We read with great interest the recent article by Carey and colleagues on the role of estrogen receptors in airway responsiveness (1). This study deals with an important area that has potential clinical significance. However, in the analysis of airway responsiveness, it is unfortunate that the authors chose to rely so heavily on a misrepresentation of the variable Penh. In an earlier letter published in the AJRCMB, this variable was explicitly criticized by leaders in the field of respiratory mechanics, stating that, “however tempting is the ease of using the unrestrained plethysmography, Penh is not a measure of airway mechanics” (2). Although Carey and coworkers did cite this reference, they nevertheless repeatedly referred to Penh as airway responsiveness in the title, text, and legends. In fact, the irony in their present use of Penh is that, although respiratory impedance was also measured in an attempt to provide validation for the Penh measurements, this validation failed!

Rn is the parameter that has been shown to best reflect airway resistance in vivo in several species, including mice (3), but in Carey and coworkers’ study this measurement clearly showed that there was in fact no change in the airway responsiveness in the ?ERKO females (Figure 2), or with ovariectomy or exogenous estradiol (Figure 4). Since the defect in asthma is with airway narrowing, why the authors chose to rely so heavily on a measurement that relates more to ventilatory control, and not one that is known to directly reflect airway size, is a mystery. Furthermore, their results actually show that the estrogen receptor is more closely related to the tissue viscoelasticity than the airway size, but this finding is not addressed.

On a related matter, since the authors tacitly assume that Penh is a measure of the airway resistance based on compression-expansion of alveolar gas, this raises questions about the reliability of their measurement of ventilation with unrestrained plethysmography in these same animals (4). This could perhaps account for the abnormally high respiratory rate and minute ventilation reported in Table 1, which are more than double what is normally observed in quietly resting, conscious mice (5, 6). Finally, perhaps the most interesting question that arises from this study is why the increased responsiveness observed in vitro in the ?ERKO does not manifest itself in vivo. There must be compensatory regulation in vivo that overcomes the intrinsic increased sensitivity to cholinergic stimulation sufficiently to allow the responsiveness of airways to remain similar to that in the wild type controls.

Conflict of Interest Statement : None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.