Comparison of Maximal BronchoconstrictionIn Vivoand Airway Smooth Muscle ResponsesIn Vitroin Nonasthmatic Humans

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Abstract
We tested the hypothesis that maximal bronchoconstriction in humans in vivo is limited by the maximal contractility of airway smooth muscle by comparison of complete in vivo and in vitro dose-response curves to methacholine in 10 nonasthmatic subjects who were scheduled for thoracotomy because of malignancies. The provocative dose of methacholine that produced a 10 and 20% decrease of baseline FEV1 (PD10, 20 FEV1 and the maximal fall in FEV1 (MFEV1) at the response plateau to inhaled methacholine were determined prior to surgery. Small airway smooth muscle preparations, obtained from the 10 resected lung tissue specimens, were examined in vitro to determine the sensitivity (−log EC50) and maximal isotonic shortening (Smax) to methacholine. In addition, the relaxation responses to the β-agonist l-isoproterenol were measured. The degree of small airways disease (SAD) was examined historically. Nine subjects showed a maximal response plateau to inhaled methacholine in vivo. The maximal fall in FEV1 at the plateau was 26 ± 3%. All airway smooth muscle preparations (n = 30) contracted to methacholine (−log EC50, 5.94 ± 0.09; Smax, 1320 ± 219 µm and relaxed to l-isoproterenol (−log EC50, 7.60 ± 0.11; maximal relaxation [Rmax], 87 ± 3%). No significant correlations were found between Smax or Rmax of the airway smooth muscle in vitro and the MFEV1 in vivo, and between −log EC50 for methacholine or l-isoproterenol in vitro and PD10 or PD20 FEV1 for methacholine in vivo. The severity of SAD was significantly correlated with the degree of baseline airflow limitation (p < 0.05), but not with in vivo or in vitro responses to methacholine. These results suggest that, in nonasthmatic subjects, the maximal bronchoconstriction and sensitivity to inhaled methacholine in vivo are not determined by the maximal contractility and sensitivity, respectively, of airway smooth muscle to methacholine, are not due to an impaired relaxation response to β-receptor stimulation, and are not related to the severity of SAD. The lack of correlation between in vivo and in vitro data further suggests that other factors, such as abnormal lung mechanics or abnormal autonomic control mechanisms, may be more important than smooth muscle as a determinant of nonasthmatic airway responsiveness.