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POINT-COUNTERPOINT
Vermont Lung Center
University of Vermont College of Medicine
Burlington, Vermont
e-mail: jason.h.bates{at}uvm.edu
POINT: LUNG IMPEDANCE MEASUREMENTS ARE MORE USEFUL THAN SIMPLER MEASUREMENTS OF LUNG FUNCTION IN ANIMAL MODELS OF PULMONARY DISEASE
Research on pulmonary disease relies increasingly on the use of animal models, commensurate with the progression of our ability to manipulate the genome and recreate noxious environmental conditions in the laboratory. Accordingly, any self-respecting biomedical research institution these days will have set up some kind of advanced animal facility. This costs a huge amount of money and involves excruciating politico-regulatory monitoring. How idiotic would it be then to throw away a significant fraction of the biological information embodied in any animal model that is produced from such effort and expense? The very fact that we are debating here the issue of lung impedance versus simpler measures of mechanics shows that some investigators still consider this an open question. I will now end the debate by explaining why impedance contains more physiological information than simpler measures of mechanics, and so by definition must be more useful.
The assessment of lung mechanics is central to the phenotypic characterization of any animal model of pulmonary disease, and many approaches have been developed. Let me first dispatch with the widely used enhanced pause (Penh) by pointing out that it has been completely discredited as a means of measuring lung mechanical function (1, 3, 14). Valid assessment of lung mechanics involves probing the lung with some kind of perturbation and observing the consequences. The level of detail that this reveals about the inner workings of the lung depends very much on the richness of the perturbation. A very simple perturbation, for example, is a single step increase in lung volume. The relative increase in airway opening pressure produced by this perturbation yields a measure of the overall lung stiffness (elastance) and is affected by a variety of pathologies. For example, an increase in elastance can result from fibrosis of the parenchyma (8), closure of airways (24), edematous filling of alveoli (13), hyperinflation (23), or inactivation of pulmonary surfactant by plasma proteins (26). Thus, while measuring elastance may be useful for discerning the presence of pathology, it hardly narrows the field of specific causes.
A perturbation with more diagnostic potential is an oscillating volume change, such as that applied during conventional mechanical ventilation. Some investigators have used the peak in the resulting oscillatory airway pressure as an index of global lung mechanics (9), but this ignores key information contained in the data and provides essentially the same discriminatory power as elastance. The dynamic nature of the oscillating volume perturbation means that its associated airway pressure signal contains information about both the resistive and elastance properties of the lung, which may be differentially altered in various diseases. The relative contributions of lung resistance (R) and elastance (E) to airway pressure are not obvious from mere inspection of the data, but they can be evaluated separately by fitting the equation
 | (1) |
), and volume (V) signals that vary with time (t; Ref. 5). Nevertheless, two independent parameters can still only provide an extremely limited window into the inner mechanical workings of a system as complicated as the lung. Just how limited is evidenced by the substantial variation of both R and E with the perturbation frequency, f. In normal animals, this f dependence is largely due to the viscoelastic properties of lung tissue (12). In disease, the situation may be complicated by the development of regional heterogeneities in lung mechanical function that further accentuate the f dependence of R and E (18).
A comprehensive assessment lung mechanics thus requires that R and E be measured as two independent, yet complimentary, functions of f. Together, they constitute a complex function of frequency known as pulmonary input impedance, Zin. The real part of Zin is called resistance because it equals R in Eq. 1 at any particular value of f. The imaginary part of Zin is known as reactance and is equal to –E/2
f in Eq. 1. Recent work (10, 11, 20) has established that Zin in normal mice is extremely well described up to 20 Hz by the following model, first described for the lung by Hantos et al. (12),
 | (2) |
is determined by G and H. Equation 2 also describes Zin in the mouse even during mild to moderate bronchoconstriction (6, 20, 24) as well as in various other pathological situations (2, 7, 16). Zin in mice can thus be accurately characterized under a wide range of conditions by only three parameters. Its real utility, however, lies in the fact that RN, G, and H have functionally important physiological interpretations. RN is essentially equal to airway resistance (Raw; Ref. 22), so a change in RN can be taken as accurate indication of a global change in airway caliber. Changes in G and H, which together characterize the viscoelastic properties of the tissue in a normal lung (12), can be indicative of two distinct types of mechanical derangement. Derecruitment of a portion of the lung causes G and H to increase in the same proportion (2, 4), while increased regional heterogeneity of mechanical function throughout the lung causes G to increase relatively more than H (4, 17, 21). By tracking the changes in RN, G, and H that occur immediately following administration of a methacholine aerosol, we can differentiate between exaggerated smooth muscle shortening versus increased closure of small airways. This has allowed us to infer that acutely allergically inflamed BALB/c mice are hyperresponsive because their airway epithelium is physically thickened and not because of any significant changes in the contractility of their airway smooth muscle (24). By contrast, when BALB/c mice are treated with an intratracheal instillation of poly-L-lysine they become hyperresponsive because of increased smooth muscle shortening (6). We also invoked changes in RN, G, and H to show that administering methacholine as an aerosol induces a significant amount of airway closure (24) that is virtually absent when the methacholine is injected intravenously (15, 25). Equation 2 has also been used to interpret measurements of Zin in other species (10, 12).
So now to address the question of whether impedance really is more useful than simpler measurements of lung function in animal models of pulmonary disease. In view of the foregoing discussion it will be obvious to enlightened readers that the answer is affirmative, but as a service to the recalcitrant skeptic, I will explicitly point out what clinches the case. Zin allows one to discern, with a reasonable degree of confidence, how an experimental intervention differentially affects airway caliber, derecruitment of lung units, and regional heterogeneity of function. This level of inference is not possible with simpler measures of lung function because they simply do not contain the required physiological information. This is not to say, of course, that Zin is the last word in the assessment of lung function. It is actually only the first term in a potentially infinite series of ever more complicated complex functions of frequency that describe the general nonlinear dynamic system (19). Nevertheless, Zin currently represents the state of the art for assessing lung function in animal models of pulmonary disease and constitutes a significant advance beyond the simpler methods that dominated investigations in the old days.
REFERENCES
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