The myth of maximal airway responsiveness in vivo

A sine qua non of hyperresponsive airway disease in asthmatic subjects is the lack of a maximal response with increasing doses of aerosol agonist challenge. Normal subjects, however, often appear to exhibit an airway response plateau effect even when challenged with high concentrations of agonist. To investigate this question of maximal narrowing in individual airways in vivo, we used high-resolution computed tomography to visualize canine airways narrowed by two routes of agonist challenge. We compared airway narrowing induced by methacholine (MCh) via the conventional aerosol route to that caused by local atomization of MCh directly to individual airways. Our results showed that, with aerosol challenge, airway responses never reached a truly flat plateau even at the highest possible nebulizer concentrations. Airway closure was never observed. However, when MCh was delivered directly to the airway luminal surface, airways could be easily narrowed to complete closure at modest (10 mg/ml) agonist concentrations. Thus neither the elastic recoil of the lung nor limitations of smooth muscle shortening can be responsible for the apparent plateauing of dose-response curves. We suggest that the plateau results from limitations associated with the delivery of high concentration of agonists via the aerosol route.