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Airway Hyperresponsiveness, Remodeling, and Smooth Muscle Mass

Right Answer, Wrong Reason?

Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; and Department of Physics, Erlangen University, Erlangen, Germany

Correspondence and requests for reprints should be addressed to Jeffrey J. Fredberg, Ph.D., Harvard School of Public Health, 665 Huntington Avenue, Building 1, Room 1308, Boston, MA 02115. E-mail: jeffrey_fredberg{at}harvard.edu

We quantified the effects of airway wall remodeling upon airway smooth muscle (ASM) shortening. Isolated ASM from sheep was attached to a servo-controller that applied a physiologic load. This load could be altered to reflect specified changes of airway wall geometry, elasticity, parenchymal tethering, transpulmonary pressure (P_L), and fluctuations in P_L associated with breathing. Starting at a reference length (L_ref), ASM was stimulated with acetlycholine and held at constant P_L of 4 cm H₂O for 2 h. When all compartments were thickened to simulate the asthmatic airway but P_L was held fixed, ASM shortened much more than that in the normal airway (to 0.52 L_ref versus 0.66 L_ref). When breathing with deep inspirations (DIs) was initiated, within the first three DIs the ASM in the normal airway lengthened to 0.84 L_ref, whereas that in the asthmatic airway remained stuck at 0.53 L_ref. Thickening of the smooth muscle layer alone produced the greatest muscle shortening (to 0.47 L_ref) when compared with thickening of only submucosal (to 0.67 L_ref) or only adventitial (to 0.62 L_ref) compartments. With increased ASM mass, the ASM failed to lengthen in response to DIs, whereas in the airway with thickened submucosal and adventitial layers ASM lengthened dramatically (to 0.83 L_ref). These findings confirm the long-held conclusion that increased muscle mass is the functionally dominant derangement, but mechanisms accounting for this conclusion differ dramatically from those previously presumed. Furthermore, increased ASM mass explained both hyperresponsiveness and the failure of a DI to relax the asthmatic airway.

Key Words: remodeling • asthma • hyperresponsiveness

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