Introduction
inflammation. 11,12 This relationship may be a more sensitive measure of airways hyperresponsiveness and The clinical manifestations of bronchial asthma inasthma severity. clude acute bronchoconstriction, cough, mucus pro-It is also likely that the relatively poor correlation duction, and increased airways responsiveness. While between airways responsiveness to methacholine and the exact mechanisms responsible for these effects are histamine and disease severity may be a consequence not fully elucidated, a number of mechanisms are of the use of inappropriate diagnostic agents. The fact thought to play a role including airway wall rethat some patients who are hyperresponsive to inhaled modelling, 1 airways inflammation, 2 and alterations in histamine are also hyperresponsive to inhaled methaneuronal function. 3 choline and exercise, has led to the suggestion that It is clear that asthmatics are exquisitely sensitive asthmatics have ''non specific'' bronchial hyperto a number of bronchoconstrictor agents and airway responsiveness. However, allergic subjects who do not hyperresponsiveness is reflected clinically by wheezing have asthma may also exhibit increased responsiveness and coughing on exercise and in the laboratory by to inhaled histamine or methacholine, and there is a the presence of airway hyperresponsiveness to inhaled tremendous overlap in the degree of airway respasmogens such as histamine and methacholine. The sponsiveness to inhaled histamine between healthy degree of bronchial hyperresponsiveness is routinely individuals and asthmatics of differing severity. 6,13 measured as the dose of inhaled spasmogen causing Thus, while most asthmatics have increased airway a 20% fall in lung function (PC 20 or PD 20 ). However, responsiveness at one end of a continuum, the response both the slope of the dose response relationship (reto inhaled histamine or methacholine is by no means activity) and the degree of plateau in the dose-response discriminatory for this disease. relationship can yield valuable information con-Recent studies have recognized that asthmatic cerning airways responsiveness to bronchoconstrictor patients cough and bronchoconstrict in response to a agents. 4 Some, [5][6][7] but not all studies 8,9 have demrange of stimuli that have modest, or no effects on onstrated the PC 20 to inhaled histamine or metharespiratory function in healthy individuals. For excholine be related to asthma severity and the ample, bradykinin, [14][15][16] sulfur dioxide (SO 2 ), 17,18 disrequirement for medication. This discrepancy would tilled H 2 O (''fog''), 19 adenosine, 20,21 and the extract of suggest that use of PC 20 in response to inhaled hishot pepper, capsaicin 22 cause bronchoconstriction in tamine or methacholine as a measure of airways asthmatic subjects. This is of considerable interest responsiveness is a poor indicator of disease severity. since all of these stimuli may cause changes in lung However, many studies fail to construct dose response function indirectly, in part, as a result of stimulating curves and thus valuable information concerning the airway nerves. Capsaicin and bradykinin, for example, true picture of the airways responsiveness is overare well known for their ability to stimulate sensory looked. The degree of airway narrowing is measured nerve endings. Together, these observations suggest either as a change in reactivity and/or loss in the that asthmatic patients can be distinguished from normal individuals on the basis of ''specific'' airway plateau of the dose-response relationship. 4,10 Studies based on mathematical modelling of asthmatic air-hyperresponsiveness to a number of stimuli that provoke airway nerves. This article reviews the evidence ways suggest that the increased airway narrowing to spasmogens in asthma correlates with thickening for an involvement of airway nerves in the pathogenesis of bronchial asthma, discusses the evidence of the airway wall, secondary to airway wall