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Neutrophilic inflammation during lung development disrupts elastin assembly and
predisposes adult mice to COPD.
Authors Benjamin JT, Plosa EJ, Sucre JM, van der Meer R, Dave S, Gutor S, Nichols DS,
Gulleman PM, Jetter CS, Han W, Xin M, Dinella PC, Catanzarite A, Kook S, Dolma
K, Lal CV, Gaggar A, Blalock JE, Newcomb DC, Richmond BW, Kropski JA, Young LR,
Guttentag SH, Blackwell TS
Submitted By Submitted Externally on 2/22/2021
Status Published
Journal The Journal of clinical investigation
Year 2021
Date Published 1/1/2021
Volume : Pages 131 : Not Specified
PubMed Reference 33108351
Abstract Emerging evidence indicates that early life events can increase the risk for
developing chronic obstructive pulmonary disease (COPD). Using an inducible
transgenic mouse model for NF-?B activation in the airway epithelium, we found
that a brief period of inflammation during the saccular stage (P3-P5) but not
alveolar stage (P10-P12) of lung development disrupted elastic fiber assembly,
resulting in permanent reduction in lung function and development of a COPD-like
lung phenotype that progressed through 24 months of age. Neutrophil depletion
prevented disruption of elastic fiber assembly and restored normal lung
development. Mechanistic studies uncovered a role for neutrophil elastase (NE)
in downregulating expression of critical elastic fiber assembly components,
particularly fibulin-5 and elastin. Further, purified human NE and NE-containing
exosomes from tracheal aspirates of premature infants with lung inflammation
downregulated elastin and fibulin-5 expression by saccular-stage mouse lung
fibroblasts. Together, our studies define a critical developmental window for
assembling the elastin scaffold in the distal lung, which is required to support
lung structure and function throughout the lifespan. Although neutrophils play a
well-recognized role in COPD development in adults, neutrophilic inflammation
may also contribute to early-life predisposition to COPD.


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