Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo

Our plain-English summary of Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo, by A. Haegens, T.F. Barrett, J. Gell, et al (The Journal of Immunology, 2007).

The study

• Authors: A. Haegens, T.F. Barrett, J. Gell, A. Shukla, M. Macpherson, P. Vacek, M.E. Poynter, K.J. Butnor, Y.M. Janssen-Heininger, C. Steele, B.T. Mossman
• Journal: The Journal of Immunology
• Published: 2007;178(3):1800-8
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

To investigate the role of bronchiolar epithelial NF-kappaB activity in the development of inflammation and fibrogenesis in a murine model of asbestos inhalation, we used transgenic (Tg) mice expressing an IkappaBalpha mutant (IkappaBalphasr) resistant to phosphorylation-induced degradation and targeted to bronchial epithelium using the CC10 promoter. Sham and chrysotile asbestos-exposed CC10-IkappaBalphasr 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-1beta were increased (p < or = 0.05) in bronchoalveolar lavage fluid (BALF) from asbestos-exposed mice, but to a lesser extent (p < or = 0.05) in Tg(+) vs Tg(-) mice. Asbestos also caused increases in IL-4, MIP-1beta, and MCP-1 in BALF that were more elevated (p < or = 0.05) in Tg(+) mice at 9 days. Differential cell counts revealed eosinophils in BALF that increased (p < or = 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 < or = 0.05) in Tg(+) vs Tg(-) mice. Our findings demonstrate that airway epithelial NF-kappaB activity plays a role in orchestrating the inflammatory response as well as cell proliferation in response to asbestos.

In plain English

This was an animal inhalation experiment in transgenic mice. The authors used CC10-IkappaBalpha superrepressor transgenic mice (Tg+), in which NF-kappaB activation is blocked specifically in airway epithelium, and their transgene-negative littermates (Tg-), with five mice in each of four groups (sham and asbestos, Tg+ and Tg-) per time point, in duplicate experiments. Mice inhaled ambient air or NIEHS chrysotile asbestos, 6 hours a day, 5 days a week, for 3, 9 or 40 days. Asbestos caused nuclear translocation of Rel-A (p65) in distal bronchiolar epithelium of Tg- but not Tg+ mice. Asbestos increased bronchiolar epithelial Ki-67 labelling at all time points, but fewer distal bronchiolar epithelial cells were labelled in Tg+ mice at 40 days. Tg+ mice showed more mucin-positive bronchiolar epithelial cells and more eosinophils in lavage fluid at 9 days, with higher IL-4, MIP-1beta and MCP-1, while KC was lower at all time points and IL-6 and IL-1beta lower at 40 days. Focal peribronchiolar fibrosis occurred in both groups.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: controlled chrysotile asbestos inhalation study in transgenic and non-transgenic mice, examined at 3, 9 and 40 days
• Who was studied: CC10-IkappaBalpha superrepressor transgenic mice (Tg+) and transgene-negative littermates (Tg-), bred into the C57BL/6 background, 8-12 weeks old; 5 mice in each of four groups per time point, in duplicate experiments; University of Vermont animal inhalation facility
• Exposure: Inhalation of National Institute of Environmental Health Sciences reference chrysotile asbestos, 6 h/day, 5 days/week for 3, 9 or 40 days, aerosol target concentration 7-10 mg/m3 air; sham animals breathed ambient air
• Main results:
  • Nuclear translocation of Rel-A (p65) in distal bronchiolar epithelium occurred after asbestos in Tg- mice but not in Tg+ mice
  • Bronchiolar epithelial proliferation (Ki-67) rose with asbestos in both genotypes at all time points, but was lower in Tg+ mice at 40 days
  • Interstitial Ki-67 labelling was not raised by asbestos at 3 or 9 days; at 40 days overall proliferation was lower in Tg+ mice (averaged over sham and asbestos groups)
  • Mucin (Alcian blue) staining of bronchiolar epithelium at 9 days was greater in asbestos-exposed Tg+ than Tg- mice; at 3 days the percentage of bronchioles with mucus production was increased only in asbestos-exposed Tg+ mice
  • Eosinophils in bronchoalveolar lavage fluid were higher in asbestos-exposed Tg+ mice than Tg- mice at 9 days
  • KC in lavage fluid was lower in asbestos-exposed Tg+ mice at all time points
  • IL-4, MIP-1beta and MCP-1 in lavage fluid were higher in asbestos-exposed Tg+ than Tg- mice at 9 days
  • IL-6 and IL-1beta in lavage fluid of asbestos-exposed Tg+ mice at 40 days were decreased, alongside lower tgf-beta1 and tenascin gene expression
  • Asbestos produced mild to moderate peribronchiolar inflammation at 3 and 9 days and focal peribronchiolar fibrosis at 40 days in both genotypes, with no apparent transgene effect on histopathology
• The authors' conclusion: The authors concluded that NF-kappaB activation in airway epithelial cells modulates epithelial differentiation and chronic proliferation after asbestos, as well as cytokine and chemokine production and inflammatory cell recruitment, supporting a role for epithelial cells in responses to asbestos
• Limitations the authors state:
  • The authors stated that fibrosis in this model was minimal and that longer exposure times would be needed to show possible differences between transgenic and non-transgenic mice
  • The authors stated that further experiments would be needed before the link between IL-4 and the increased eosinophilia and mucin production could be called causal

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Epithelium, Chrysotile, Cytokine, Bronchoalveolar Lavage (BAL), Ki-67, Interstitial.

Related studies

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• Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-delta knockout mice — A. Shukla, K.M. Lounsbury, et al. (2007)
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• Analysis of asbestos-induced gene expression changes in bronchiolar epithelial cells using laser capture microdissection and quantitative reverse transcriptase-polymerase chain reaction — C.B. Manning, B.T. Mossman, et al. (2006)
• The relationship between large airway inflammation and airway metaplasia — W.W. Merrill, D. Carter, et al. (1991)

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