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Published ahead of print on July 7, 2005, doi:10.1164/rccm.200412-1647OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 962-971, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200412-1647OC

I{kappa}-B Kinase-2 Inhibitor Blocks Inflammation in Human Airway Smooth Muscle and a Rat Model of Asthma

Mark A. Birrell, Elizabeth Hardaker, Sissie Wong, Kerryn McCluskie, Matthew Catley, Jorge De Alba, Robert Newton, Saleem Haj-Yahia, K. Tao Pun, Clarissa J. Watts, Robert J. Shaw, Tony J. Savage and Maria G. Belvisi

Respiratory Pharmacology, Airway Diseases Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London; Royal Brompton and Harefield Hospital, London; and Departments of Asthma Biology and Drug Metabolism and Pharmacokinetics, GlaxoSmithKline PLC, Stevenage, United Kingdom; Faculty of Medicine, University of Calgary, Canada

Correspondence and requests for reprints should be addressed to Professor Maria G. Belvisi, B.Sc., Ph.D., Head Respiratory Pharmacology Group, Imperial College Faculty of Medicine, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK. E-mail: m.belvisi{at}imperial.ac.uk

Rationale: Nuclear factor (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 inhibitor of {kappa}B (I-{kappa}B) kinase-2 (IKK-2), allows NF-{kappa}B to enter the nucleus.

Objectives: To determine the impact of inhibiting IKK-2 on in vitro and in vivo models of airway inflammation.

Methods: The effect of inhibiting IKK-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 IKK-2 activity completely blocked cytokine release from cultured cells, whereas the two glucocorticoid comparators had limited impact on granulocyte colony–stimulating factor, interleukin 8, and eotaxin release. In addition, in an in vivo antigen-driven model of airway inflammation, the IKK-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 IKK-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 with that of a steroid.

Key Words: asthma • lung • nuclear factor-{kappa}B inhibitor • rodent




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