PLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity.

TitlePLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity.
Publication TypeJournal Article
Year of Publication2009
AuthorsYang Y-S, Yang M-CW, Guo Y, Williams OW, Weissler JC
JournalAm J Physiol Lung Cell Mol Physiol
Volume297
Issue3
PaginationL455-66
Date Published2009 Sep
ISSN1522-1504
KeywordsAged, Animals, Bronchioles, Cell Death, DNA-Binding Proteins, Epithelial Cells, Epithelium, Female, Humans, Lung Compliance, Male, Membrane Proteins, Mice, Mice, Transgenic, Middle Aged, Mitochondrial Proteins, Pulmonary Alveoli, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Pulmonary Surfactant-Associated Protein C, RNA-Binding Proteins, Transcription Factors, Transgenes
Abstract

Emphysema and bronchitis are major components of chronic obstructive pulmonary disease (COPD). Pleomorphic adenoma gene like-2 (PLAGL2), a zinc finger DNA-binding protein, is a transcription factor of the surfactant protein C (SP-C) promoter. Using an inducible transgenic mouse model, PLAGL2 and SP-C were ectopically expressed in lung epithelial cells of terminal bronchiole including the bronchoalveolar duct junction (BADJ), where only few cells express both genes under normal conditions. Ectopic PLAGL2 was also expressed in alveolar type II cells of induced mice. The overexpression of PLAGL2 was associated with the development of air space enlargement in the distal airways of adult mice. Defective alveolar septa and degraded airway fragments were found in the lesions of emphysematous lungs, indicating chronic airway destruction. Female mice were particularly sensitive to the effects of PLAGL2 overexpression with more dramatic emphysematous changes compared with male mice. In addition, analysis of the respiratory system mechanics in the mice indicated that the induction of PLAGL2 resulted in a significant increase in respiratory system compliance. Both TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 analyses showed that apoptotic activity was increased in epithelial cells within the emphysematous lesions as well as at the BADJ. Our results indicate that increased cell injury and/or death could be caused directly by the upregulation of PLAGL2 downstream gene, bNip3, a preapoptotic molecule that dimerizes with Bcl-2, or indirectly by the aberrant expression of SP-C-induced endoplasmic reticulum stress in epithelial cells. Finally, increased expression of PLAGL2 in alveolar epithelial cells correlated with the development of emphysema in the lung of COPD patients. In summary, our data from both animal and human studies support a novel pathogenic role of PLAGL2 in pulmonary emphysema, a critical aspect of severe COPD.

DOI10.1152/ajplung.00144.2009
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID19574421
PubMed Central IDPMC2739772
Grant ListR03-HL-095407 / HL / NHLBI NIH HHS / United States