The role of the inhibitory molecule IkappaBalpha in the priming of lung injury after resuscitated hemorrhagic shock: Molecular mechanisms and significance

The magnitude of an inflammatory response represents a balance between pro- and counter-inflammatory molecules. We hypothesized that altered regulation of IκBα contributes to cell signaling and inflammatory gene expression.; Resuscitated hemorrhagic shock primes for an increased inflammatory response by inducing rapid degradation of IκBα. This was found to be mediated by a mechanism of increased phosphorylation by IKK. Since N-acetylcystein, a potent anti-oxidant, abrogated this increase in IKK activity, this effect was likely mediated by oxidants.; Hemorrhagic shock also primes for increased NF-κB activity by inhibiting the synthesis of new IκBα protein. This was found to be mediated by a mechanism of decreased mRNA stability, and not by decreased IκBα gene transcription. Hemorrhagic shock induced decrease in mRNA stability of IκBα was reversed by the anti-inflammatory cytokine IL-10. IL-10 increased IκBα mRNA expression by a mechanism of increased mRNA stability. This is a novel role for this cytokine.