Bronchial hyperresponsiveness. Modulation by allergen and long-acting b2-agonist

Abstract

Bronchial hyperresponsiveness (BHR) is a characteristic feature of bronchial asthma, defined as an increased tendency of the airways to constrict after exposure to different stimuli. BHR is considered to be related to airway inflammation. Allergen exposure and anti-asthma treatment modulate BHR. High-dose bronchial allergen challenge is used experimentally to study pathophysiological processes and effects by anti-asthma treatments. Repeated exposure to a low dose of allergen may be a more natural type of allergen exposure. To establish a repeated low-dose allergen exposure model, mild allergic asthmatics were in a placebo-controlled way repeatedly exposed to an individually titrated low dose of allergen via a dosimeter. The low-dose allergen exposure resulted in increased BHR, asthma symptoms, lung function variability and inflammatory parameters. After a high-dose allergen challenge preceded by repeated low-dose allergen exposure, the late asthmatic response was significantly attenuated, and indications of an attenuated proliferative response of T cells were found. Salmeterol and formoterol are two long-acting b2-agonists for inhalation. We determined that the relative potency of salmeterol 50 mg correspond to formoterol 9 mg (3-19 mg; CI 95%). To determine the protective effects on allergen airway responsiveness, a single dose of formoterol was given before a bronchial allergen challenge. Both the early and late response were significantly inhibited. The efficacy of formoterol in comparison to salmeterol was evaluated as the maximal protective effect on BHR, measured as methacholine responsiveness. Formoterol caused a dose-dependent and significantly better maximal protective effect on BHR than salmeterol. In conclusion, repeated low-dose allergen exposure induces clinical, functional and inflammatory events, as in mild asthma exacerbations. Following repeated low-dose allergen exposure, the BHR is increased and the allergen-induced late response is attenuated, possibly mediated via T cell tolerance. Pretreatment with formoterol inhibits the early and late allergen-induced asthmatic response. The maximal protection against BHR is higher by formoterol than by salmeterol, confirming that salmeterol is a partial agonist in relation to formoterol in asthmatic patients.