Effects of the P2RX4 antagonist BR11595 in a guinea pig model of chronic asthma.

BACKGROUND AND PURPOSE: Asthma is characterized by airway hyperresponsiveness (AHR), allergic inflammation, and airway remodelling. Although recent studies have shown that asthma pathophysiology involves P2X4 receptor activation, a potential link with chronic asthma remains to be explored. We investigated the effect of a novel P2X4 receptor antagonist BR11595 on allergen-induced airway responses in a guinea pig model of chronic asthma.

EXPERIMENTAL APPROACH: Sensitized guinea pigs were exposed to saline or ovalbumin (OVA) once weekly via aerosolization for 12 weeks. BR11595 (10 mg·kg-1) was injected intraperitoneally five times per week, for four different regimens: all 12 weeks, first 6 weeks, last 6 weeks, or last week only. Airway responsiveness to histamine was assessed 24 h before and 6 h after OVA exposure in weeks 1, 6, and 12. Lung tissue inflammation and remodelling were determined 24 h after the last OVA exposure.

KEY

RESULTS

OVA induced AHR at weeks 1, 6, and 12 compared with saline-challenged animals. The AHR was less pronounced in week 12 compared with week 1. BR11595 significantly reduced OVA-induced AHR in week 6 in guinea pigs treated with BR11595 for 6 weeks. AHR in week 12 was reduced after BR11595 treatment in week 12 only, next to OVA-induced eosinophilia and Goblet cell hyperplasia, indicating an acute role of P2X4 receptors on chronic inflammation.

CONCLUSION AND IMPLICATIONS: The P2X4-receptor antagonist BR11595 acutely inhibits AHR, eosinophilia, and Goblet cell hyperplasia after 12 weeks, indicating its potential as a therapeutic target for acute intervention of chronic asthma attacks or exacerbations.