A humanized protease-activated receptor-2 mouse as a model for allergic asthma

Abstract

Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) inflammation, and mucus overproduction, and has differential presentation in males and females. There exists strong demand to improve upon current asthma treatments by targeting upstream signaling pathways, including the G-protein coupled receptor protease-activated receptor-2 (PAR2). We have recently shown effectiveness of full (C391) and ß-arrestin biased (C781) PAR2 antagonism in limiting allergen-induced asthma indicators in mouse models (C57Bl/6 and Balb/C). To better test PAR2 antagonists as asthma drugs, we have developed a transgenic mouse model that expresses human PAR2 without mouse PAR2 expression in a C57Bl/6 background (htgPAR2). The htgPAR2 mice have heightened responses to asthma allergens [house dust mite (HDM) or Alternaria alternata] following acute exposure. Limited sex differences were observed in the HDM challenge model. However, when challenged with A. alternata there was significantly higher AHR in the male mice and significantly higher inflammatory and mucus responses in the female mice. The full and ß-arrestin biased PAR2 antagonists also displayed differential effects with C781 providing broader control of allergen-induced indicators (AHR, inflammation and mucus overproduction). We conclude that the htgPAR2 mouse model is a promising tool for preclinical in vivo screening of potential asthma treatments targeting PAR2. Grants from the National Institute of Health (NS098826, AI140257, HL16024, HL152942) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.