What does this research mean for the field?

Antagonism of the human protease-activated receptor-2 (PAR2) effectively prevents and reverses house dust mite-induced airway hyperresponsiveness in acute and chronic mouse models, though it does not sustain protection against inflammation and mucus overproduction during chronic exposure. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to assess the effectiveness of PAR2 antagonism in controlling allergen-induced asthma in humanized mice.

May 20, 2026

B33-17 Protease-Activated Receptor-2 (PAR2) Antagonism Limits Allergen-Induced Asthma in Acute and Chronic Humanized Mouse Models

Puntos clave

This research aims to assess the effectiveness of PAR2 antagonism in controlling allergen-induced asthma in humanized mice.
Used PAR2-humanized C57Bl/6 mice models for acute and chronic house dust mite exposure
Evaluated outcomes using flexiVent for airway hyperresponsiveness, bronchoalveolar lavage for inflammation, and lung staining for mucus production
Administered intranasal and oropharyngeal PAR2 antagonist or control treatments during allergen exposure
In the acute model, PAR2 antagonism significantly prevented HDM-induced airway hyperresponsiveness and reduced inflammation
In the chronic model, airway hyperresponsiveness was restored to normal levels with PAR2 antagonism despite ongoing allergen exposure
Protection against inflammation and mucus production was diminished in the chronic model after PAR2 antagonist treatment

Resumen

Abstract Rationale Asthma is a chronic lung disease characterized by airway inflammation, mucus overproduction, and airway hyperresponsiveness (AHR), and affects over 300 million people worldwide. Asthma-related exacerbations remain a significant cause of morbidity and mortality even in “mild” asthmatics. We have targeted a G-protein-coupled receptor, protease-activated receptor-2 (PAR2), for the development of novel asthma drugs. We evaluated the efficacy of PAR2 antagonism in controlling house dust mite (HDM)-induced asthma in a PAR2-humanized mouse. Methods We used a C57Bl/6 mouse strain that expresses both mouse and human PAR2 (PAR2hm). We used acute and chronic HDM exposure models to evaluate PAR2 antagonist efficacy against intranasal allergen exposure. For our acute model, 8-week-old mice were exposed to vehicle, HDM, or HDM with PAR2 antagonist on Days 0, 7, 14 in a co-administered intranasal application. For our chronic model we first establish HDM-induced asthma in 6-week-old mice with the acute exposure protocol. Following development of asthma-like indicators, this protocol was extended 3 weeks with biweekly exposures using oropharyngeal delivery of PAR2 antagonist (or saline control) followed by intranasal delivery of HDM (or saline control). At the end of the acute or chronic protocols we used flexiVent to assay AHR, along with bronchoalveolar lavage and lung section staining to evaluate inflammation and mucus production. Results In the acute model, antagonism of PAR2 prevented HDM-induced AHR and modestly reduced inflammation with minimal effects on mucus overproduction. In the chronic model, AHR of HDM-treated PAR2hm mice was restored to normal with PAR2 antagonism despite the presence of continued HDM exposure. However, protection against airway inflammation and mucus overproduction was lost. Conclusions PAR2 antagonism of the human receptor is an effective prophylactic and therapeutic treatment for HDM-induced acute AHR in mouse models. PAR2 antagonists could be a beneficial addition to the current standard of care for asthma. This abstract is funded by: National Institutes of Health: AI140257, NS098826, HL160424, AI174540

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