Telomerase in pulmonary fibrosis: A link to alveolar cell apoptosis and differentiation
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Department of Pneumonology, University Hospital of Alexandroupolis, Medical school, Democritus University of Thrace, Greece
Department of Pathology, VA Hospital - N.I.M.T.S, Athens, Greece
Department of Pathology, University Hospital of Heraklion, Crete
Department of Pathology, Sotiria General Hospital, Athens, Greece
Department of Cardiothoracic surgery, University Hospital of Alexandroupolis, Medical school, Democritus University of Thrace, Greece
Department of Hematology, University Hospital of Alexandroupolis, Medical school, Democritus University of Thrace, Greece
Argyris Tzouvelekis   

Medical School, Democritus University of Thrace, Department of Pneumonology, University Hospital of Alexandroupolis, Alexandroupolis 68100
Pneumon 2010;23(3):224–239
Telomerase is crucial for extended life span and differentiation and is linked to immortality. Therefore, its role may be crucial in the pathogenesis of pulmonary fibrosis. Our objective was to implicate telomerase in the pathogenesis of idiopathic fibrotic lung disease.

Patients and Methods:
Assessment of telomerase activity and expression was carried out using TRAP detection kit and qRT-PCR. Experimental procedure was enhanced by a series of immunostainings and fluorescence in situ hybridization analysis in tissue microarrays constructed with tissue samples from patients with idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP).

We demonstrated significant downregulation of telomerase expression and activity in patients with fibrotic lung disease compared to controls. Immunolocalization studies coupled by FISH analysis revealed the presence of two subpopulations of type II AECs based on their telomerase expression levels: telomerase positive type II AECs, mainly overlying areas of active fibrosis and telomerase negative type II AECs, mainly localized in areas of established fibrosis.

Downregulation of telomerase expression and activity in IPF may indicate a causal relationship between low telomerase expression and disease pathogenesis. The duality phenomenon in telomerase expression suggests that telomerase may regulate the fate of AECs towards either an apoptotic or a mesenchymal phenotype contributing directly to fibrosis.

This work was partly supported by the Society for Respiratory Research and Treatment of Eastern Macedonia and Thrace (AT, DB) and a European Commission Network of Excellence grant QLRT-CT-2001-01407 (V.A.) and a Hellenic Ministry for Development grant GSRTPENED- 136 (V.A.). AT is a recipient of an annual research grant in respiratory medicine provided by GlaxoSmithKline for the year 2005-2006. We are also grateful to Vassileios Vasdekis (Department of Economics and Business, Kapodistrian University of Athens, Greece) for carrying out the statistical analysis of our manuscript.
Greider CW. Telomeres, telomerase and senescence. Bioessays 1990;12:363-369.
Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 1989;337:331-337.
Nakamura TM, Morin GB, Chapman KB, et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997;277:955-959.
Harley CB. Human ageing and telomeres. Ciba Found Symp 1997;211:129-39.
Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990;345:458-460.
Satoh H, Hiyama K, Takeda M, et al. Telomere shortening in peripheral blood cells was related with aging but not with white blood cell count. Jpn J Hum Genet 1996;41: 413-417.
Hiyama K, Hirai Y, Kyoizumi S, et al. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 1995;155:3711-3715.
Funk WD, Wang CK, Shelton DN, et al. Telomerase expression restores dermal integrity to in vitro-aged fibroblasts in a reconstituted skin model. Exp Cell Res 2000;258:270-278.
Nakayama J, Tahara H, Tahara E, et al. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet 1998;18:65-68.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.
Demedts M, Thomeer M. New classifications and concepts of pathogenesis and management of diffuse interstitial lung diseases. Verh K Acad Geneeskd Belg 2003;65:337-350.
Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136- 151.
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304.
Lappi-Blanco E, Kaarteenaho-Wiik R, Salo S, et al. Laminin-5 gamma2 chain in cryptogenic organizing pneumonia and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004;169:27-33.
Phan SH. Fibroblast phenotypes in pulmonary fibrosis. Am J Respir Cell Mol Biol 2003;29(3 Suppl):S87-92.
Liu T, Nozaki Y, Phan SH. Regulation of telomerase activity in rat lung fibroblasts. Am J Respir Cell Mol Biol 2002;26:534-540.
Nozaki Y, Liu T, Hatano K, et al. Induction of telomerase activity in fibroblasts from bleomycin-injured lungs. Am J Respir Cell Mol Biol 2000;23:p. 460-5.
Schissel SL, Layne MD. Telomerase, myofibroblasts, and pulmonary fibrosis: Am J Respir Cell Mol Biol 2006;34:520-522.
Liu T, Hu B, Chung MJ, et al. Telomerase regulation of myofibroblast differentiation. Am J Respir Cell Mol Biol 2006;34:625- 633.
Fridlender ZG, Cohen PY, Golan O, et al. Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis. Eur Respir J 2007;30:205-213.
Liu T, Chung MJ, Ullenbruch M, et al. Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice. J Clin Invest 2007;117:3800-3809.
Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007;356:1317-1326.
Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA 2007;104:7552-7557.
Marshall RP, Puddicombe A, Cookson WO, et al. Adult familial cryptogenic fibrosing alveolitis in the United Kingdom. Thorax 2000;55:143-146.
Tzouvelekis A, Karameris A, Bouros D, et al. Morphometric study of telomerase activity in patients with idiopathic pulmonary fibrosis with the use of tissue microarrays. Eur Respir J 2006.
Tzouvelekis A, Tsiambas E, Karameris A, et al. Induction of Telomerase Expression in Alveolar Type II Epithelial Cells in Patients with Idiopathic Pulmonary Fibrosis and Cryptogenic Organizing Pneumonia. A Tissue Microarray Study. Am J Respir Crit Care Med, 2007.
Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994;266:2011-2015.
Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998;4:844-847.
Liu X, Zou H, Slaughter C, et al. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 1997;89:175-184.
Utz JP, Ryu JH, Myers JL, et al. Usual interstitial pneumonia complicating dyskeratosis congenita. Mayo Clin Proc 2005;80:817- 821.
Armanios, M, Chen JL, Chang YP, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci USA 2005;102:15960-15964.
Golan-Gerstl R, Wallach-Dayan SB, Amir G, et al. Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis. Am J Respir Cell Mol Biol 2007;36:270-275.
Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006;3:350- 356.
Uhal BD, Joshi I, True AL, et al. Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro. Am J Physiol 1995;269:L819-828.
Lappi-Blanco E, Soini Y, Kinnula V, et al. VEGF and bFGF are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia. J Pathol 2002;196:220- 227.
Lappi-Blanco E, Kaarteenaho-Wiik R, Soini Y, et al. Intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia are highly capillarized. Hum Pathol 1999;30:1192- 1196.
Tzouvelekis A, Anevlavis S, Bouros D. Angiogenesis in interstitial lung diseases: a pathogenetic hallmark or a bystander? Respir Res 2006;7:82.
Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 2006;3:364-372.
Strieter RM. Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 2005;128(5 Suppl 1):526S-532S.
Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 2006;103:13180-13185.
Tzouvelekis A, Harokopos V, Paparountas T, et al. Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. Am J Respir Crit Care Med 2007;176:1108-1119.
Tsiambas E, Stamatelopoulos A, Baltayiannis N, et al. Evaluation of combined telomerase and c-myc expression in non-small cell lung carcinomas using tissue microarrays and computerized image analysis. J Buon 2005;10:533-539.
Reddy R, Buckley S, Doerken M, et al. Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. Am J Physiol Lung Cell Mol Physiol 2004;286:15.
Selman M, Pardo A. Idiopathic pulmonary fibrosis: misunderstandings between epithelial cells and fibroblasts? Sarcoidosis Vasc Diffuse Lung Dis 2004;21:165-72.
Selman M, Pardo A. The epithelial/fibroblastic pathway in the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2003;29(3 Suppl):S93-97.
Antoniou KM, Nicholson AG, Dimadi M, et al. Long-term clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis. Eur Respir J 2006;28:496-504.
Bouros D, Antoniou KM. Current and future therapeutic approaches in idiopathic pulmonary fibrosis. Eur Respir J 2005;26:693-702.
Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med 2007;175:875-880.
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-133.