Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

被引:80
作者
Liu, Tianju
Chung, Myoung Ja
Ullenbruch, Matthew
Yu, Hongfeng
Jin, Hong
Hu, Biao
Choi, Yoon Young
Ishikawa, Fuyuki
Phan, Sem H.
机构
[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[2] Kyoto Univ, Grad Sch Biostudies, Dept Gene Mech, Lab Cell Cycle Regulat, Kyoto, Japan
关键词
D O I
10.1172/JCI32369
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
In addition to its well-known expression in the germline and in cells of certain cancers, telomerase activity is induced in lung fibrosis, although its role in this process is unknown. To identify the pathogenetic importance of telomerase in lung fibrosis, we examined the effects of telomerase reverse transcriptase (TERT) deficiency in a murine model of pulmonary injury. TERT-deficient mice showed significantly reduced lung fibrosis following bleomycin (BLM) insult. This was accompanied by a significant reduction in expression of lung alpha-SMA, a marker of myofibroblast differentiation. Furthermore, lung fibroblasts isolated from BLM-treated TERT-deficient mice showed significantly decreased proliferation and increased apoptosis rates compared with cells isolated from control mice. Transplantation of WT BM into TERT-deficient mice restored BLM-induced lung telomerase activity and fibrosis to WT levels. Conversely, transplantation of BM from TERT-deficient mice into WT recipients resulted in reduced telomerase activity and fibrosis. These findings suggest that induction of telomerase in injured lungs may be caused by BM-derived cells, which appear to play an important role in pulmonary fibrosis. Moreover, TERT induction is associated with increased survival of lung fibroblasts, which favors the development of fibrosis instead of injury resolution.
引用
收藏
页码:3800 / 3809
页数:10
相关论文
共 58 条
[1]   Telomerase mutations in families with idiopathic pulmonary fibrosis [J].
Armanios, Mary Y. ;
Chen, Julian J. -L. ;
Cogan, Joy D. ;
Alder, Jonathan K. ;
Ingersoll, Roxann G. ;
Markin, Cheryl ;
Lawson, William E. ;
Xie, Mingyi ;
Vulto, Irma ;
Phillips, John A., III ;
Lansdorp, Peter M. ;
Greider, Carol W. ;
Loyd, James E. .
NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (13) :1317-1326
[2]   Bleomycin-induced DNA damage and repair in Xenopus laevis and Xenopus tropicalis [J].
Banner, Sarah H. ;
Ruben, Laurens N. ;
Johnson, Rachel O. .
JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY, 2007, 307A (02) :84-90
[3]   Telomerase is not an epidermal stem cell marker and is downregulated by calcium [J].
Bickenbach, JR ;
Vornwald-Dogan, V ;
Bachor, C ;
Bleuel, K ;
Schnapp, G ;
Boukamp, P .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1998, 111 (06) :1045-1052
[4]   Telomeres and human disease: Ageing, cancer and beyond [J].
Blasco, MA .
NATURE REVIEWS GENETICS, 2005, 6 (08) :611-622
[5]   Telomerase beyond telomeres [J].
Blasco, MA .
NATURE REVIEWS CANCER, 2002, 2 (08) :627-632
[6]  
Blasco Maria A., 1999, Genes and Development, V13, P2353, DOI 10.1101/gad.13.18.2353
[7]   Extension of life-span by introduction of telomerase into normal human cells [J].
Bodnar, AG ;
Ouellette, M ;
Frolkis, M ;
Holt, SE ;
Chiu, CP ;
Morin, GB ;
Harley, CB ;
Shay, JW ;
Lichtsteiner, S ;
Wright, WE .
SCIENCE, 1998, 279 (5349) :349-352
[8]   Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: Effect of ectopic hTERT [J].
Brachner, A ;
Sasgary, S ;
Pirker, C ;
Rodgarkia, C ;
Mikula, M ;
Mikulits, W ;
Bergmeister, H ;
Setinek, U ;
Wieser, M ;
Chin, SF ;
Caldas, C ;
Micksche, M ;
Cerni, C ;
Berger, W .
CANCER RESEARCH, 2006, 66 (07) :3584-3592
[9]   TELOMERASE ACTIVITY IN NORMAL AND MALIGNANT HEMATOPOIETIC-CELLS [J].
BROCCOLI, D ;
YOUNG, JW ;
DELANGE, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9082-9086
[10]   Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase [J].
Counter, CM ;
Meyerson, M ;
Eaton, EN ;
Ellisen, LW ;
Caddle, SD ;
Haber, DA ;
Weinberg, RA .
ONCOGENE, 1998, 16 (09) :1217-1222