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.

The pattern recognition receptor Nod1 activates CCAAT/enhancer binding protein beta signalling in lung epithelial cells.

The innate immune receptor nucleotide-binding oligomerisation domain protein 1 (Nod1) recognises peptidoglycan containing meso-diaminopimelic acid found in all Gram-negative and some Gram-positive bacteria. Nod1 has been shown to activate nuclear factor (NF)-kappaB. The aim of the present study was to examine the expression of Nod1 in the lung, particularly in lung epithelial cells, and to investigate the activation of CCAAT/enhancer binding protein (C/EBP) transcription factors downstream of the Nod1 receptor in these cells. The expression of Nod1 in mouse lung was examined using immunohistochemistry. A tissue array was used to determine the expression pattern in the human lung. Signalling downstream of Nod1 was examined in the human lung epithelial cell type, BEAS-2B, by electrophoretic mobility shift assay and reporter gene activation. Nod1 expression was seen in various cell types in the lung, including epithelial cells. Activation of Nod1 in these cells resulted in modest activation of NF-kappaB, together with strong activation of the C/EBP transcription factors, particularly C/EBPbeta. This activation appears to be independent of de novo protein synthesis. The present study showed that nucleotide-binding oligomerisation domain protein 1 is expressed in lung epithelial cells. The results demonstrate a novel pathway downstream of the nucleotide-binding oligomerisation domain protein 1 receptor in these cells and suggest that C/EBPbeta may play a role in immune responses to meso-diaminopimelic acid-containing bacteria in the lung.