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Targeted Deletion of Jun/AP-1 in Alveolar Epithelial Cells Causes Progressive Emphysema and Worsens Cigarette Smoke-Induced Lung Inflammation

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posted on 21.08.2012 by Narsa M. Reddy, Suryanaraya Vegiraju, Ashley Irving, Bogdan C. Paun, Irina G. Luzina, Sergei P. Atamas, Shyam Biswal, Navas-Acien Ana, Wayne Mitzner, Sekhar P. Reddy
The c-Jun/AP-1 transcriptional factor is known to regulate cell proliferation, apoptosis, and inflammatory responses; however its role in lung pathogenesis is largely unknown. Here we report that the declined expression levels of c-Jun mRNA and protein in the lung tissues of advanced chronic obstructive pulmonary disease (COPD) patients, and that 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 6 weeks of age, when exposed to chronic cigarette smoke, c-Jun mutant mice display more lung inflammation with perivascular and peribronchiolar infiltrates. These results demonstrate that the c-Jun/AP-1 pathway is critical for maintaining lung alveolar cell homeostasis and that loss of its expression can contribute to lung inflammation and progressive emphysema.

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Funding

This work was funded by National Institute of Health grants: RO1-ES11863, RO1-HL66109 and RO3-HL96933 (to SPR), the Flight Attendant Medical Research Institute CIA-award (to SPR), and the NIEHS training grant ES007141 (to SV). We thank both Pathology Core of the ALI-SCCOR (P50-HL073994) and COPD-SCCOR (P50-HL084945) supported by Hopkins-NIEHS center for utilizing their facilities and services in the present study. We also thank Dr. Erwin Wagner for proving c-Junf/f mice and Dr. Brigid Hogan for providing SPC-Cre mice.

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Publisher Statement

NOTICE: this is the author’s version of a work that was accepted for publication in the American Journal of Pathology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in the American Journal of Pathology, Vol 180, Issue 2, Feb 2012. DOI: 10.1016/j.ajpath.2011.10.029

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Elsevier

Language

en_US

issn

0002-9440

Issue date

01/02/2012

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