Proteasome inhibition: A novel mechanism to combat asthma☆☆☆

Abstract 

Background: Nuclear factor-κB (NF-κB) is a critical transcription factor required for the regulation of many genes involved in inflammatory responses to noxious stimuli. On activation, NF-κB induces the transcription of numerous proinflammatory cytokines, enzymes, and cellular adhesion molecules. Blockade of the proteasome with selective inhibitors attenuates the effects of NF-κB, leading to suppression of the inflammatory response. Objective: We sought to determine whether proteasome inhibitors would be active 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 reduced leukocyte numbers, particularly the selective increase in eosinophils. Because steroids are the mainstay anti-inflammatory therapy in asthma, and data is available to suggest their possible interaction to suppress the activation of NF-κB, rats were also treated by inhalation with combinations of a steroid and the proteasome inhibitor. In both the delayed-type hypersensitivity and the animal eosinophil model, low doses of proteasome inhibitors were shown to be effective when given with low doses of steroids. Conclusion: Taken together, the present data suggest that proteasome inhibition may represent a novel strategy for the treatment of inflammatory lung diseases such as asthma. (J Allergy Clin Immunol 1999;104:294-300.)

Keywords:  Asthma, cell adhesion molecules, cytokines, delayed-type hypersensitivity, eosinophils, leukocytes, nuclear transcription factor-κB, proteasome, steroids

Abbreviations:  DNFB , 2,4-Dinitrofluorobenzene, DTH , Delayed-type hypersensitivity, IκB , Inhibitor factor-κB, NF-κB , Nuclear transcription factor-κB