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Am J Respir Crit Care Med. 2005 Oct 15;172(8):962-71. Epub 2005 Jul 7.

Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma.

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1
Respiratory Pharmacology Group, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, UK.

Abstract

RATIONALE:

Nuclear factor (NF)-kappaB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappaB is held inactive in the cytoplasm, bound to I-kappaB. The removal of I-kappaB, via the actions of inhibitor of kappaB (I-kappaB) kinase-2 (IKK-2), allows NF-kappaB 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-kappaB 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.

PMID:
16002568
DOI:
10.1164/rccm.200412-1647OC
[Indexed for MEDLINE]
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