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Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

Abstract Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.
PMID
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Authors

Mayor MeshTerms

Aging

Inflammation

Lung

Lung Diseases

Models, Biological

Keywords
Journal Title plos computational biology
Publication Year Start




PMID- 28837561
OWN - NLM
STAT- MEDLINE
DA  - 20170824
DCOM- 20170905
LR  - 20170910
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Linking)
VI  - 13
IP  - 8
DP  - 2017 Aug
TI  - Histologic and biochemical alterations predict pulmonary mechanical dysfunction
      in aging mice with chronic lung inflammation.
PG  - e1005570
LID - 10.1371/journal.pcbi.1005570 [doi]
AB  - Both aging and chronic inflammation produce complex structural and biochemical
      alterations to the lung known to impact work of breathing. Mice deficient in
      surfactant protein D (Sftpd) develop progressive age-related lung pathology
      characterized by tissue destruction/remodeling, accumulation of foamy macrophages
      and alteration in surfactant composition. This study proposes to relate changes
      in tissue structure seen in normal aging and in chronic inflammation to altered
      lung mechanics using a computational model. Alterations in lung function in aging
      and Sftpd -/- mice have been inferred from fitting simple mechanical models to
      respiratory impedance data (Zrs), however interpretation has been confounded by
      the simultaneous presence of multiple coexisting pathophysiologic processes. In
      contrast to the inverse modeling approach, this study uses simulation from
      experimental measurements to recapitulate how aging and inflammation alter Zrs.
      Histologic and mechanical measurements were made in C57BL6/J mice and congenic
      Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic
      computational model based on published airway morphometry was developed and Zrs
      was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in
      airway caliber and recruitment were estimated from mechanical measurements.
      Tissue elements were simulated using the constant phase model of viscoelasticity.
      Baseline elastance distribution was estimated in 8-week-old wild type mice, and
      stochastically varied for each condition based on experimentally measured
      alteration in elastic fiber composition, alveolar geometry and surfactant
      composition. Weighing reduction in model error against increasing model
      complexity allowed for identification of essential features underlying mechanical
      pathology and their contribution to Zrs. Using a maximum likelihood approach,
      alteration in lung recruitment and diminished elastic fiber density were shown
      predictive of mechanical alteration at airway opening, to a greater extent than
      overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung
      recruitment correlate with altered lung lining fluid composition independent of
      age or genotype.
FAU - Massa, Christopher B
AU  - Massa CB
AUID- ORCID: http://orcid.org/0000-0002-7319-3742
AD  - Department of Pharmacology and Toxicology, The Ernest Mario School of Pharmacy,
      Rutgers University, Piscataway, New Jersey, United States of America.
FAU - Groves, Angela M
AU  - Groves AM
AUID- ORCID: http://orcid.org/0000-0003-1810-5532
AD  - Department of Pharmacology and Toxicology, The Ernest Mario School of Pharmacy,
      Rutgers University, Piscataway, New Jersey, United States of America.
FAU - Jaggernauth, Smita U
AU  - Jaggernauth SU
AUID- ORCID: http://orcid.org/0000-0002-1716-826X
AD  - Department of Pharmacology and Toxicology, The Ernest Mario School of Pharmacy,
      Rutgers University, Piscataway, New Jersey, United States of America.
FAU - Laskin, Debra L
AU  - Laskin DL
AD  - Department of Pharmacology and Toxicology, The Ernest Mario School of Pharmacy,
      Rutgers University, Piscataway, New Jersey, United States of America.
FAU - Gow, Andrew J
AU  - Gow AJ
AD  - Department of Pharmacology and Toxicology, The Ernest Mario School of Pharmacy,
      Rutgers University, Piscataway, New Jersey, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170824
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
SB  - IM
MH  - *Aging/metabolism/pathology/physiology
MH  - Animals
MH  - Chronic Disease
MH  - Computational Biology
MH  - *Inflammation/metabolism/pathology/physiopathology
MH  - *Lung/anatomy & histology/metabolism/pathology/physiopathology
MH  - *Lung Diseases/metabolism/pathology/physiopathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Models, Biological
PMC - PMC5570219
EDAT- 2017/08/25 06:00
MHDA- 2017/09/07 06:00
CRDT- 2017/08/25 06:00
PHST- 2016/06/15 [received]
PHST- 2017/05/12 [accepted]
AID - 10.1371/journal.pcbi.1005570 [doi]
AID - PCOMPBIOL-D-16-00966 [pii]
PST - epublish
SO  - PLoS Comput Biol. 2017 Aug 24;13(8):e1005570. doi: 10.1371/journal.pcbi.1005570. 
      eCollection 2017 Aug.