Targeted deletion of Jun/AP-1 in alveolar epithelial cells causes progressive emphysema and worsens cigarette smoke-induced lung inflammation

TitleTargeted deletion of Jun/AP-1 in alveolar epithelial cells causes progressive emphysema and worsens cigarette smoke-induced lung inflammation
Publication TypeJournal Article
Year of Publication2012
AuthorsReddy NM, Vegiraju S, Irving A, Paun BC, Luzina IG, Atamas SP, Biswal S, Ana N-A, Mitzner W, Reddy SP
JournalAm J Pathol
Volume180
Issue2
Pagination562-74
Date Published2012 Feb
ISSN1525-2191
KeywordsAged, Animals, Antioxidants, Cytokines, Female, Gene Deletion, Gene Expression, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Pneumonia, Proto-Oncogene Proteins c-jun, Pulmonary Alveoli, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Respiratory Mucosa, RNA, Messenger, Smoke, Smoking, Transcription Factor AP-1
Abstract

Chronic obstructive pulmonary disease appears to occur slowly and progressively over many years, with both genetic factors and environmental modifiers contributing to its pathogenesis. Although the c-Jun/activator protein 1 transcriptional factor regulates cell proliferation, apoptosis, and inflammatory responses, its role in lung pathogenesis is largely unknown. In this study, we report decreased expression levels of c-Jun mRNA and protein in the lung tissues of patients with advanced chronic obstructive pulmonary disease, and the genetic deletion of c-Jun specifically in alveolar epithelial cells causes progressive emphysema with lung inflammation and alveolar air space enlargement, which are cardinal features of emphysema. Although mice lacking c-Jun specifically in lung alveolar epithelial cells appear normal at the age of 6 weeks, when exposed to long-term cigarette smoke, c-Jun-mutant mice display more lung inflammation with perivascular and peribronchiolar infiltrates compared with controls. These results demonstrate that the c-Jun/activator protein 1 pathway is critical for maintaining lung alveolar cell homeostasis and that loss of its expression can contribute to lung inflammation and progressive emphysema.

DOI10.1016/j.ajpath.2011.10.029
Alternate JournalAm. J. Pathol.
PubMed ID22265050
PubMed Central IDPMC3349866
Grant ListES007141 / ES / NIEHS NIH HHS / United States
P50-HL073994 / HL / NHLBI NIH HHS / United States
P50HL084945 / HL / NHLBI NIH HHS / United States
R01-ES11863 / ES / NIEHS NIH HHS / United States
R01-HL66109 / HL / NHLBI NIH HHS / United States
R03-HL96933 / HL / NHLBI NIH HHS / United States