Document Detail

Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma.
MedLine Citation:
PMID:  16002568     Owner:  NLM     Status:  MEDLINE    
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.
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; Maria G Belvisi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-07-07
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  172     ISSN:  1073-449X     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-10-11     Completed Date:  2006-01-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  962-71     Citation Subset:  AIM; IM    
Respiratory Pharmacology Group, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, UK.
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MeSH Terms
Amides / immunology,  therapeutic use*
Anti-Inflammatory Agents / immunology,  therapeutic use
Asthma / drug therapy*,  immunology,  physiopathology
Budesonide / immunology,  therapeutic use
Cells, Cultured / drug effects,  immunology
Chemokine CCL11
Chemokines, CC / immunology
Dexamethasone / immunology,  therapeutic use
Disease Models, Animal*
Drug Evaluation, Preclinical
Gene Expression / drug effects,  immunology
Granulocyte Colony-Stimulating Factor / drug effects,  immunology
I-kappa B Kinase / antagonists & inhibitors*,  immunology
Interleukin-8 / immunology
Muscle, Smooth / cytology,  drug effects*,  immunology,  physiopathology
NF-kappa B / drug effects,  immunology
Respiratory System / cytology,  drug effects*,  immunology,  physiopathology
Thiophenes / immunology,  therapeutic use*
Reg. No./Substance:
0/2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; 0/Amides; 0/Anti-Inflammatory Agents; 0/CCL11 protein, human; 0/Ccl11 protein, rat; 0/Chemokine CCL11; 0/Chemokines, CC; 0/Interleukin-8; 0/NF-kappa B; 0/Thiophenes; 143011-72-7/Granulocyte Colony-Stimulating Factor; 50-02-2/Dexamethasone; 51333-22-3/Budesonide; EC B Kinase

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