Airway hyperresponsiveness is an important feature of clinical asthma. This means that asthmatic patients will develop bronchoconstriction after inhaling a smaller concentration of a bronchoconstrictor agonist (usually 10-100 times less) than is needed to induce the same degree of bronchoconstriction in nonasthmatic subjects. Airway hyperresponsiveness is not only an objective measurement which can distinguish asthmatic from normal subjects, but also the degree of airway hyperresponsiveness is related to the severity of asthma, and to the amount of treatment needed to optimally control symptoms.
In many asthmatic subjects, airway hyperresponsiveness is a stable phenomenon when measured over several years; however, in some subjects, airway responsiveness can be increased after exposure to inhaled allergens, ozone, upper respiratory tract infections or occupational sensitizing agents. This increase in airway responsiveness is associated with increased symptoms of asthma. All of these stimuli are naturally occurring stimuli; however, allergen, ozone and occupational sensitizing agents such as toluene diisocyanate (TDI) have been used in both human and animal preparations to study the pathogenesis of airway hyperresponsiveness in the research laboratory.
Each of the stimuli known to induce airway hyperresponsiveness has been thought, in addition, to cause acute airway inflammation. The first direct evidence, however, that airway hyperresponsiveness and airway inflammation may be causally related came from studies examining the pathogenesis of airway hyperresponsiveness which can be induced by inhalation of ozone in dogs. When dogs inhale ozone (2-3ppm for 2h), airway hyperresponsiveness to inhaled acetylcholine develops lh after the exposure, is still present 24h later, and is returned to baseline values by one week. Initial studies by Holtzman et al documented a temporal association between the development of airway hyperresponsiveness and an acute inflammatory response in the central airways of dogs, as measured by an influx of neutrophils into the epithelial and sub-epithelial layers of the airway. These observations were confirmed by Fabbri et alu from the same laboratory, who demonstrated a large influx of neutrophils, as well as desquamated epithelial cells in bronchoalveolar lavage fluid from dogs with airway hyperresponsiveness after inhaling ozone. Subsequently, other investigators using other animal preparations confirmed that airway inflammation had occurred at the same time as airway hyperresponsiveness had developed. For example, Marsh et al demonstrated an influx of polymorphonuclear cells and monocytes in lavage fluid when rabbits were made hyperresponsive after allergen. Also, Mur-las and Roum have shown that airway mucosal injury and mast cell infiltration has occurred when guinea pigs are hyperresponsive after ozone inhalation. Lastly, and most importantly, Stelzer et al demonstrated an influx of neutrophils into lavage fluid of human subjects made hyperresponsive after ozone exposure. Thus, while the type of inflammatory response may differ because of the different species studied or different stimulus used to induce airway hyperresponsiveness, each of these studies was consistent with the hypothesis that some component of an acute inflammatory response was responsible for the development of airway hyperresponsiveness.