Nuclear factor κB (NF-κB) 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 demonstrated increased NF-κB pathway activation in a
steroid-sensitive animal model of
lipopolysaccharide (LPS)-driven airway inflammation. It is noteworthy
that this phenomenon
was not observed in a steroid-insensitive model of
elastase-induced inflammation in the rat. The aim of this study was to
gather further evidence to suggest that these
similar profiles of neutrophilic inflammation can be NF-κB-dependent or
-independent
by determining the impact of an IκB kinase-2
(IKK-2) inhibitor,
2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide
(TPCA-1). In the LPS model, TPCA-1 blocked the
increase in NF-κB DNA binding, a marker of NF-κB pathway activation.
This inhibition
was associated with a reduction in inflammatory
mediator release [tumor necrosis factor α (TNFα)/interleukin-1β
(IL-1β)/matrix
metalloproteinase-9 (MMP-9)] and lung inflammatory
cell burden (neutrophilia/eosinophilia). These data were paralleled with
a steroid and in human cell based assays. In the
elastase-driven inflammation model, in which our group has previously
failed
to measure an increase in NF-κB DNA binding,
neither TPCA-1 nor the steroid, affected mediator release (IL-1β/MMP-9)
or cellular
burden (neutrophilia/lymphomononuclear cells). This
is the first study to examine the effect of an IKK-2 inhibitor in well
validated models that mimic aspects of the
inflammatory lesion evident in diseases such as COPD. In conclusion, we
have demonstrated
that animal models with similar profiles of airway
inflammation can be IKK-2 inhibitor/steroid-sensitive or -insensitive.
If both profiles of inflammation exist in the
clinic, then this finding is extremely exciting and may lead to greater
understanding
of disease pathology and the discovery of novel
anti-inflammatory targets.
Journal
Title
Mol Pharmacol. 2006 Jun;69(6):1791-800. Epub 2006 Mar 3.