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- Title
Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD.
- Authors
Benjamin, John T.; Plosa, Erin J.; Sucre, Jennifer M. S.; van der Meer, Riet; Dave, Shivangi; Gutor, Sergey; Nichols, David S.; Gulleman, Peter M.; Jetter, Christopher S.; Wei Han; Xin, Matthew; Dinella, Peter C.; Catanzarite, Ashley; Seunghyi Kook; Dolma, Kalsang; Lal, Charitharth V.; Gaggar, Amit; Blalock, J. Edwin; Newcomb, Dawn C.; Richmond, Bradley W.
- 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 (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.
- Subjects
LUNG development; OBSTRUCTIVE lung diseases; PNEUMONIA; ELASTIN; LEUCOCYTE elastase; PROTEIN metabolism; PULMONARY alveoli; PROTEINS; RESEARCH; INFLAMMATION; ANIMAL experimentation; RESEARCH methodology; PROTEOLYTIC enzymes; MEDICAL cooperation; EVALUATION research; NEUTROPHILS; COMPARATIVE studies; RESEARCH funding; MICE
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 1, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI139481