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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
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.
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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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