Intrinsic and antigen-induced airway hyperresponsiveness are the result of diverse physiological mechanisms

Vermont Lung Center, Department of Pulmonary and Critical Care Medicine, University of Vermont College of Medicine, Burlington, Vermont Submitted 2 November 2005 ; accepted in final form 21 September 2006 Airway hyperresponsiveness (AHR) is a defining feature of asthma. We have previously shown, in mice sensitized and challenged with antigen, that AHR is attributable to normal airway smooth muscle contraction with exaggerated airway closure. In the present study we sought to determine if the same was true for mice known to have intrinsic AHR, the genetic strain of mice, A/J. We found that A/J mice have AHR characterized by minimal increase in elastance following aerosolized methacholine challenge compared with mice (BALB/c) that have been antigen sensitized and challenged [concentration that evokes 50% change in elastance (PC 50 ): 22.9 ± 5.7 mg/ml for A/J vs. 3.3 ± 0.4 mg/ml for antigen-challenged and -sensitized mice; P < 0.004]. Similar results were found when intravenous methacholine was used (PC 30 0.22 ± 0.08 mg/ml for A/J vs. 0.03 ± 0.004 mg/ml for antigen-challenged and -sensitized mice). Computational model analysis revealed that the AHR in A/J mice is dominated by exaggerated airway smooth muscle contraction and that when the route of methacholine administration was changed to intravenous, central airway constriction dominates. Absorption atelectasis was used to provide evidence of the lack of airway closure in A/J mice. Bronchoconstriction during ventilation with 100% oxygen resulted in a mean 9.8% loss of visible lung area in A/J mice compared with 28% in antigen-sensitized and -challenged mice ( P < 0.02). We conclude that the physiology of AHR depends on the mouse model used and the route of bronchial agonist administration. computational model; airway closure; asthma; mouse models of asthma Address for reprint requests and other correspondence: C. G. Irvin, Vermont Lung Center, Univ. of Vermont, Dept. of Medicine and Physiology, Rm. 226, HSRF, 149 Beaumont Ave., Burlington, VT 05405-0075 (e-mail: charles.irvin{at}uvm.edu )