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Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence
BACKGROUND: Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to “low pulmonary reserve”, ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunc...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119663/ https://www.ncbi.nlm.nih.gov/pubmed/21713037 http://dx.doi.org/10.1371/journal.pone.0020712 |
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author | Calvi, Carla L. Podowski, Megan D'Alessio, Franco R. Metzger, Shana L. Misono, Kaori Poonyagariyagorn, Hataya Lopez-Mercado, Armando Ku, Therese Lauer, Thomas Cheadle, Christopher Talbot, C. Conover Jie, Chunfa McGrath-Morrow, Sharon King, Landon S. Walston, Jeremy Neptune, Enid R. |
author_facet | Calvi, Carla L. Podowski, Megan D'Alessio, Franco R. Metzger, Shana L. Misono, Kaori Poonyagariyagorn, Hataya Lopez-Mercado, Armando Ku, Therese Lauer, Thomas Cheadle, Christopher Talbot, C. Conover Jie, Chunfa McGrath-Morrow, Sharon King, Landon S. Walston, Jeremy Neptune, Enid R. |
author_sort | Calvi, Carla L. |
collection | PubMed |
description | BACKGROUND: Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to “low pulmonary reserve”, ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction. METHODS/PRINCIPAL FINDINGS: Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages. CONCLUSION/SIGNIFICANCE: Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology. |
format | Online Article Text |
id | pubmed-3119663 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31196632011-06-27 Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence Calvi, Carla L. Podowski, Megan D'Alessio, Franco R. Metzger, Shana L. Misono, Kaori Poonyagariyagorn, Hataya Lopez-Mercado, Armando Ku, Therese Lauer, Thomas Cheadle, Christopher Talbot, C. Conover Jie, Chunfa McGrath-Morrow, Sharon King, Landon S. Walston, Jeremy Neptune, Enid R. PLoS One Research Article BACKGROUND: Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to “low pulmonary reserve”, ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction. METHODS/PRINCIPAL FINDINGS: Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages. CONCLUSION/SIGNIFICANCE: Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology. Public Library of Science 2011-06-21 /pmc/articles/PMC3119663/ /pubmed/21713037 http://dx.doi.org/10.1371/journal.pone.0020712 Text en Calvi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Calvi, Carla L. Podowski, Megan D'Alessio, Franco R. Metzger, Shana L. Misono, Kaori Poonyagariyagorn, Hataya Lopez-Mercado, Armando Ku, Therese Lauer, Thomas Cheadle, Christopher Talbot, C. Conover Jie, Chunfa McGrath-Morrow, Sharon King, Landon S. Walston, Jeremy Neptune, Enid R. Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence |
title | Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence |
title_full | Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence |
title_fullStr | Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence |
title_full_unstemmed | Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence |
title_short | Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence |
title_sort | critical transition in tissue homeostasis accompanies murine lung senescence |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119663/ https://www.ncbi.nlm.nih.gov/pubmed/21713037 http://dx.doi.org/10.1371/journal.pone.0020712 |
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