Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD

AUTHORS

Benjamin John , Plosa Erin , Sucre Jennifer , van der Meer Riet , Dave Shivangi , Gutor Sergey , Nichols David , Gulleman Peter , Jetter Christopher , Han Wei , Xin Matthew , Dinella Peter , Catanzarite Ashley , Kook Seunghyi , Dolma Kalsang , Lal Charitharth , Gaggar Amit , Blalock J Edwin , Newcomb Dawn , Richmond Bradley , Kropski Jonathan , Young Lisa , Guttentag Susan , Blackwell Timothy , . . 2020 10 27; ().

PMID: 33108351 [PubMed].

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-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage [postnatal day (PN)3 – PN5] but not alveolar stage (PN10 – PN12) of lung development disrupts elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progresses 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, both purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation down-regulated 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. While neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early life predisposition to COPD.