Proteasome inhibition: A novel mechanism to combat asthma

Background: Nuclear factor-kappa B (NF-kappa B) is a critical transcription factor required for the regulation of many genes involved in inflammatory responses to noxious stimuli, On activation, NF-kappa B induces the transcr iption of numerous proinflammatory cytokines, enzymes, and cellular adhesio n molecules, Blockade of the proteasome with selective inhibitors attenuate s the effects of NF-kappa B, leading to suppression of the inflammatory res ponse, Objective: We sought to determine whether proteasome inhibitors would be ac tive in a model of asthma, Methods: The mouse delayed-type hypersensitivity model was used to screen a panel of compounds for in vivo activity, The proteasome inhibitor, PS-519, was shown to be the most active in this model and was selected for further development. Allergen-induced pulmonary eosinophilia in Brown Norway rats was used subsequently to determine anti-inflammatory activity in an animal model. Results: Direct administration of PS-519 into the lungs significantly reduc ed leukocyte numbers, particularly the selective increase in eosinophils, B ecause steroids are the mainstay antiinflammatory therapy in asthma, and da ta is available to suggest their possible interaction to suppress the activ ation of NF-kappa B, rats were also treated by inhalation with combinations of a steroid and the proteasome inhibitor, In both the delayed-type hypers ensitivity and the animal eosinophil. model, low doses of proteasome inhibi tors were shown to be effective when given with low doses of steroids. Conclusion: Taken together, the present data suggest that proteasome inhibi tion may represent a novel strategy for the treatment of inflammatory lung diseases such as asthma.