Provoked models of asthma: what have we learnt?

Abstract

Asthma is a chronic inflammatory disease of the airways characterized by physiological abnormalities of variable airflow obstruction and airway hyperresponsiveness (AHR) to a wide variety of physical and inhaled chemical stimuli and the presence of symptoms. AHR is measured by challenging the airways with a variety of agonists and naturally occurring stimuli, which results in constriction of the airway smooth muscle, leading to airway narrowing and airflow limitation. There are two distinct mechanisms by which the airways can narrow to a constrictor stimulus and these are defined by the pathways they take to induce AHR. Direct stimuli are pharmacological agents administered exogenously (such as histamine or methacholine) that act 'directly' on specific receptors on the bronchial smooth muscle to cause constriction. The other mechanism by which the airway can narrow is via the inhalation of indirect stimuli, which include natural stimuli, such as allergen or exercise, and pharmacological agents such as adenosine monophosphate and hyper-osmotic agents (e.g. hypertonic saline or dry powder mannitol). These stimuli induce airway narrowing 'indirectly' by causing the endogenous release of mediators of bronchoconstriction from airway inflammatory cells. Provoked models of asthma have been extremely valuable in understanding the pathobiology of asthma, in aiding diagnosis, in helping to clarify the mechanisms of actions of effective drugs and in the development of new entities to treat asthma. Some provoked models are valuable clinically, particularly those that measure direct AHR, while others, particularly allergen challenge, have been used in animal models and in humans to study the mechanisms of allergen-induced airway inflammation and the associated physiological changes, as well in the development of new drugs for asthma. An emerging role for measurements of AHR is in the evaluation of the optimal treatment for patients with asthma.