Bronchoprovocation studies to define mechanisms in asthma and airway inflammation

Abstract

Bronchial provocations with a variety of stimuli have been widely used over the past 70 years in both asthma research as well as in daily clinical praxis in order to aid the physician to establish the asthma diagnosis. In research, the bronchoprovocation model represents an excellent tool to better understand asthma pathophysiology, and to assess the effects of different interventions and new investigational therapies. Most of the currently approved asthma therapeutic options have shown efficacy in previous studies using the bronchoprovocation setting. In the current thesis, a range of bronchial provocations was performed prior to and after treatment with pharmacological interventions with different mode of actions. Responses were measured in the airways in the form of induced bronchoconstriction and airway inflammation (sputum cell counts), as well as in other matrices (skin, blood, urine).

For the first time, it was shown that treatment with the combination of budesonide-formoterol (bud/form) in a single inhaler taken three to four times per week provided the same magnitude of protection against exercise-induced bronchoconstriction (EIB) as to regular treatment with a low dose of budesonide. Moreover, subjects who received monotherapy with the short acting β2 agonist (SABA) terbutaline had no protection against EIB over time. These results question the place of SABA monotherapy in asthma treatment even for subjects with mild asthma. It is recommended to replace SABA monotherapy with intermittent use of bud/form, which can also be an alternative option to regular treatment with low dose inhaled corticosteroids (ICS). Furthermore, using an allergen bronchoprovocation model, it was demonstrated that treatment with the second-generation anti-IgE monoclonal antibody QGE031 (ligelizumab) elicited an inhibition of the early allergic response (EAR) that was three times greater than what was achieved by the currently approved anti-IgE treatment with omalizumab. In addition, the data showed that there were important differences in the allergen response in the airways compared to the skin during QGE031 therapy; the highest dose of QGE031 consistently supressed allergen induced skin test responses that persisted six weeks after the last dose was given, while there was a variable effect on the airway response that did not last six weeks after the last dose. These results elucidate the complexity of the IgE pathway and the different kinetics and tissue responses to anti-IgE therapy.

Finally, this thesis answered some important questions about the role of cysteinyl leukotrienes (CysLTs) and in particular leukotriene E4 (LTE4) in asthma. The data showed that treatment with the potent CysLT1 receptor antagonist montelukast completely abolished the bronchoconstriction elicited by LTE4 inhalation in subjects with mild asthma. Urine was collected during the LTE4 provocations for analysis of lipid mediator excretion, which led to the serendipitous discovery of increased urinary excretion of metabolites of prostaglandin (PG) D2, as well as other lipid mediators after LTE4 inhalation. These novel findings add a new dimension, namely that LTE4, in addition to a direct bronchoconstrictive action, can also activate both the mast cell as well as other cells to produce secondary responses that can amplify or modify its primary effect. Thus, this thesis demonstrates that carefully planned and conducted studies using bronchial provocations in combination with various pharmacological interventions, can elucidate important mechanisms in asthma pathogenesis and reveal potential new targets for treatment.