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Published ahead of print on July 7, 2005, doi:10.1164/rccm.200412-1647OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 8, October 2005, 962-971

A more recent version of this article appeared on October 15, 2005
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Submitted on December 8, 2004
Accepted on July 3, 2005

IK-B Kinase-2 Inhibitor Blocks Inflammation in Human Airway Smooth Muscle and a rat Model of Asthma

Mark A Birrell1, Elizabeth Hardaker1, Sissie Wong1, Kerryn McCluskie1, Matthew Catley1, Jorge De Alba1, Robert Newton1, Saleem Haj-Yahia2, K. Tao Pun3, Clarissa J Watts3, Robert J Shaw3, Tony J Savage3, and Maria G Belvisi1*

1 Department of Respiratory Pharmacology, Imperial College, Faculty of Medicine, National Heart and Lung Institute, London, United Kingdom, 2 Royal Brompton and Harefield Hospital, London, United Kingdom, 3 Department of Asthma Biology and Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline PLC, Stevenage, United Kingdom

* To whom correspondence should be addressed. E-mail: m.belvisi{at}imperial.ac.uk.

Rationale: NF-{kappa}B is a transcription factor known to regulate the expression of many inflammatory genes including cytokines, chemokines and adhesion molecules. NF-{kappa}B is held inactive in the cytoplasm, bound to I-{kappa}B. The removal of I-{kappa}B, via the actions of I-{kappa}B kinase-2, allows NF-{kappa}B to enter the nucleus. Objectives: To determine the impact of inhibiting I-{kappa}B kinase-2 on in vitro and in vivo models of airway inflammation. Methods: The effect of inhibiting I-{kappa}B kinase-2 was assessed in stimulated, cultured, primary human airway smooth muscle cells and an antigen-driven rat model of lung inflammation. Measurements: The release of cytokines from cultured cells and inflammatory cytokine expression and cellular burden in the lung were determined. Main results: Two structurally distinct molecules and dominant negative technology, demonstrated that inhibition of I-{kappa}B kinase-2 activity completely blocked cytokine release from cultured cells. Whereas, the two glucocorticoid comparators had limited impact on G-CSF, IL-8 and eotaxin release. Additionally, in an in vivo antigen driven model of airway inflammation the I-{kappa}B kinase-2 inhibitor blocked NF-{kappa}B nuclear translocation, which was associated with a reduction in inflammatory cytokine gene and protein expression, airway eosinophilia and late asthmatic reaction, similar in magnitude to that obtained with budesonide. Conclusion: this study demonstrates that inhibiting I-{kappa}B kinase-2 results in a general reduction of the inflammatory response in vitro and in vivo. Compounds of this class could have therapeutic utility in the treatment of asthma and may, in certain respects, possess a beneficial efficacy profile compared to that of a steroid.
Key words: Lung, asthma, rodent, NF-KB inhibitor




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