| Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice. | |
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MedLine Citation:
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PMID: 18952756 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Shortened telomeres are a normal consequence of cell division. However, telomere shortening past a critical point results in cellular senescence and death. To determine the effect of telomere shortening on lung, four generations of B6.Cg-Terc(tm1Rdp) mice, null for the terc component of telomerase, the holoenzyme that maintains telomeres, were bred and analyzed. Generational inbreeding of terc-/- mice caused sequential shortening of telomeres. Lung histology from the generation with the shortest telomeres (terc-/- F4) showed alveolar wall thinning and increased alveolar size. Morphometric analysis confirmed a significant increase in mean linear intercept (MLI). terc-/- F4 lung showed normal elastin deposition but had significantly decreased collagen content. Both airway and alveolar epithelial type 1 cells (AEC1) appeared normal by immunohistochemistry, and the percentage of alveolar epithelial type 2 cells (AEC2) per total cell number was similar to wild type. However, because of a decrease in distal lung cellularity, the absolute number of AEC2 in terc-/- F4 lung was significantly reduced. In contrast to wild type, terc-/- F4 distal lung epithelium from normoxia-maintained mice exhibited DNA damage by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick end labeling (TUNEL) and 8-oxoguanine immunohistochemistry. Western blotting of freshly isolated AEC2 lysates for stress signaling kinases confirmed that the stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) stress response pathway is stimulated in telomerase-null AEC2 even under normoxic conditions. Expression of downstream apoptotic/stress markers, including caspase-3, caspase-6, Bax, and HSP-25, was also observed in telomerase-null, but not wild-type, AEC2. TUNEL analysis of freshly isolated normoxic AEC2 showed that DNA strand breaks, essentially absent in wild-type cells, increased with each successive terc-/- generation and correlated strongly with telomere length (R(2) = 0.9631). Thus lung alveolar integrity, particularly in the distal epithelial compartment, depends on proper telomere maintenance. |
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Authors:
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Jooeun Lee; Raghava Reddy; Lora Barsky; Jessica Scholes; Hui Chen; Wei Shi; Barbara Driscoll |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-10-24 |
Journal Detail:
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Title: American journal of physiology. Lung cellular and molecular physiology Volume: 296 ISSN: 1040-0605 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-30 Completed Date: 2009-02-23 Revised Date: 2010-09-21 |
Medline Journal Info:
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Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
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Languages: eng Pagination: L57-70 Citation Subset: IM |
Affiliation:
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Saban Inst. for Research, Childrens Hospital Los Angeles, MS 35, 4661 Sunset Blvd., Los Angeles, CA 90027, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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metabolism Animals Biological Markers / metabolism Collagen / metabolism DNA Damage Elastin / metabolism Female In Situ Nick-End Labeling JNK Mitogen-Activated Protein Kinases / metabolism Male Mice Mice, Inbred C57BL Mice, Mutant Strains Oxidative Stress / physiology Peptides / metabolism Pulmonary Alveoli / metabolism, pathology* RNA / genetics*, metabolism Respiratory Mucosa / metabolism, pathology Signal Transduction / physiology Telomerase / genetics*, metabolism Telomere / genetics*, pathology* |
| Grant Support | |
ID/Acronym/Agency:
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2R01-HL-65352-7/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/Biological Markers; 0/Peptides; 0/Sftpc protein, mouse; 0/telomerase RNA; 63231-63-0/RNA; 9007-34-5/Collagen; 9007-58-3/Elastin; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.7.49/Telomerase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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