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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2208-2222
Number of pages15
JournalBritish Journal of Pharmacology
Volume179
Issue number10
DOIs
StatePublished - May 2022

Keywords

  • Alternaria alternata
  • C391
  • PAR2
  • airway hyperresponsiveness
  • airway inflammation
  • allergen-induced asthma
  • mucus cell hyperplasia

ASJC Scopus subject areas

  • Pharmacology

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