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

J Clin Invest. 2021 Jan 4;131(1):e139481. doi: 10.1172/JCI139481.


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 (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.

Keywords: COPD; Extracellular matrix; Inflammation; Neutrophils; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Elastin / genetics
  • Elastin / metabolism*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / metabolism
  • Mice
  • Mice, Transgenic
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Alveoli / pathology
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Pulmonary Disease, Chronic Obstructive / pathology


  • Elastin
  • Elane protein, mouse
  • Leukocyte Elastase