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
Plett et al. (Fri,) studied this question.
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