title: Targeted deletion of Jun/AP-1 in alveolar epithelial cells causes progressive emphysema and worsens cigarette smoke-induced lung inflammation.
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.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Narsa M
authors.initials: NM
authors.lastname: Reddy
authors.forename: Suryanaraya
authors.initials: S
authors.lastname: Vegiraju
authors.forename: Ashley
authors.initials: A
authors.lastname: Irving
authors.forename: Bogdan C
authors.initials: BC
authors.lastname: Paun
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Navas-Acien
authors.initials: NA
authors.lastname: Ana
authors.forename: Wayne
authors.initials: W
authors.lastname: Mitzner
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D000368:Aged; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011014:Pneumonia / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D012906:Smoke; D018808:Transcription Factor AP-1