Ikappa-B kinase-2 Inhibitor Blocks Inflammation Inhuman Airways Mooth Muscle And Arat Model Of Asthma.

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Journal Title, Volume, Page: 
Ikappa-B kinase-2 Inhibitor Blocks Inflammation Inhuman Airways Mooth Muscle And Arat Model Of Asthma. Volume 172, Issue 8
Year of Publication: 
Mark A. Birrell
Sissie Wong
Elizabeth L. Hardaker
Matthew C. Catley
Kerryn McCluskie
Michael Collins
Saleem Haj-Yahia
Maria G. Belvisi
Preferred Abstract (Original): 
Rationale: Nuclear factor (NF)-κB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-κB is held inactive in the cytoplasm, bound to I-κB. The removal of I-κB, via the actions of inhibitor of κB (I-κB) kinase-2 (IKK-2), allows NF-κB 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-κB 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.

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