Abstract and Keywords
Background and Purpose : Despite availability of a variety of
treatment options, many asthma patients have poorly controlled disease
with frequent exacerbations. Proteinase-activated receptor-2 (PAR2) has
been identified in pre-clinical animal models as important to asthma
initiation and progression following allergen exposure. Proteinase
activation of PAR2 induces intracellular Ca2+, mitogen
activated protein kinase (MAPK) and β-arrestin signaling the airway,
leading to both inflammatory and protective effects. We have developed
C391, a potent PAR2 antagonist effective in blocking peptidomimetic- and
trypsin-induced PAR2 signaling in vitro as well as reducing
inflammatory PAR2-associated pain in vivo . We hypothesized that
PAR2 reduction with C391 would attenuate allergen-induced asthma
indicators in murine models.
Experimental Approach : We evaluated the ability for C391 to
alter Alternaria alternata -induced PAR2 signaling pathwaysin vitro using a human airway epithelial cell line that naturally
expresses PAR2 (16HBE14o-) and a transfected embryonic cell line (HEK
293). We next evaluated the ability for C391 to reduce A.
alternata -induced asthma indicators in vivo in two murine
strains.
Key Results : C391 blocked A. alternata -induced,
PAR2-dependent Ca2+ and MAPK signaling in 16HBE14o-
cells, as well as β-arrestin recruitment in HEK 293 cells. C391
effectively attenuated A. alternata -induced inflammation, mucus
production, mucus cell hyperplasia and airway hyperresponsiveness in
acute asthma murine models.
Conclusions and Implications : To our knowledge, this is the
first demonstration of pharmacological intervention of PAR2 to reduce
allergen-induced asthma indicators in vivo . These data support
further development of PAR2 antagonists as potential first-in-class
allergic asthma drugs.
Key Words : Airway Inflammation; Airway Hyperresponsiveness;
Allergen-induced asthma; Alternaria alternata ; C391; Mucus cell
hyperplasia; PAR2;