Alpha 1-antitrypsin and ilomastat inhibit inflammatory proteases present in human middle ear effusions.
OBJECTIVE
Proteases of both the serine and metalloproteinase families have been shown to play a role in the pathogenesis of otitis media (OM). Inhibitors of proteases from each of these families have been shown to beneficially impact disease progression in a number of related chronic inflammatory conditions, but their use has not been studied in OM. The purpose of this study was to assess the activity of the protease inhibitors recombinant alpha 1-antitrypsin (rAAT) and ilomastat on inflammatory proteases present in human middle ear effusions (MEEs), with a view to their potential utility in the treatment of OM.


METHODS
Prospective and ex vivo.


METHODS
MEEs were collected from 100 patients presenting for middle ear surgery, most commonly tympanostomy tube placement or treatment of acute posttympanostomy otorrhea (APTO). MEEs were analyzed for the presence of matrix metalloproteinases (MMPs) and human neutrophil elastase (HNE) and the inhibitory activity of rAAT and ilomastat on these proteases, respectively.


RESULTS
MMP levels were highest in APTO, and HNE was highest in chronic suppurative OM and APTO. High levels of MMP and HNE (>3 mAU/min) were found in 52% and 37% of MEEs, respectively. Ilomastat and rAAT demonstrated significant inhibition of MMP and HNE activity (>30% reduction), respectively, in 80% and 82% of MEEs with high levels of activity.


CONCLUSIONS
Proteases are commonly found in OM. Ilomastat and rAAT are potent inhibitors of proteases in MEEs across a wide range of OM in humans. Investigation into the potential therapeutic benefits of these protease inhibitors is warranted.
Antonelli
Patrick J
PJ
Department of Otolarynology, University of Florida, Gainesville, 32610-0264, USA. antonpj@ent.ufl.edu
Schultz
Gregory S
GS
Kim
Karen M
KM
Cantwell
John S
JS
Sundin
David J
DJ
Pemberton
Philip A
PA
Barr
Philip J
PJ
D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D002908:Chronic Disease; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010034:Otitis Media with Effusion / Q000201:enzymology*; D010035:Otitis Media, Suppurative / Q000201:enzymology; D012008:Recurrence; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D006877:Hydroxamic Acids; D007211:Indoles; D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C119203:ilomastat