Comments for:

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In response to Mitzner and Weibel

Submitter: Jack Elias | jack.elias@yale.edu

Authors: Min-Jong Kang, Charles Dela Cruz, Chjun Geun Lee

Yale University School of Medicine

Published March 30, 2009

We are pleased that Drs. Mitzner and Weibel found our study to be a very provocative article dealing with the interactions of cigarette smoke and viral infections in the pathogenesis of emphysema. In our study, we used airspace chord length (mean linear intercept: Lm) and lung volume changes as indices of emphysematous alveolar remodeling in mice. Although there has been a lot of debate over the proper application of morphometric analyses to quantitate emphysematous changes in animal models and in humans (1, 2), a number of studies strongly support the mean linear intercept (Lm) as a reliable index of pulmonary emphysema (2). As pointed out, previous investigators reported a simple mathematical relationship between alveolar surface area, lung volume (V) and Lm (Lm= 4V/surface Area) (3). However, we do not believe this mathematical equation can be considered the gold standard for the diagnosis of emphysema. Substantial discrepancies between surface area measurements and Lm values have been described in studies of emphysematous lungs. Specifically, Thurlbeck demonstrated that the internal alveolar surface area (ISA; measured at 25 cm H2O or total lung capacity) of most human lungs with emphysema fell within the normal range and that the Lm was a more reliable index to distinguish between normal and emphysematous tissues (4). Similar studies from other investigators also demonstrated that the ISA measurement was the least reliable index of emphysema (5) and Hogg and colleagues demonstrated that alveolar surface area was only decreased in severe cases of emphysema (6). These studies clearly highlight the poor sensitivity of this assessment in the diagnosis of emphysema and the practical difficulties in the simple application of this theoretical equation to the interpretation of complex human and experimental specimens. In accord with these complexities, surface area measurements are not used clinically to diagnose human emphysema. Drs. Mitzner and Weibel, also quote old literature to suggest that emphysema is an irreversible process due to destruction of alveolar walls. We agree that tissue destruction is an integral aspect of the pathogenesis of this disease. In accord with this concept we have convincingly shown alveolar wall destruction in our murine model (Figs 2 and Fig 11). We further demonstrated impressive levels of epithelial apoptosis at these sites of pathology that likely generate these destructive alterations (Figs.9-11, S3). Lastly, it is important to point out that the concept that emphysema are irreversible is antiquated and defeatist. The alterations in emphysema are the result of the antagonistic effects of injury and repair. If the latter can be augmented by interventions that increase repair and or regeneration true emphysema may actually be a reversible process. Experimental data illustrating this concept have already been reported (7, 8). Therefore, we do not agree with the letter’s final conclusion because it is drawn on the basis of a mathematical equation that does not appropriately consider the complexity of the emphysematous response, ignores the readily apparent alveolar damage in our modeling system and does not include important concepts relating to the balance of injury and repair in the lung.
Jack A. Elias
Min-Jong Kang
Charles Dela Cruz
Chjun Geun Lee

References

1. Weibel, E.R. 2006. Morphological quantitation of emphysema: a debate. J Appl Physiol 100:1419-1420; author reply 1420-1411.
2. Mitzner, W. 2008. Use of mean airspace chord length to assess emphysema. J Appl Physiol 105:1980-1981.
3. Campbell, H., and Tomkeieff, S.I. 1952. Calculation of the internal surface of a lung. Nature 170:116-117.
4. Thurlbeck, W.M. 1967. Internal surface area and other measurements in emphysema. Thorax 22:483-496.
5. Hasleton, P.S. 1972. The internal surface area in normal and emphysematous lungs. J Pathol 106:P3.
6. Coxson, H.O., Rogers, R.M., Whittall, K.P., D'Yachkova, Y., Pare, P.D., Sciurba, F.C., and Hogg, J.C. 1999. A quantification of the lung surface area in emphysema using computed tomography. Am J Respir Crit Care Med 159:851-856.
7. Massaro, G.D., and Massaro, D. 1997. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 3:675-677.
8. Hind, M., and Maden, M. 2004. Retinoic acid induces alveolar regeneration in the adult mouse lung. Eur Respir J 23:20-27.

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Comment on Kang et al.

Submitter: Wayne Mitzner | wmitzner@jhsph.edu

Authors: Ewald Weibel

The Johns Hopkins School of Hygiene and Public Health Division of Physiology

Published March 23, 2009

We congratulate Dr. Kang and colleagues for a very provocative article dealing with the interaction of cigarette smoke and viral infections on mechanisms that may underlie the pathogenesis of emphysema (1). However, we wish to point out one methodological aspect of this work that will affect the interpretation. To detect the occurrence of emphysema mean airspace chord length is measured and reported in several graphs; in Figs. 2 and 11 changes in lung volume are also reported. Figures 2B and 2C, and similarly in Fig.11, show increases in both the mean chord length (Lm) and mean lung volume (V) in two of the experimental groups, and these increases are used as evidence of emphysema. Since both of these increases are roughly proportional, this suggests that the alveolar surface area, calculated as 4V/Lm (2, 3), was actually not changed. However, in emphysema there should be an irreversible loss of surface area by destruction of alveolar walls (4), but the figures presented confirm that this was not found with the insults in this study. The increased Lm simply reflects more highly inflated airspaces as a result of higher volumes of the fixed lung. From the methodological point of view this shows the importance of observing sampling rules of stereology, mainly the consideration of changes in the reference parameters, here the lung volume (5). That the virus and cigarette smoke caused some functional change is clear, since the increased compliance of the lung allowed greater inflation at the same pressure, but emphysema is more than just increased lung compliance. Therefore, the acute changes observed in this paper might simply reflect a combination of the relatively short-term irritant and inflammatory insults, and may have little relation to what occurs in clinical emphysema.
Wayne Mitzner, Johns Hopkins University
Ewald Weibel, University of Bern

References

1. Kang, M.J., Lee, C.G., Lee, J.Y., Dela Cruz, C.S., Chen, Z.J., Enelow, R., and Elias, J.A. 2008. Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest 118:2771-2784.
2. Weibel, E.R. 1963. Principles and methods for the morphometric study of the lung and other organs. Lab Invest 12:131-155.
3. Campbell, H., and Tomkeieff, S.I. 1952. Calculation of the internal surface of a lung. Nature 170:117.
4. Snider, G.L., Kleinerman, J., Thurlbeck, W.M., and Bengali, Z.H. 1985. The definition of emphysema: Report of a National Heart, Lung, and Blood Institute workshop. . Am Rev Respir Dis 132:http://www-test. thoracic.org/copd/pdf/copddoc.pdf.
5. Weibel, E.R., Hsia, C.C., and Ochs, M. 2007. How much is there really? Why stereology is essential in lung morphometry. J Appl Physiol 102:459-467.