Lung-specific inactivation of CCAAT/enhancer binding protein alpha causes a pathological pattern characteristic of COPD.

The link between respiratory complications in prematurely born infants and susceptibility for developing chronic obstructive pulmonary disease (COPD) is receiving increasing attention. We have previously found that CCAAT/enhancer binding protein (C/EBP) activity in airway epithelial cells of COPD patients is decreased compared to healthy smokers, suggesting a previously unknown role for C/EBPs in COPD pathogenesis. To investigate the role of the transcription factor C/EBPalpha in lung development and its potential role in COPD, mice with a lung epithelial-specific disruption of the C/EBPalpha gene (Cebpa(DeltaLE)) were generated using Cre-mediated excision, and the resulting pathology was studied during development and into adulthood. Cebpa(DeltaLE) mice exhibit impaired lung development and epithelial differentiation, as well as affected vascularity. Furthermore, Cebpa(DeltaLE) mice that survive until adulthood develop a severe pathological picture with irregular emphysema; bronchiolitis, including goblet cell hyperplasia, bronchiolar metaplasia, fibrosis and mucus plugging; and an inflammatory cell and gene expression profile similar to COPD. Cebpa(DeltaLE) mice display lung immaturity during development, and adult Cebpa(DeltaLE) mice develop a majority of the histopathological and inflammatory characteristics of COPD. Cebpa(DeltaLE) mice could thus provide new valuable insights into understanding the long-term consequences of lung immaturity and the link to susceptibility of developing COPD.