Airway Epithelial NF-κB Activation Modulates Asbestos-Induced Inflammation and Mucin Production In Vivo

Abstract

To investigate the role of bronchiolar epithelial NF-κB activity in the development of inflammation and fibrogenesis in a murine model of asbestos inhalation, we used transgenic (Tg) mice expressing an IκBα mutant (IκBαsr) resistant to phosphorylation-induced degradation and targeted to bronchial epithelium using the CC10 promoter. Sham and chrysotile asbestos-exposed CC10-IκBαsr Tg+ and Tg− mice were examined for altered epithelial cell proliferation and differentiation, cytokine profiles, lung inflammation, and fibrogenesis at 3, 9, and 40 days. KC, IL-6 and IL-1β were increased (p ≤ 0.05) in bronchoalveolar lavage fluid (BALF) from asbestos-exposed mice, but to a lesser extent (p ≤ 0.05) in Tg+ vs Tg− mice. Asbestos also caused increases in IL-4, MIP-1β, and MCP-1 in BALF that were more elevated (p ≤ 0.05) in Tg+ mice at 9 days. Differential cell counts revealed eosinophils in BALF that increased (p ≤ 0.05) in Tg+ mice at 9 days, a time point corresponding with significantly increased numbers of bronchiolar epithelial cells staining positively for mucus production. At all time points, asbestos caused increased numbers of distal bronchiolar epithelial cells and peribronchiolar cells incorporating the proliferation marker, Ki-67. However, bronchiolar epithelial cell and interstitial cell labeling was diminished at 40 days (p ≤ 0.05) in Tg+ vs Tg− mice. Our findings demonstrate that airway epithelial NF-κB activity plays a role in orchestrating the inflammatory response as well as cell proliferation in response to asbestos.

Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica

“…To investigate the in vivo significance of the Nalp3 inflammasome in asbestos-induced inflammation, Nalp3 −/− and Nalp3 +/+ littermate mice were exposed for 9 days to chrysotile asbestos and markers of injury, inflammation and cytokine production were analysed on day 10. As previously shown (19,20), asbestos-exposed mice exhibited increased total cell numbers in bronchoalveolar lavage fluid (BALF) compared to air-exposed mice. However, significantly fewer cells were recruited to the lungs of Nalp3 −/− mice after exposure to asbestos (Fig.…”

Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols

“…We also determined that LPS exposure robustly increases TNFa, KC, and IL-6 levels in the BALF, with ENO treatment attenuating this response. All these inflammatory mediators are expressed by the respiratory epithelium and are NF-kB dependent (34,35), thus providing further evidence that NF-kB inhibition is the mechanism by which ENO attenuates airway inflammation. Lung inflammation is partially resolved by leukocyte apoptosis and, as SNO inhibition of NF-kB induces apoptosis (25), we examined whether ENO treatment increases apoptosis of airway inflammatory cells.…”

Coordinated Changes in mRNA Turnover, Translation, and RNA Processing Bodies in Bronchial Epithelial Cells following Inflammatory Stimulation

“…VOL. 28,2008 mRNA REGULATION IN ACTIVATED BRONCHIAL BEAS-2B CELLS 7421 activated bronchial epithelial cells, both in vitro and in vivo ( Fig. 6 and 7), suggest that decreased mRNA turnover, upregulation of translation, and the loss of P bodies are general features of activated bronchial epithelial cells during allergic airway inflammation.…”

“…Previous studies have revealed a wealth of knowledge about the complex transcriptional programs that regulate the expression of genes coding for various mediators of inflammation (13,28,30,56). However, relatively little is known about the mechanisms controlling the expression of these genes at posttranscriptional levels in inflammation.…”