Proteasome inhibition: A novel mechanism to combat asthma

J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):294-300. doi: 10.1016/s0091-6749(99)70369-6.


Background: Nuclear factor-kappaB (NF-kappaB) is a critical transcription factor required for the regulation of many genes involved in inflammatory responses to noxious stimuli. On activation, NF-kappaB induces the transcription of numerous proinflammatory cytokines, enzymes, and cellular adhesion molecules. Blockade of the proteasome with selective inhibitors attenuates the effects of NF-kappaB, 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-kappaB, 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.

MeSH terms

  • Animals
  • Asthma / physiopathology
  • Asthma / prevention & control
  • Cysteine Endopeptidases / drug effects*
  • Cysteine Proteinase Inhibitors / physiology*
  • Dexamethasone / adverse effects
  • Hypersensitivity, Delayed / chemically induced
  • Lactones / chemistry
  • Lactones / pharmacology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Multienzyme Complexes / drug effects*
  • Proteasome Endopeptidase Complex
  • Pulmonary Eosinophilia / immunology
  • Pulmonary Eosinophilia / physiopathology
  • Pulmonary Eosinophilia / prevention & control
  • Rats
  • Rats, Inbred BN
  • Structure-Activity Relationship


  • Cysteine Proteinase Inhibitors
  • Lactones
  • Multienzyme Complexes
  • Dexamethasone
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex