PMID- 28101062
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1664-042X (Print)
IS  - 1664-042X (Electronic)
IS  - 1664-042X (Linking)
VI  - 7
DP  - 2016
TI  - Elastase-Induced Parenchymal Disruption and Airway Hyper Responsiveness in Mouse 
      Precision Cut Lung Slices: Toward an Ex vivo COPD Model.
PG  - 657
LID - 10.3389/fphys.2016.00657 [doi]
LID - 657
AB  - Background: COPD is a progressive lung disease characterized by emphysema and 
      enhanced bronchoconstriction. Current treatments focused on bronchodilation can 
      delay disease progression to some extent, but recovery or normalization of loss 
      of lung function is impossible. Therefore, novel therapeutic targets are needed. 
      The importance of the parenchyma in airway narrowing is increasingly recognized. 
      In COPD, the parenchyma and extracellular matrix are altered, possibly affecting 
      airway mechanics and enhancing bronchoconstriction. Our aim was to set up a 
      comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a 
      pathophysiology resembling that of COPD and integrate multiple readouts in order 
      to study the relationship between parenchyma, airway functionality, and lung 
      repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo 
      with elastase (2.5 mug/ml) or H(2)O(2) (200 muM) for 16 h. Following treatment, 
      parenchymal structure, airway narrowing, and gene expression levels of alveolar 
      Type I and II cell repair were assessed. Results: Following elastase, but not 
      H(2)O(2) treatment, slices showed a significant increase in mean linear intercept 
      (Lmi), reflective of emphysema. Only elastase-treated slices showed 
      disorganization of elastin and collagen fibers. In addition, elastase treatment 
      lowered both alveolar Type I and II marker expression, whereas H(2)O(2) 
      stimulation lowered alveolar Type I marker expression only. Furthermore, 
      elastase-treated slices showed enhanced methacholine-induced airway narrowing as 
      reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) 
      and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway 
      opening. The increase in pEC50 correlated with an increase in mean Lmi. 
      Conclusion: Using this model, we show that structural disruption of elastin 
      fibers leads to impaired alveolar repair, disruption of the parenchymal 
      compartment, and altered airway biomechanics, enhancing airway contraction. This 
      finding may have implications for COPD, as the amount of elastin fiber and 
      parenchymal tissue disruption is associated with disease severity. Therefore, we 
      suggest that PCLS can be used to model certain aspects of COPD pathophysiology 
      and that the parenchymal tissue damage observed in COPD contributes to lung 
      function decline by disrupting airway biomechanics. Targeting the parenchymal 
      compartment may therefore be a promising therapeutic target in the treatment of 
      COPD.
FAU - Van Dijk, Eline M
AU  - Van Dijk EM
AD  - Department of Molecular Pharmacology, University of GroningenGroningen, 
      Netherlands; Groningen Research Institute for Asthma and COPD, University Medical 
      Center Groningen, University of GroningenGroningen, Netherlands.
FAU - Culha, Sule
AU  - Culha S
AD  - Department of Molecular Pharmacology, University of GroningenGroningen, 
      Netherlands; Groningen Research Institute for Asthma and COPD, University Medical 
      Center Groningen, University of GroningenGroningen, Netherlands.
FAU - Menzen, Mark H
AU  - Menzen MH
AD  - Department of Molecular Pharmacology, University of GroningenGroningen, 
      Netherlands; Groningen Research Institute for Asthma and COPD, University Medical 
      Center Groningen, University of GroningenGroningen, Netherlands.
FAU - Bidan, Cecile M
AU  - Bidan CM
AD  - Universite Grenoble Alpes, Centre National de la Recherche Scientifique, LIPhy 
      Grenoble, France.
FAU - Gosens, Reinoud
AU  - Gosens R
AD  - Department of Molecular Pharmacology, University of GroningenGroningen, 
      Netherlands; Groningen Research Institute for Asthma and COPD, University Medical 
      Center Groningen, University of GroningenGroningen, Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20170104
PL  - Switzerland
TA  - Front Physiol
JT  - Frontiers in physiology
JID - 101549006
PMC - PMC5209351
OTO - NOTNLM
OT  - airway mechanics
OT  - chronic obstructive pulmonary disease
OT  - extracellular matrix
EDAT- 2017/01/20 06:00
MHDA- 2017/01/20 06:01
PMCR- 2017/01/04
CRDT- 2017/01/20 06:00
PHST- 2016/09/27 00:00 [received]
PHST- 2016/12/14 00:00 [accepted]
PHST- 2017/01/20 06:00 [entrez]
PHST- 2017/01/20 06:00 [pubmed]
PHST- 2017/01/20 06:01 [medline]
PHST- 2017/01/04 00:00 [pmc-release]
AID - 10.3389/fphys.2016.00657 [doi]
PST - epublish
SO  - Front Physiol. 2017 Jan 4;7:657. doi: 10.3389/fphys.2016.00657. eCollection 2016.