The nuclear factor-κB (NF-κB) is a major transcription factor involved in the inflammatory responses seen in asthma and chronic obstructive pulmonary disease (COPD). The inhibitory factor-κB kinase-2 (IKK-2) protein mediates cytokine-triggered NF-κB activation, and IKK-2 inhibitors have been evaluated for COPD treatment but systemic toxicities have limited progress. In this issue, Sommers et al., describe a study that tested two new, tight-binding IKK-2 inhibitors, one of which was designed for local delivery and high systemic clearance. The results indicate that the IKK-2 inhibitors have a broad-acting concentration-dependent anti-inflammatory profile in vitro comparable to that of a corticosteroid in a number of human cell types associated with airway disease. The authors also report that IKK-2 inhibition is able to repress inflammatory mediator expression in an inhaled lipopolysaccharide-induced rat model of neutrophilia. Administration of locally acting inhibitor via the trachea to rats produced a marked dose-dependent suppression of infiltrating cells into the lung associated with a repression of inflammatory cytokines and chemokines similar to that seen with the oral inhibitor. It is important to note that, in contrast to the data seen with intratracheal fluticasone, the localized delivery had no systemic effect. The data suggest that topical administration of inhibitor to the airways may have beneficial effects in airways diseases, including severe asthma and COPD with few systemic side effects.
See article at J Pharmacol Exp Ther 2009, 330:377-388.
- The American Society for Pharmacology and Experimental Therapeutics