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Published ahead of print on April 26, 2007, doi:10.1165/rcmb.2006-0418OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 3, September 2007, 264-272

A more recent version of this article appeared on September 1, 2007
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Submitted on November 7, 2006
Revised on April 20, 2007

Airway Hyperresponsiveness, Remodeling, and Smooth Muscle Mass: Right Answer, Wrong Reason?

Madavi N Oliver1, Ben Fabry2, Aleksandar Marinkovic1, Srboljub M Mijailovich1, James P Butler1, and Jeffrey J Fredberg1*

1 Department of Environmental Health, Physiology Program, Harvard School of Public Health, Boston, MA, USA, 2 Department of Physics, Erlangen University, Erlangen, Germany

* To whom correspondence should be addressed. E-mail: Jeffrey_fredberg{at}harvard.edu.

We quantified the effects of airway wall remodeling upon airway smooth muscle (ASM) shortening. Isolated ASM from the sheep was attached to a servo-controller that applied a physiological load. This load could be altered to reflect specified changes of airway wall geometry, elasticity, parenchymal tethering, transpulmonary pressure (PL), and fluctuations in PL associated with breathing. Starting at a reference length (Lref), ASM was stimulated with acetlycholine and held at constant PL of 4 cmH2O for 2h. When all compartments were thickened to simulate the asthmatic airway but PL was held fixed, ASM shortened much more than that in the normal airway (to 0.52Lref vs. 0.66Lref). When breathing with deep inspirations (DIs) was initiated, within the first 3 DIs the ASM in the normal airway lengthened to 0.84 Lref whereas that in the asthmatic airway remained stuck at 0.53 Lref. Thickening of the smooth muscle layer alone produced the greatest muscle shortening (to 0.47Lref) when compared with thickening of only submucosal (to 0.67Lref) or only adventitial (to 0.62Lref) 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 Lref). These findings confirm the long-held conclusion that increased muscle mass is the functionally dominant derangement, but mechanisms accounting for this derangement differ dramatically from those previously presumed. Furthermore, increased ASM mass explained both hyperresponsiveness and the failure of a DI to relax the asthmatic airway.




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