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INVITED EDITORIALS
Department of Physiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
ASSESSMENT OF AIRWAY FUNCTION in the mouse has become a critical need for many investigations of asthma and other lung diseases involving airways. Although there are several methods available to quantify airway function in anesthetized mice that are subsequently killed, there are obvious advantages for a method to assess airway resistance that can be used in conscious mice that can be individually restudied. Indeed, this desire led to the unfortunate use of an index known as Penh, which has since been shown to provide an unreliable and invalid measure of airway resistance (1). The desire to assess airway size in conscious freely breathing mice, however, remains a high priority.
Although imaging may be the only direct way to quantify this size, there are limits to the size of airways in the mouse that can be quantified even with the best µCT presently available. A measure of airway resistance has a clear relation to the diameter of the airways, although a direct link between the sizes of all the airways in series and parallel and the single measure of resistance is obviously not a simple one. Nevertheless, among the various measurements of pulmonary function, resistance is perhaps the best estimate of airway size, and for this reason, several investigators have recently presented methods analyzing the pressure in a body plethysmograph containing a freely breathing mouse. When this is done, the pressure signal from the box contains a component due to gas compression (a function of the airway resistance and flow) and another related to the warming and humidification of inspired gas (a function of tidal volume). With quiet breathing, the tidal volume component is dominant, on the order of 10 times the other (6), but in humans, the gas compression (resistive) component is maximized by having the subjects voluntarily breath with low tidal volume at very high frequency (3). Unfortunately, mice are rarely so cooperative, and although some may believe that mice already breath at high frequency and low tidal volume in the extreme, it is still not nearly enough to make the resistive component dominant.
This problem in the mouse was independently analyzed by two groups (2, 4, 5), using different methodological approaches in conscious spontaneously breathing mice to show how it is possible to make a measurement that can be closely linked to airway resistance (Raw). In these methods, however, there were several procedures involved that may make the methods not routine for others to use, including heating the plethysmograph to body temperature, assuming a stable thoracic flow pattern, a complex analytical approach, or an X-ray facility. In a study in the Journal of Applied Physiology, however, Reynolds et al. (8) describe a very novel method that appears sufficiently simple to perhaps be more easily used in other laboratories. The method involves changes in acoustic resonance in a body plethysmograph to assess changes in lung volume in spontaneously breathing mice. With some straightforward calculations as previously described for a double-chamber plethysmograph with a neck seal (7), the investigators show not only how specific Raw (sRaw) can be calculated but also that the procedure can be used to generate methacholine (MCh) dose-response curves. An additional advantage of this resistance measurement is that it does not include tissue resistances of the lung and chest wall, which can comprise a variable nontrivial fraction of the total resistance when it is measured in anesthetized animals.
Although this new approach (or either of the previously mentioned ones) does achieve the goal of allowing repeated measurements of airway resistance in individual unrestrained mice, it is still not the Holy Grail of airway function. There are at least two reasons why a noninvasive measure of Raw needs to be interpreted with some caution. First, with any resistance measurement in a spontaneously breathing intact animal, the measurement must include the series resistance of the upper airway. This may in fact be the major fraction of the total resistance (2, 4), and if it changes with whatever intervention is being studied, the relation to the size of intraparenchymal airways may be difficult to interpret or even detect. Second, if one is only measuring sRaw (8), this includes the lung volume as a direct multiplier, so any changes in lung volume, as may occur with MCh challenge (4), will change the magnitude, independently of changes in airway size. Whether these issues in conscious mice create more problems than those associated with the assumptions involved in measuring and interpreting impedance and resistance in anesthetized mice remains to be decided by individual investigators. It is somewhat ironic that the only species where an unequivocal measure of airway resistance can be made is humans, but even then, the effort of using a body plethysmograph with a panting subject has limited its occasional use to specialized pulmonary function laboratories. Whether this same fate awaits the now three approaches to measuring Raw or sRaw noninvasively in conscious mice remains to be seen.
FOOTNOTES
Address for reprint requests and other correspondence: W. Mitzner, Johns Hopkins Univ., Bloomberg School of Public Health, Dept. of Physiology, 615 N. Wolfe St., Baltimore, MD 21205-2103 (e-mail: wmitzner{at}jhsph.edu)
REFERENCES
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