova:

Telomeres – Telomere length – Diagnostic medicine – Fibrosis – Pulmonary fibrosis – Lungs – Biopsy – Fluorescent in situ hybridization

Zdroje

1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011 Mar 15;183(6):788–824. doi: 10.1164/rccm.2009-040GL 21471066

2. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013 Sep 15;188(6):733–748. doi: 10.1164/rccm.201308-1483ST 24032382

3. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A 2007 May 1;104(18):7552–7557. doi: 10.1073/pnas.0701009104 17460043

4. Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE, Lansdorp PM, et al. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet 2011 Mar;7(3):e1001352. doi: 10.1371/journal.pgen.1001352 21483807

5. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007 Mar 29;356(13):1317–1326. doi: 10.1056/NEJMoa066157 17392301

6. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997 Aug 15;277(5328):955–959. doi: 10.1126/science.277.5328.955 9252327

7. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003 Nov 13;426(6963):194–198. doi: 10.1038/nature02118 14608368

8. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 2017 Feb 23;8:14532. doi: 10.1038/ncomms14532 28230051

9. Victorelli S, Passos JF. Telomeres and Cell Senescence—Size Matters Not. EBioMedicine 2017 Jul;21:14–20. doi: 10.1016/j.ebiom.2017.03.027 28347656

10. Citrin DE, Shankavaram U, Horton JA, Shield W,3rd, Zhao S, Asano H, et al. Role of type II pneumocyte senescence in radiation-induced lung fibrosis. J Natl Cancer Inst 2013 Oct 2;105(19):1474–1484. doi: 10.1093/jnci/djt212 24052614

11. Lehmann M, Korfei M, Mutze K, Klee S, Skronska-Wasek W, Alsafadi HN, et al. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. Eur Respir J 2017 Aug 3;50(2): doi: 10.1183/13993003.02367–2016 Print 2017 Aug.

12. Borie R, Tabeze L, Thabut G, Nunes H, Cottin V, Marchand-Adam S, et al. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis. Eur Respir J 2016 Dec;48(6):1721–1731. doi: 10.1183/13993003.02115-2015 27836952

13. Hoffman TW, van Moorsel CHM, Borie R, Crestani B. Pulmonary phenotypes associated with genetic variation in telomere-related genes. Curr Opin Pulm Med 2018 May;24(3):269–280. doi: 10.1097/MCP.0000000000000475 29474209

14. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D, et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 2005 Dec 16;123(6):1121–1131. doi: 10.1016/j.cell.2005.11.020 16360040

15. Snetselaar R, van Moorsel CH, Kazemier KM, van der Vis JJ, Zanen P, van Oosterhout MF, et al. Telomere length in interstitial lung diseases. Chest 2015 Oct;148(4):1011–1018. doi: 10.1378/chest.14-3078 25973743

16. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A 2008 Sep 2;105(35):13051–13056. doi: 10.1073/pnas.0804280105 18753630

17. Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med 2008 Oct 1;178(7):729–737. doi: 10.1164/rccm.200804-550OC 18635888

18. Stuart BD, Lee JS, Kozlitina J, Noth I, Devine MS, Glazer CS, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med 2014 Jul;2(7):557–565. doi: 10.1016/S2213-2600(14)70124-9 24948432

19. Nawrot TS, Staessen JA, Gardner JP, Aviv A. Telomere length and possible link to X chromosome. Lancet 2004 Feb 14;363(9408):507–510. doi: 10.1016/S0140-6736(04)15535-9 14975611

20. Dlouha D, Maluskova J, Kralova Lesna I, Lanska V, Hubacek JA. Comparison of the relative telomere length measured in leukocytes and eleven different human tissues. Physiol Res 2014;63 Suppl 3:S343–50.

21. Friedrich U, Griese E, Schwab M, Fritz P, Thon K, Klotz U. Telomere length in different tissues of elderly patients. Mech Ageing Dev 2000 Nov 15;119(3):89–99. doi: 10.1016/s0047-6374(00)00173-1 11080530

22. Daniali L, Benetos A, Susser E, Kark JD, Labat C, Kimura M, et al. Telomeres shorten at equivalent rates in somatic tissues of adults. Nat Commun 2013;4:1597. doi: 10.1038/ncomms2602 23511462

23. Granick M, Kimura M, Kim S, Daniali L, Cao X, Herbig U, et al. Telomere dynamics in keloids. Eplasty 2011 Mar 16;11:e15. 21436892

24. Gardner JP, Kimura M, Chai W, Durrani JF, Tchakmakjian L, Cao X, et al. Telomere dynamics in macaques and humans. J Gerontol A Biol Sci Med Sci 2007 Apr;62(4):367–374. doi: 10.1093/gerona/62.4.367 17452729

25. Snetselaar R, van Batenburg AA, van Oosterhout MFM, Kazemier KM, Roothaan SM, Peeters T, et al. Short telomere length in IPF lung associates with fibrotic lesions and predicts survival. PLoS One 2017 Dec 27;12(12):e0189467. doi: 10.1371/journal.pone.0189467 29281671

26. Everaerts S, Lammertyn EJ, Martens DS, De Sadeleer LJ, Maes K, van Batenburg AA, et al. The aging lung: tissue telomere shortening in health and disease. Respir Res 2018 May 11;19(1):95-018–0794-z.

27. van Batenburg AA, Kazemier KM, Peeters T, van Oosterhout MFM, van dV, Grutters JC, et al. Cell Type–Specific Quantification of Telomere Length and DNA Double-Strand Breaks in Individual Lung Cells by Fluorescence In Situ Hybridization and Fluorescent Immunohistochemistry. J Histochem Cytochem 2018 03/12; 2018/04:0022155418761351.

28. Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. 2009 feb;37(3):e21.

29. Aubert G, Hills M, Lansdorp PM. Telomere length measurement-caveats and a critical assessment of the available technologies and tools. Mutat Res 2012 Feb 1;730(1–2):59–67. doi: 10.1016/j.mrfmmm.2011.04.003 21663926

30. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405–424. doi: 10.1038/gim.2015.30 25741868

31. Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J, Burdett L, et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet 2013 Apr;132(4):473–480. doi: 10.1007/s00439-013-1265-8 23329068

32. Petrovski S, Todd JL, Durheim MT, Wang Q, Chien JW, Kelly FL, et al. An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. Am J Respir Crit Care Med 2017 Jul 1;196(1):82–93. doi: 10.1164/rccm.201610-2088OC 28099038

33. Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, et al. Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci U S A 2018 Mar 6;115(10):E2358–E2365. doi: 10.1073/pnas.1720427115 29463756

34. Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. 2013 mar;123(3):996–1002.

35. Carulli L. Telomere shortening as genetic risk factor of liver cirrhosis. World J Gastroenterol 2015 Jan 14;21(2):379–383. doi: 10.3748/wjg.v21.i2.379 25593453

36. Martinez FJ, Flaherty K. Pulmonary function testing in idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006 Jun;3(4):315–321. doi: 10.1513/pats.200602-022TK 16738195

37. Chilosi M, Poletti V, Rossi A. The pathogenesis of COPD and IPF: distinct horns of the same devil? Respir Res 2012 Jan 11;13:3-9921–13-3.

38. Alder JK, Barkauskas CE, Limjunyawong N, Stanley SE, Kembou F, Tuder RM, et al. Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci U S A 2015 Apr 21;112(16):5099–5104. doi: 10.1073/pnas.1504780112 25840590

39. Naikawadi RP, Disayabutr S, Mallavia B, Donne ML, Green G, La JL, et al. Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis. JCI Insight 2016 Sep 8;1(14):e86704. doi: 10.1172/jci.insight.86704 27699234

40. Cha SI, Groshong SD, Frankel SK, Edelman BL, Cosgrove GP, Terry-Powers JL, et al. Compartmentalized expression of c-FLIP in lung tissues of patients with idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2010 Feb;42(2):140–148. doi: 10.1165/rcmb.2008-0419OC 19372246