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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 373-374, 2004
© 2004 American Thoracic Society

Correspondence

The Use and Misuse of Penh in Animal Models of Lung Disease

Jason Batesa, Charles Irvina, Vito Brusascob, Jeffrey Drazenc, Jeffrey Fredbergc, Stephen Loringc, David Eidelmand, Mara Ludwigd, Peter Macklemd, James Martind, J. Milic-Emilid, Zoltan Hantose, Robert Hyattf, Stephen Lai-Fookg, Alan Leffh, Julian Solwayh, Kenneth Lutcheni, Bela Sukii, Wayne Mitznerj, Peter Parék, Neil Pridel and Peter Slym

a University of Vermont Burlington, Vermont
b University of Genoa Genoa, Italy
c Harvard University Boston, Massachusetts
d McGill University Montreal, Canada
e University of Szeged Szeged, Hungary
f Brookeville, Maryland
g University of Kentucky Lexington, Kentucky
h University of Chicago Chicago, Illinois
i Boston University Boston, Massachusetts
j Johns Hopkins University Baltimore, Maryland
k University of British Columbia Vancouver, Canada
l National Heart and Lung Institute London, United Kingdom
m University of Western Australia Perth, Australia

To the Editors:

Many papers in the AJRCMB make efforts to translate basic cell and molecular insights to the effects on airways in the whole animal. However, these efforts are often flawed by an overinterpretation of the functional measurements that rely on the empiric variable, "enhanced pause" or Penh, which has been shown to be primarily related to ventilatory timing and unrelated to airway resistance (1–3). We are quite concerned about the increasingly widespread (over 30 articles) and often uncritical applications of the Penh method that have appeared in recent years in the AJRCMB and its sister journal, the AJRCCM. This uncritical application of Penh has also spread to some of the world's most prestigious scientific journals, including PNAS, Nature Medicine, Nature Immunology, Nature Genetics, and Journal of Clinical Investigation. The basis for this usage stems from studies that have shown changes in Penh to sometimes correlate with changes in pulmonary resistance in small experimental animals (4–6). However, despite these empirical correlations observed by some investigators, several others have shown that changes in Penh and respiratory resistance often do not correlate (7–11). This should not be surprising, because there have been no published papers that have provided any theoretical basis for such a link, whereas there are analytic and experimental studies on the physics of whole-body plethysmography showing why they should not be expected to correlate (1–3). Nonetheless, despite this theoretical weakness, in some circumstances Penh may be suitable as a preliminary technique. For example, gene-hunting experiments sometimes involve breeding strategies that require large numbers of mice to be phenotyped quickly in assembly-line fashion. It should be emphasized, however, that the bred phenotype in such cases must still be validated with independent assessment of pulmonary mechanics in a subset of animals. This example highlights the critical issue that, since there is no way to know or predict when there is going to be a correlation between Penh and airway resistance (Raw), it is inappropriate scientifically to use Penh to reflect airway function, without an independent assessment of Raw. Because this requirement has already been emphasized in review articles (12–14) and an editorial (15), it is disappointing that many investigators still fail to validate changes in Penh with an independent measure of airway size. Of course such validation will still totally miss those experimental situations where airways respond with minimal effects on ventilatory control, as has been recently reported (16).

The American Thoracic Society has had a long history of publishing the most state-of-the-art techniques and measurements of pulmonary function. For this reason alone, authors and reviewers should pay particular attention to the use and interpretation of a variable whose primary asset is that it can be easily measured. However tempting is the ease of using the unrestrained plethysmography, Penh is not a measure of airway mechanics, and in the absence of confirmatory methods based on physical principles, should not be used to invoke terms such as "airway (hyper)reactivity" or "airway (hyper)responsiveness." The increasing uncritical use of unrestrained plethysmography imparts a danger of mass-producing false experimental evidence in the search for mechanisms of respiratory disease. We hope that the AJRCMB and its reviewers will take the lead in holding authors accountable for justifying their use of this potentially misleading assessment of airway function.

Footnotes

Conflict of Interest Statement: The authors have no declared conflicts of interest.

References

  1. Lundblad, L. K. A., C. G. Irvin, A. Adler, and J. H. T. Bates. 2002. A reevaluation of the validity of unrestrained plethysmography in mice. J Appl Physiol 93:1198–1207.[Abstract/Free Full Text]
  2. Mitzner, W., C. Tankersley, L. K. Lundblad, A. Adler, C. G. Irvin, and J. H. Bates. 2003. Interpreting Penh in mice. J. Appl. Physiol. 94:828–832.[Free Full Text]
  3. Mitzner, W., and C. Tankersley. 1998. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 158:340–341.
  4. Hamelmann, E., J. Schwarze, K. Takeda, A. Oshiba, G. L. Larsen, C. G. Irvin, and E. W. Gelfand. 1997. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156:766–775.[Abstract/Free Full Text]
  5. Chong, B. T., D. K. Agrawal, F. A. Romero, and R. G. Townley. 1998. Measurement of bronchoconstriction using whole-body plethysmograph: comparison of freely moving versus restrained guinea pigs. J. Pharmacol. Toxicol. Methods 39:163–168.[CrossRef][Medline]
  6. Bergren, D. R. 2001. Chronic tobacco smoke exposure increases airway sensitivity to capsaicin in awake guinea pigs. J. Appl. Physiol. 90:695–704.[Abstract/Free Full Text]
  7. Flandre, T. D., P. L. Leroy, and D. J. Desmecht. 2003. Effect of somatic growth, strain, and sex on double-chamber plethysmographic respiratory function values in healthy mice. J. Appl. Physiol. 94:1129–1136.[Abstract/Free Full Text]
  8. Petak, F., W. Habre, Y. R. Donati, Z. Hantos, and C. Barazzone-Argiroffo. 2001. Hyperoxia-induced changes in mouse lung mechanics: forced oscillations vs. barometric plethysmography. J. Appl. Physiol. 90:2221–2230.[Abstract/Free Full Text]
  9. Adler, A., G. Cieslewicz, and C. G. Irvin. 2004. Unrestrained plethysmography is an unreliable measure of airways responsiveness in BALB/c and C57BL6 mice. J. Appl. Physiol. (In press)
  10. DeLorme, M. P., and O. R. Moss. 2002. Pulmonary function assessment by whole-body plethysmography in restrained versus unrestrained mice. J. Pharmacol. Toxicol. Methods 47:1–10.[CrossRef][Medline]
  11. Pauluhn, J. 2004. Comparative analysis of pulmonary irritation by measurements of Penh and protein in bronchoalveolar lavage fluid in brown norway rats and wistar rats expsosed to irritant aerosols. Inhal. Toxicol. 16:159–175.[CrossRef][Medline]
  12. Drazen, J. M., P. W. Finn, and G. T. De Sanctis. 1999. Mouse models of airway responsiveness: physiological basis of observed outcomes and analysis of selected examples using these outcome indicators. Annu. Rev. Physiol. 61:593–625.[CrossRef][Medline]
  13. Kips, J. C., G. P. Anderson, J. J. Fredberg, U. Herz, M. D. Inman, M. Jordana, D. M. Kemeny, J. Lotvall, R. A. Pauwels, C. G. Plopper, D. Schmidt, P. J. Sterk, A. J. Van Oosterhout, B. B. Vargaftig, and K. F. Chung. 2003. Murine models of asthma. Eur. Respir. J. 22:374–382.[Abstract/Free Full Text]
  14. Bates, J. H., and C. G. Irvin. 2003. Measuring lung function in mice: the phenotyping uncertainty principle. J. Appl. Physiol. 94:1297–1306.[Abstract/Free Full Text]
  15. Hantos, Z., and V. Brusasco. 2002. Assessment of respiratory mechanics in small animals: the simpler the better? J. Appl. Physiol. 93:1196–1197.[Free Full Text]
  16. Hjoberg, J., S. A. Shore, L. Kobzik, S. Okinaga, A. Hallock, J. Vallone, V. Subramaniam, G. T. DeSanctis, J. A. Elias, J. M. Drazen, and E. S. Silverman. 2004. Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness. J. Appl. Physiol. (In press)



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