Response to a Recently Published Manuscript

The following is the abstract of the article discussed in the subsequent letter:

	ABSTRACT

Volgyesi, G. A., L. N. Tremblay, P. Webster, N. Zamel, and A. S. Slutsky. A new ventilator for monitoring lung mechanics in small animals. J Appl Physiol 89: 413-421, 2000.Researchers investigating the genetic component of various disease states rely increasingly on murine models. We have developed a ventilator to simplify respiratory research in small animals down to murine size. The new ventilator provides constant-flow inflation and tidal volume delivery independent of respiratory parameter changes. The inclusion of end-inspiratory and end-expiratory pauses simplifies the measurement of airway resistance and compliance and allows the detection of dynamic hyperinflation (auto-positive end-expiratory pressure). After bench testing, we performed intravenous methacholine challenge on two strains of mice (A/J and C57bl/bj) known to differ in their responses by using the new ventilator. Dynamic hyperinflation and a decrease in compliance developed during methacholine challenge whenever respiratory rates of 60-120 breaths/min were employed. In contrast, if dynamic hyperinflation was prevented by lengthening expiratory time, (respiratory rate = 20 breaths/min), static compliance remained constant. More importantly, the coefficient of variation of the results decreased when lung volume shifts were prevented. In conclusion, airway challenge studies have greater precision when dynamic hyperinflation is prevented.

	LETTER

Response to a Recently Published Manuscript

To the Editor: It was with some interest that we read the recent paper in Journal of Applied Physiology, "A new ventilator for monitoring lung mechanics in small animals, by Volgyesi et al. (5). The paper describes ventilation in mice with a solenoid-controlled airflow. Of some concern, however, is the use of the adjective "new" in the title and paper. With regard to this particular ventilator and mode of ventilation, this usage is at best misleading. The basic design of this new ventilator was already published five years ago in this same Journal, along with similar strains, the same ventilatory waveforms, and essentially the same analysis (2). Although the authors do reference this earlier work, they summarily dismiss it as not providing sufficient details regarding the design and testing. Whereas it may be true that this original paper did not provide lots of design details, the basic ventilator has been field tested many times over the past 10 years (1-4, 6). The authors also suggest a potential use of their new ventilator in longitudinal studies, but, had they been a bit more familiar with the most recent literature, they might have noted the use of our identical "old" ventilator in longitudinal studies in individual mice, which includes measurement of both respiratory mechanics and bronchoalveolar lavage (6).

On a more positive note, we do recognize that the paper by Volgyesi et al. does contain several experimental validations of our ventilator that are of considerable interest. The comparison with the more conventional Harvard ventilator is important, as is the discussion of potential dynamic hyperventilation with methacholine constriction. The mechanical changes they observed following sudden changes in the inspiration-to-expiration ratio also suggest several interesting experiments that might provide new insights into airway smooth muscle dynamics.

In summary, we believe that it does not benefit the respiratory community to suggest that a study is novel when it is not warranted. It makes the field look old and tired and ultimately weakens the Journal as well. In today's exciting research environment, there is surely more than enough true new work to be done, without having to apply that adjective to testing and validation of previous studies.

	REFERENCES

1.   Brown, RH, Walters DM, Greenberg RS, and Mitzner W. A method of endotracheal intubation and pulmonary functional assessment for repeated studies in mice. J Appl Physiol 87: 2362-2365, 1999[Abstract/Free Full Text].

2.   Ewart, SL, Levitt RC, and Mitzner W. Respiratory system mechanics in mice measured by end-inflation occlusion. J Appl Physiol 79: 560-566, 1995[Abstract/Free Full Text].

3.   Ewart, SL, Mitzner W, DiSilvestre DA, Meyers DA, and Levitt RC. Airway hyperresponsiveness to acetylcholine: segregration analysis and evidence for linkage to murine chromosome 6. Am J Respir Cell Mol Biol 14: 487-495, 1996[Abstract].

4.   Levitt, RC, and Mitzner W. Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine. J Appl Physiol 67: 1125-1132, 1989[Abstract/Free Full Text].

5.   Volgyesi, GA, Tremblay LN, Webster P, Zamel N, and Slutsky AS. A new ventilator for monitoring lung mechanics in small animals. J Appl Physiol 89: 413-421, 2000[Abstract/Free Full Text].

6.   Walters, DM, Wills-Karp M, and Mitzner W. Assessment of cellular profile and lung function with repeated bronchoalveolar lavage in individual mice. Physiol Genom 2: 29-36, 2000[Abstract/Free Full Text].

Susan Ewart, Roy Levitt, Wayne Mitzner, Department of Environmental Health Sciences School of Hygiene and Public Health The Johns Hopkins University Baltimore, Maryland 21205 E-mail: wmitzner{at}jhsph.edu

	REPLY

To the Editor: We thank Ewart et al., who are indeed true pioneers in this field, for their interest in our paper (2).

Although we do agree that the word "new" in describing our ventilator and methodology may not have been the best choice ("improved" would have been better), we would like to point out the differences between the approach used by Ewart et al. and our approach, concerning both equipment and methodology. They use a metering valve (whose resistance is almost certainly flow dependent) for administering constant flow, whereas we use a capillary tube whose resistance we proved to be independent of flow over the range of flows that are relevant. They assume that inspiratory flow is constant and independent of tracheal pressure; however, from their Fig. 3B of Ref. 1, this is clearly not the case. More seriously, on careful examination of the figures in Ref. 1, their basic assumption that each expiration terminates at the same function residual capacity does not appear to be justified. Dynamic hyperinflation (indicated by the ascent of tracheal pressure during end-expiratory pause), nearly absent in their baseline recording (see Fig. 3A in Ref. 1), is clearly present after ACh administration (see Fig. 3B in Ref. 1). Changes in resistance and elastance were not estimated at the same lung volume and are therefore unreliable. This methodological error, which tends to decrease the sensitivity of discrimination of interstrain differences, has been repeated in most of their other studies cited in the above letter. As to the issue of longitudinal studies alluded to in Ref. 3 (which was published just after our paper was submitted), Fig. 1 in Ref. 3 shows only the timing of ventilatory maneuvers, without any details describing their implementation.

Part of the excitement of today's research environment is the continual development and improvement of tools that make new work possible. One purpose of our publication was to describe such a tool in considerable detail and thus enable others to pursue similar research on small animals. Another purpose was to raise serious concern regarding traditionally accepted methodology for performing airway challenge on small animals.

	REFERENCES

1.   Ewart, SL, Levitt RC, and Mitzner W. Respiratory system mechanics in mice measured by end-inflation occlusion. J Appl Physiol 79: 560-566, 1995.

2.   Volgyesi, GA, Tremblay LN, Webster P, Zamel N, and Slutsky AS. A new ventilator for monitoring lung mechanics in small animals. J Appl Physiol 89: 413-421, 2000.

3.   Walters, DM, Wills-Karp M, and Mitzner W. Assessment of cellular profile and lung function with repeated bronchoalveolar lavage in individual mice. Physiol Genom 2: 29-36, 2000.

George Volgyesi, Lorraine Tremblay, Peter Webster, Noe Zamel, Arthur Slutsky, Department of Medicine St. Michaels Hospital University of Toronto Toronto, Ontario, Canada M5B 1W8 E-mail: george.volgyesi{at}utoronto.ca