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Published ahead of print on February 8, 2008, doi:10.1164/rccm.200707-1096OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 9, May 2008, 959-969

A more recent version of this article appeared on May 1, 2008
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Submitted on July 24, 2007
Accepted on February 7, 2008

Nuclear Factor kappa B Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

Cristen Pantano1, Jennifer L Ather1, John F Alcorn1, Matthew E Poynter2, Amy L Brown1, Amy S Guala1, Stacie L Beuschel1, Gilman B Allen, III2, Laurie A Whittaker2, Mieke Bevelander2, Charles G Irvin2, and Yvonne MW Janssen-Heininger1*

1 Department of Pathology, University of Vermont, Burlington, VT, USA, 2 Department of Medicine, University of Vermont, Burlington, VT, USA

* To whom correspondence should be addressed. E-mail: yvonne.janssen{at}uvm.edu.

Rationale: Nuclear factor kappa B is a prominent pro-inflammatory transcription factor that plays a critical role in allergic airway disease. Previous studies demonstrated that inhibition of nuclear factor kappa B in airway epithelium causes attenuation of allergic inflammation. Objectives: We sought to determine if selective activation of nuclear factor kappa B within the airway epithelium in absence of other agonists is sufficient to cause allergic airway disease. Methods: A transgenic mouse expressing a doxycycline-inducible, constitutively-active version of I{kappa}B kinase-beta under transcriptional control of the rat CC10 promoter, was generated. Measurements and Main Results: Following administration of doxycycline, expression of the CA-IKK{beta} transgene induced the nuclear translocation of RelA in airway epithelium. IKK{beta}-triggered activation of nuclear factor kappa B led to an increased content of neutrophils and lymphocytes, and concomitant production of pro-inflammatory mediators, responses that were not observed in transgenic mice not receiving doxycycline, or in transgene-negative littermate controls fed doxycycline. Unexpectedly, expression of the IKK{beta} transgene in airway epithelium was sufficient to cause airway hyperresponsiveness and smooth muscle thickening in absence of an antigen sensitization and challenge regimen, the presence of eosinophils, or the induction of mucus metaplasia. Conclusions: These findings demonstrate that selective activation nuclear factor kappa B in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.
Key words: Airway epithelium, Nuclear Factor kappa B, Inhibitory kappa B kinase beta, airway hyper responsiveness, smooth muscle cell




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