A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis

Claude T Chapman, Philip Davy, Christopher Brampton, Seema S Ahuja, Steven Fauce, Pooja Shivshankar, Hieu Nguyen, Mahesh Ramaseshan, Robert Tressler, Zhu Pirot, Calvin B. Harley, Richard Allsopp

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

Original languageEnglish (US)
Article numbere58423
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 14 2013

Fingerprint

telomerase
Idiopathic Pulmonary Fibrosis
Telomerase
fibrosis
animal models
lungs
Lung
Fibrosis
epithelial cells
Epithelial Cells
Chemical activation
Molecules
Aplastic Anemia
Pulmonary Fibrosis
telomeres
Telomere
Bleomycin
Fibroblasts
bone marrow
anemia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chapman, C. T., Davy, P., Brampton, C., Ahuja, S. S., Fauce, S., Shivshankar, P., ... Allsopp, R. (2013). A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis. PLoS One, 8(3), [e58423]. https://doi.org/10.1371/journal.pone.0058423

A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis. / Chapman, Claude T; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B.; Allsopp, Richard.

In: PLoS One, Vol. 8, No. 3, e58423, 14.03.2013.

Research output: Contribution to journalArticle

Chapman, CT, Davy, P, Brampton, C, Ahuja, SS, Fauce, S, Shivshankar, P, Nguyen, H, Ramaseshan, M, Tressler, R, Pirot, Z, Harley, CB & Allsopp, R 2013, 'A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis', PLoS One, vol. 8, no. 3, e58423. https://doi.org/10.1371/journal.pone.0058423
Chapman, Claude T ; Davy, Philip ; Brampton, Christopher ; Ahuja, Seema S ; Fauce, Steven ; Shivshankar, Pooja ; Nguyen, Hieu ; Ramaseshan, Mahesh ; Tressler, Robert ; Pirot, Zhu ; Harley, Calvin B. ; Allsopp, Richard. / A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis. In: PLoS One. 2013 ; Vol. 8, No. 3.
@article{f335d0b0f47c40b28bbc4c4e18102a4e,
title = "A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis",
abstract = "The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.",
author = "Chapman, {Claude T} and Philip Davy and Christopher Brampton and Ahuja, {Seema S} and Steven Fauce and Pooja Shivshankar and Hieu Nguyen and Mahesh Ramaseshan and Robert Tressler and Zhu Pirot and Harley, {Calvin B.} and Richard Allsopp",
year = "2013",
month = "3",
day = "14",
doi = "10.1371/journal.pone.0058423",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis

AU - Chapman, Claude T

AU - Davy, Philip

AU - Brampton, Christopher

AU - Ahuja, Seema S

AU - Fauce, Steven

AU - Shivshankar, Pooja

AU - Nguyen, Hieu

AU - Ramaseshan, Mahesh

AU - Tressler, Robert

AU - Pirot, Zhu

AU - Harley, Calvin B.

AU - Allsopp, Richard

PY - 2013/3/14

Y1 - 2013/3/14

N2 - The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

AB - The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=84875031700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875031700&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0058423

DO - 10.1371/journal.pone.0058423

M3 - Article

C2 - 23516479

AN - SCOPUS:84875031700

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e58423

ER -