Critical transition in tissue homeostasis accompanies murine lung senescence

Carla L. Calvi, Megan Podowski, Franco D'Alessio, Shana L. Metzger, Kaori Misono, Hataya Poonyagariyagorn, Armando Lopez-Mercado, Therese Ku, Thomas Lauer, Christopher Cheadle, C. Conover Talbot, Chunfa Jie, Sharon A McGrath-Morrow, Landon Stuart King, Jeremy D Walston, Enid Neptune

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere20712
JournalPLoS One
Volume6
Issue number6
DOIs
StatePublished - 2011

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Tissue homeostasis
homeostasis
Homeostasis
Aging of materials
lungs
Lung
mice
Oxidative stress
Macrophages
Pancreatic Elastase
Chemical activation
Cell death
elastase
Immunoglobulins
Transcriptome
transcriptome
B-lymphocytes
cell death
Tissue
Oxidative Stress

ASJC Scopus subject areas

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

Cite this

Critical transition in tissue homeostasis accompanies murine lung senescence. / Calvi, Carla L.; Podowski, Megan; D'Alessio, Franco; Metzger, Shana L.; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; Cheadle, Christopher; Talbot, C. Conover; Jie, Chunfa; McGrath-Morrow, Sharon A; King, Landon Stuart; Walston, Jeremy D; Neptune, Enid.

In: PLoS One, Vol. 6, No. 6, e20712, 2011.

Research output: Contribution to journalArticle

Calvi, CL, Podowski, M, D'Alessio, F, Metzger, SL, Misono, K, Poonyagariyagorn, H, Lopez-Mercado, A, Ku, T, Lauer, T, Cheadle, C, Talbot, CC, Jie, C, McGrath-Morrow, SA, King, LS, Walston, JD & Neptune, E 2011, 'Critical transition in tissue homeostasis accompanies murine lung senescence', PLoS One, vol. 6, no. 6, e20712. https://doi.org/10.1371/journal.pone.0020712
Calvi, Carla L. ; Podowski, Megan ; D'Alessio, Franco ; Metzger, Shana L. ; Misono, Kaori ; Poonyagariyagorn, Hataya ; Lopez-Mercado, Armando ; Ku, Therese ; Lauer, Thomas ; Cheadle, Christopher ; Talbot, C. Conover ; Jie, Chunfa ; McGrath-Morrow, Sharon A ; King, Landon Stuart ; Walston, Jeremy D ; Neptune, Enid. / Critical transition in tissue homeostasis accompanies murine lung senescence. In: PLoS One. 2011 ; Vol. 6, No. 6.
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AU - Calvi, Carla L.

AU - Podowski, Megan

AU - D'Alessio, Franco

AU - Metzger, Shana L.

AU - Misono, Kaori

AU - Poonyagariyagorn, Hataya

AU - Lopez-Mercado, Armando

AU - Ku, Therese

AU - Lauer, Thomas

AU - Cheadle, Christopher

AU - Talbot, C. Conover

AU - Jie, Chunfa

AU - McGrath-Morrow, Sharon A

AU - King, Landon Stuart

AU - Walston, Jeremy D

AU - Neptune, Enid

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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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