A bradykinin-antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep

Abstract

The effects of a new bradykinin-antagonist, NPC-567 (D-Arg [hydroxyproline3, D-phenylalanine7] bradykinin) were studied on antigen-induced airway hyperresponsiveness and inflammation in allergic sheep (n = 7). Specific lung resistance (sRL) was used to assess airway responses to inhaled Ascaris suum-antigen. Airway responsiveness was determined from slopes of cumulative dose-response-curves (DRC) to inhaled carbachol. DRCs were performed at baseline and 2 h after an inhalation challenge with antigen. Bronchoalveolar lavage, performed before antigen-challenge and after the post-challenge DRC was used to assess antigen-induced inflammatory changes. For these studies NPC-567 was given as an aerosol (20 breaths, 10 mg/ml) 30 min before antigen challenge and (400 breaths, 2 mg/ml) co-administered with the Ascaris suum antigen. The immediate increase in specific lung resistance (sRL) after antigen challenge was not different with (232 +/- 152% increase) or without drug pre-treatment (148 +/- 129% increase). In the control trial, antigen challenge led to an increase in slope of the post-challenge DRC by 123 +/- 118% compared to baseline (p less than 0.05). This hyperresponsiveness was almost completely prevented by NPC-567 (increase in slope 32 +/- 64%, p less than 0.05 vs. control). Similarly, the antigen-induced inflammatory response, characterized by a significant 3.3-fold increase over baseline in the percentage of neutrophils in the control-experiment, was blocked by the bradykinin-antagonist. These results suggest that bradykinin may be involved in the pathogenesis of antigen-induced airway inflammation and the consequent development of airway hyperresponsiveness in sheep.