Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 49, Pages 17723-17728Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0509235102
Keywords
asthma; NF-kappa B; eosinophil; TGF-beta
Categories
Funding
- NIAID NIH HHS [R01 AI038425, R37 AI038425, AI38425] Funding Source: Medline
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In response to inflammation or injury, airway epithelial cells express inducible genes that may contribute to allergen-induced airway remodeling. To determine the contribution of epithelial cell NF-kappa B activation to the remodeling response, we generated CC10-Cre(tg)/ikk beta(Delta/Delta) mice in which NF-KB signaling through I kappa B kinase beta (IKK beta) is selectively ablated in the airway epithelium by conditional Cre-recombinase expression from the Clara cell (CC10) promoter. Repetitive ovalbumin challenge of mice deficient in airway epithelial lKK beta prevented nuclear translocation of the ReIA NF-KB subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cre(tg)/Ikk beta(Delta/Delta) mice compared with littermate controls as assessed by peribronchial trichrome staining and total lung collagen content. Levels of airway mucus, airway eosinophils, and peribronchial CD4(+) cells in ovalbumin-challenged mice were also reduced significantly upon airway epithelial Ikk beta ablation. The diminished inflammatory response was associated with reduced expression of NF-kappa B-regulated chemokines, including eotaxin-1 and thymus- and activation-regulated chemokine, which attract eosinophils and Th2 cells, respectively, into the airway. The number of peribronchial cells expressing TGF-beta 1, as well as TGF-beta 1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium lKK beta. Overall, these studies show an important role for NF-KB regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.
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