Dosimetry counts: molecular hypersensitivity may not drive pulmonary hyperresponsiveness

Airway hyperresponsiveness is one measure of allergic asthma. One such test, the methacholine challenge, uses an inhaled aerosol to induce changes in resistance to breathing. The test is also used to test hyperresponsiveness in rodent models of asthma. For two varieties of mice, the B6C3F1 and the Balb/c, exposure to aerosolized methacholine demonstrates that the Balb/c is 12x more responsive based on the concentration of methacholine in the solution used to produce the inhaled aerosol (the normally accepted dose-metric). Here we show that the 12x difference in exposure disappears when measurements of airway dimensions of generations 1-6 are used first to calculate deposited mass of methacholine; and second to account for the physiology of airway constriction and pressure drop. These observations in mice provide one explanation of how some hyperresponsive subjects can have no underlying molecular sensitivity; and how constriction in the upper airways can have greater impact on breathing than constriction of airway generations 6-16.