title: Telomerase and telomere length in pulmonary fibrosis.
abstract: In addition to its expression in stem cells and many cancers, telomerase activity is transiently induced in murine bleomycin (BLM)-induced pulmonary fibrosis with increased levels of telomerase transcriptase (TERT) expression, which is essential for fibrosis. To extend these observations to human chronic fibrotic lung disease, we investigated the expression of telomerase activity in lung fibroblasts from patients with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). The results showed that telomerase activity was induced in more than 66% of IPF lung fibroblast samples, in comparison with less than 29% from control samples, some of which were obtained from lung cancer resections. Less than 4% of the human IPF lung fibroblast samples exhibited shortened telomeres, whereas less than 6% of peripheral blood leukocyte samples from patients with IPF or hypersensitivity pneumonitis demonstrated shortened telomeres. Moreover, shortened telomeres in late-generation telomerase RNA component knockout mice did not exert a significant effect on BLM-induced pulmonary fibrosis. In contrast, TERT knockout mice exhibited deficient fibrosis that was independent of telomere length. Finally, TERT expression was up-regulated by a histone deacetylase inhibitor, while the induction of TERT in lung fibroblasts was associated with the binding of acetylated histone H3K9 to the TERT promoter region. These findings indicate that significant telomerase induction was evident in fibroblasts from fibrotic murine lungs and a majority of IPF lung samples, whereas telomere shortening was not a common finding in the human blood and lung fibroblast samples. Notably, the animal studies indicated that the pathogenesis of pulmonary fibrosis was independent of telomere length.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: Tianju
authors.initials: T
authors.lastname: Liu
authors.forename: Matthew
authors.initials: M
authors.lastname: Ullenbruch
authors.forename: Yoon
authors.initials: Y
authors.lastname: Young Choi
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Ding
authors.forename: Antoni
authors.initials: A
authors.lastname: Xaubet
authors.forename: Javier
authors.initials: J
authors.lastname: Pereda
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: Peter B
authors.initials: PB
authors.lastname: Bitterman
authors.forename: Craig A
authors.initials: CA
authors.lastname: Henke
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Sem H
authors.initials: SH
authors.lastname: Phan
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000542:Alveolitis, Extrinsic Allergic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D006657:Histones; D001761:Bleomycin; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse