To the Editor:
We read with interest the Brief Communication by Moore and
colleagues (1), concerned with the dose-response plateau in normal subjects. This article concludes that the plateau results from either a maximal level of muscle activation or limitations in airway smooth muscle shortening that can be balanced by
an increasing passive load. However, on the basis of recent
measurements (2), we suggest that these suggested mechanisms cannot account for the normal plateau. Our work studied airway size changes in a canine model in response to two
different kinds of methacholine (Mch) challenge. With a conventional aerosol challenge, there is an apparent dose-response
plateau similar to that observed in normal humans by Moore
and colleagues (1). However, if the airway smooth muscle in
vivo is stimulated more directly with a device that allows direct atomization of Mch to individual airways, we found unequivocal evidence that, not only can the airway smooth muscle contract further, but also that this contraction can easily cause sufficient shortening to result in closure of even large conducting airways. This observation demonstrates that shortening of airway smooth muscle in vivo is not limited by either
passive mechanical loads or by reaching a maximal level of activation. We suggest that the often observed plateau in normal
individuals may be related to the inability of aerosol challenge
to deliver sufficiently high Mch dose to the contracted airways. If this is the explanation in normal subjects, then the increased responsiveness of asthmatic airways and their lack of
a clear plateau might simply reflect an increased sensitivity to
exogenous stimulation.
ROBERT H. BROWN
WAYNE MITZNER
Department of Environmental Health Sciences
School of Hygiene and Public Health
The Johns Hopkins University
Baltimore, Maryland
1.
Moore, B. J.,
G. G. King,
Y. D'yachkova,
H. R. Ahmad, and
P. Paré.
1998.
Mechanism of methacholine dose-response plateaus in normal
subjects.
Am. J. Respir. Crit. Care Med.
158:
666-669
2.
Brown, R. H., and
W. Mitzner.
1998.
The myth of maximal airway responsiveness in vivo.
J. Appl. Physiol.
85:
2012-2017
From the Authors: In our Brief Communication (1) we reported results of our study in which we examined if, at the plateau of methacholine dose-response curves, airway smooth muscle (ASM) was maximally activated or alternatively, force generation was still increasing but being balanced by increasing load from lung elastic recoil. If the latter were true, this would mean that ASM was not maximally activated at the plateau despite administration of up to 256 mg/ml of methacholine. We measured pulmonary resistance (RL) and also lung elastic recoil pressure at zero flow during tidal breathing to quantify the load acting against ASM after each concentration of methacholine and we found that when RL plateaued, the lung elastic recoil pressure also plateaued. This suggested that force generation by ASM was not increasing at the plateau, possibly because it was maximally activated. Yet the plateau occurred after only a modest increase in RL which could be predicted to be caused by only approximately 25% ASM shortening; substantially less than occurs in maximally activated and unloaded ASM. Very interesting and potentially conflicting findings were reported in the recent article by Brown and colleagues (2). They showed that canine airways reached a plateau of narrowing after approximately 80-90% decrease in lumen area as measured by high-resolution CT when challenged with agonist aerosols that were administered by five moderate-size breaths. However, airways closed completely (no plateau) when agonist was delivered locally by an intrabronchial catheter during which the animal was presumably apneic. The differences between our results and those of Brown and coworkers could be due to species differences and/or to differences in technique; (1) ASM from central airways of humans (3) does not shorten as much as does the ASM from canine central airways (4), and (2) the increase in airway narrowing seen with direct instillation of agonist may have been due to the absence of deep breaths during agonist administration, which has been shown to be important in modulating ASM shortening during ASM activation (5). Brown and colleagues interpreted our results as being a reflection of incomplete activation secondary to decreased agonist delivery by aerosol. However, if decreased aerosol delivery during methacholine challenges explained the plateau, then one would expect a plateau to be present in asthmatic subjects, albeit at lower concentrations of methacholine. In addition, if aerosol delivery is critical, giving the final concentration of methacholine as a single dose should cause greater airway narrowing than when given by the more usual doubling concentration method. However, this phenomenon has not so far been reported. GREGORY G. KING B. J. MOORE PETER D. PARÉ McDonald Research Laboratories The University of British Columbia Vancouver, British Columbia, Canada
1. Moore, B. J., G. G. King, Y. D'yachkova, H. R. Ahmad, and P. D. Paré. 1998. Mechanism of methacholine dose-response plateaus in normal subjects. Am. J. Respir. Crit. Care Med. 159: 666-669 . 2. Brown, R. H., and W. Mitzner. 1998. The myth of maximal airway responsiveness in vivo. J. Appl. Physiol. 85: 2012-2017 . 3.
Ishida, K.,
P. D. Paré,
J. Hards, and
R. R. Schellenberg.
1992.
Mechanical
properties of human bronchial smooth muscle in vitro.
J. Appl. Physiol.
73:
1481-1485
4.
Okazawa, M.,
K. Ishida,
J. Road,
R. R. Schellenberg, and
P. D. Paré.
1992.
In vivo and in vitro correlation of trachealis muscle contraction in
dogs.
J. Appl. Physiol.
73:
1486-1493
5.
Shen, X.,
S. J. Gunst, and
R. S. Tepper.
1997.
Effect of tidal volume and
frequency on airway responsiveness in mechanically ventilated rabbits.
J. Appl. Physiol.
83:
1202-1208
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |