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Received for publication October 3, 2005.
Revised March 1, 2006.
Accepted for publication March 2, 2006.
-B kinase - 2 independent inflammation in an airway
disease model: relevance to the clinic
NF-
B is a transcription factor believed to be
central in the expression of numerous inflammatory genes
and the pathogenesis of many respiratory diseases. We
have previously shown that a steroid sensitive LPS, but
not a steroid insensitive elastase, driven rat model of
airway inflammation exhibits increased NF-B
pathway activation. The aim of this study was to gather
further evidence to suggest that these similar profiles
of inflammation can be NF-B dependent or
independent by determining the impact of an I-B
kinase-2 (IKK-2) inhibitor, TPCA-1. In the LPS driven
inflammation TPCA-1 blocked the increase in p65:DNA
binding, a marker of NF-B pathway activation.
This inhibition was associated with a reduction in
inflammatory mediator release (TNF
/IL-l
/MMP-9) and lung cell burden
(neutrophilia/eosinophilia), data paralleled with a
steroid and in human cell based assays. In elastase
driven inflammation we failed to measure an increase in
p65:DNA binding and neither TPCA-1, nor the steroid,
impacted on mediator release (IL-1/MMP-9) or
cellular burden (neutrophilia/lymphomononuclear cells).
In conclusion we have demonstrated that similar profiles
of airway inflammation can be IKK-2 inhibitor/steroid
sensitive or insensitive. This is the first study
examining the utility of an IKK-2 inhibitor in well
validated models which mimic aspects of the inflammatory
lesion evident in diseases such as COPD. This finding,
if similar inflammation exists in the clinic, is
extremely exciting and may lead to greater understanding
of disease pathology and the discovery of novel anti-
inflammatory targets.
Key words:
NFkappaB, Regulation of gene expression, Leukocytes/Mast cells
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