Proteinase-activated receptor-2 antagonist C391 inhibits Alternaria-induced airway epithelial signalling and asthma indicators in acute exposure mouse models.

Abstract

BACKGROUND AND PURPOSE:

Despite the 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 preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca2+ , inducing MAPK and β-arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic- and trypsin-induced PAR2 signalling in vitro as well as reducing inflammatory PAR2-associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen-induced acutely expressed asthma indicators in murine models.

EXPERIMENTAL APPROACH:

We evaluated the ability of C391 to alter Alternaria alternata-induced PAR2 signalling pathways in 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 acutely expressed asthma indicators in vivo in two murine strains.

KEY RESULTS:

C391 blocked A. alternata-induced, PAR2-dependent Ca2+ and MAPK signalling 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 allergen-challenged murine models.

CONCLUSIONS AND IMPLICATIONS:

To our best 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.

• Authors: Candy M Rivas, Michael C Yee, Kenneth J Addison, Marissa Lovett, Kasturi Pal, Julie G Ledford, Gregory Dussor, Theodore J Price, Josef Vagner, Kathryn A DeFea, Scott Boitano
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 10 Pg. 2208-2222 (05 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34841515 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021 The British Pharmacological Society.

Chemical References

• Allergens
• Receptor, PAR-2

Topics

• Allergens
• Alternaria (metabolism)
• Animals
• Asthma (drug therapy, metabolism)
• HEK293 Cells
• Humans
• Mice
• Receptor, PAR-2