Proteasome inhibition: A novel mechanism to combat asthma.
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.


CONCLUSIONS
Taken together, the present data suggest that proteasome inhibition may represent a novel strategy for the treatment of inflammatory lung diseases such as asthma.
Elliott
P J
PJ
ProScript, Inc, Cambridge, MA 02319, USA.
Pien
C S
CS
McCormack
T A
TA
Chapman
I D
ID
Adams
J
J
D000818:Animals; D001249:Asthma / Q000503:physiopathology / Q000517:prevention & control; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000502:physiology*; D003907:Dexamethasone / Q000009:adverse effects; D006968:Hypersensitivity, Delayed / Q000139:chemically induced; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D011914:Rats, Inbred BN; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D007783:Lactones; D009097:Multienzyme Complexes; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex