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DOI: 10.1148/radiol.2413051456
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(Radiology 2006;241:763-770.)
© RSNA, 2006

Experimental Studies

Elastase-induced Pulmonary Emphysema in Rats: Comparison of Computed Density and Microscopic Morphometry1

Cécile Onclinx, DVM, Viviane De Maertelaer, PhD, Pascal Gustin, DVM, PhD and Pierre Alain Gevenois, MD, PhD

1 From the Department for Functional Sciences, Section of Pharmacology, Pharmacotherapy, and Toxicology, Faculty of Veterinary Medicine, University of Liege, Belgium (C.O., P.G.); Statistical Unit, Institute of Interdisciplinary Research in Human and Molecular Biology, University of Brussels, Belgium (V.D.M.); and Department of Radiology, Erasme Hospital, University of Brussels, Route de Lennik 808, 1070 Brussels, Belgium (P.A.G.). Received August 30, 2005; revision requested November 2; revision received December 13; accepted January 3, 2006; final version accepted February 8. Supported by the Walloon Region (grants 021/5112 and 021/5354). Address correspondence to P.A.G. (e-mail: pierre.alain.gevenois{at}ulb.ac.be).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively compare computed tomographic (CT) quantification of pulmonary emphysema in elastase-treated rats with morphometry and to evaluate the information yielded by CT quantification and pulmonary function tests.

Materials and Methods: This study was approved by the local committee on care and use of animals in research. Thirty-six animals were used. Emphysema was produced by means of one or two tracheal injections of 300 IU of elastase, 8 weeks apart, in seven and 12 rats, respectively. As a control group, 10 rats received an injection of normal saline. The dynamic resistance, dynamic compliance, and static compliance were measured. CT was performed with 1-mm section thickness and 3-mm intervals. Relative areas of lung with attenuation coefficients lower than nine chosen thresholds (from –900 to –980 HU) and eight percentiles (from 1st to 18th percentiles) of the distribution of attenuation coefficients were compared with measurements of alveoli size—that is, mean interwall distance (MIWD) and mean perimeter per field (MP). Correlations between data obtained with thresholds and percentiles and MIWD and MP were investigated by means of Spearman coefficients (rs). Values of pulmonary function tests, most appropriate relative area threshold, and percentile were investigated by means of stepwise multiple regressions.

Results: For thresholds, relative surface area with attenuation coefficients less than –940 HU (RA940) showed the strongest correlations with findings at microscopy (rs = 0.676, P < .001 for MIWD; rs = –0.720, P < .001 for MP). For percentiles, the 3rd percentile showed the strongest correlations (rs = –0.647, P < .001 for MIWD; rs = 0.701, P < .001 for MP). Dynamic compliance and RA940 or 3rd percentile were complementary for predicting microscopic measurements.

Conclusion: In rats, RA940 and the 3rd percentile reflect the extent of elastase-induced pulmonary emphysema and are complementary to dynamic compliance to predict microscopic extent.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Pulmonary emphysema is defined as a "condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by the destruction of their walls, and without obvious fibrosis" (1). Study results suggesting that alveolar number and surface-to-volume ratio can be restored by means of therapeutic intervention in rats with elastase-induced emphysema imply the need for measurement techniques that can be used to accurately assess the effectiveness of such therapeutic interventions (2). As emphysema is defined on the basis of histologic criteria, its quantification should ideally be based on morphometric measurements. In animal models for longitudinal studies, quantification of emphysema is either indirect and is based on results of pulmonary function tests (PFTs) that reflect the increased lung compliance or it is animal-consuming, where animals are sacrificed for lung sampling (3).

In humans, computed tomography (CT) is an imaging method accepted for in vivo diagnosis and quantification of pulmonary emphysema (4,5). On CT scans, emphysema is characterized by areas of lung with reduced attenuation coefficients. Authors of several studies have investigated indexes derived from the frequency distribution curve of this coefficient (4–9), but this technique has not been validated in animals. Therefore, the purpose of our study was to prospectively compare CT quantification of pulmonary emphysema in elastase-treated rats with morphometry and to evaluate the information yielded by means of CT quantification and PFT.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animals
Thirty-six Sprague-Dawley male rats, which were 14 weeks old and weighed 402 g ± 5 (mean ± standard error of the mean) at the start of the study, were included. The animals were obtained from the University of Liege animal breeding unit. They were housed in groups of two individuals in appropriate cages on wood shavings, and they received food and water ad libitum. The cages were cleaned twice weekly, and water was changed every 2 days. The animals were kept at 21°C, with a 12-hour light-dark cycle. The experiments were performed in accordance with the "Guide for the Care and Use of Laboratory Animals" (10), as approved by the council of the American Physiological Society (Bethesda, Md), and were approved by the Committee on the Care and Use of Animals in Research of the School of Medicine of our university.

Animals were randomly distributed into three groups. Group 1 served as a control group and consisted of 12 rats that received a tracheal injection of 200 µL of sterile normal saline (Lohmann-Rauscher International, Rengsdorf, Germany). Group 2 consisted of 12 rats that received one tracheal injection of 300 IU of purified porcine pancreatic elastase (Roche Diagnostics, Mannheim, Germany) dissolved in 200 µL of sterile normal saline (11). Group 3 consisted of 12 rats that received two tracheal injections of elastase, with the second injection administered 8 weeks after the first. Four animals had to be excluded because they lost their ear tag, which prevented us from knowing if they were control animals or if they had received a tracheal injection of elastase.

Animal Preparation
Animals first received a subcutaneous injection of 300 µg medetomidine HCl (Domitor; Pfizer/Orion, Espoo, Finland) per kilogram of body weight. After 15 minutes, they were anesthetized with an intraperitoneal injection of 50 mg of ketamine HCl (Imalgene 1000; Merial, Brussels, Belgium) per kilogram of body weight and were then intubated with a 12-gauge catheter. A microtube was inserted into the endotracheal catheter for injection of normal saline or elastase. One animal in group 2 died during recovery after anesthesia.

Elastase was prepared immediately before endotracheal instillation, which was performed by a veterinarian (C.O.). The specific amount was 130 IU/mg, where 1 IU was defined as the amount of enzyme catalyzing 1 mg of elastin in 20 minutes at a pH of 8.8 and 37°C.

PFT Measurements
Before PFT measurements, the ventilator (Flexivent; Scireq, Montreal, Canada) was calibrated in two steps. First, calibration for reference pressures was performed by connecting the ventilator to a manometer ensuring 0 and 20 cm H2O. Second, the 12-gauge catheter used for tracheal intubation was connected to the ventilator, and volume and pressure were measured twice while a standard respiratory cycle was simulated—once with the catheter open to room air, and once with it closed. Piston displacement and cylinder pressure measured during these two steps were used to take into account the mechanical characteristics of the ventilator in further measurements.

PFTs were performed on the same day as CT scanning, either 8 weeks after tracheal injection in groups 1 and 2 or 16 weeks after the first tracheal injection in group 3.

For PFTs and CT scanning, animals were anesthetized and laid in a cradle in the supine position. Curarization was performed with 0.5 mg (12) of atracurium besilate (Tracrium; GlaxoSmithKline, Genval, Belgium) per kilogram of body weight, and then mechanical ventilation was performed with a tidal volume of 10 mL/kg (with a maximum of 5 mL); respiratory rate was maintained at 90 breaths per minute and inflation pressure was limited to 20 cm H2O.

Pulmonary function was measured 10 minutes after the injection of atracurium besilate in order to ensure complete muscular relaxation. Variations in pressure following controlled variations of volume were measured twice. Dynamic resistance and both dynamic and static compliance were then calculated by one of the investigators (C.O.).

CT Examinations
Thin-section CT scans were obtained by using a commercially available CT scanner (Somatom Plus; Siemens Medical Solutions, Forchheim, Germany). Animals were examined in the same position as for PFTs, and none received contrast material. CT scanning was performed during a breath hold at a constant pressure of 25 cm H2O, which was ensured by means of continuous oxygen delivery controlled by a water column. It was estimated that at this level of pressure, the animals would be at total lung capacity. Scanning time lasted 1 second, tube current was 105 mA, and voltage was 80 kV. Section thickness was 1 mm, with a 3-mm intersection interval. All examinations were performed from the apex to the base of the lungs. Images were reconstructed by using the AB70 (Siemens Medical Solutions) reconstruction kernel algorithm. The size of the image matrix was 512 x 512 and the field of view was 50 mm, which resulted in a resolution per pixel of 0.1 mm.

By using the Pulmo CT program (Siemens Medical Solutions), which automatically recognizes the lung and traces lung contours, attenuation coefficients of CT sections of both lungs were determined. From these coefficients, the relative areas of lungs (expressed as percentages) with attenuation coefficients lower than thresholds ranging from –900 to –980 HU (ie, –900, –910, –920, –930, –940, –950, –960, –970, and –980 HU) and the 1st to 18th percentiles considered in a previous human study (1st, 3rd, 5th, 7th, 10th, 12th, 15th, and 18th) were calculated for both lungs (13).

Lung Fixation
After PFTs and CT scanning, animals were sacrificed by means of a lethal intraperitoneal injection of 200 mg pentobarbital (Dolethal; Vetoquinol, Lure, France) per kilogram of body weight, performed 8 weeks after the tracheal injection for groups 1 and 2 and 16 weeks after the first tracheal injection for group 3. The chest wall was then opened and the heart removed. The pulmonary tract, including the trachea, was carefully removed from the chest. Two catheters were successively introduced through the trachea into the main bronchi and were ligatured. Right and left lungs were immediately fixed with 4% buffered formalin at a constant distending pulmonary pressure of 25 cm H2O for 1 week. Thereafter, lungs were kept in the same solution of formalin until processed for histomorphometric evaluation. Two lung specimens from two animals in group 2 could not be fixed because of pleural perforation. These animals were therefore excluded. This procedure was conducted by one of the investigators (C.O.).

Microscopic Measurements
After fixation, lungs were cut into sagittal slices, and seven samples per lung were embedded in paraffin. The paraffin blocks were cut into 3-µm-thick slices and stained with hematoxylin-eosin. One slice from each block (and thus seven slices from each lung) was considered for further measurements. Lung slices were observed at x50 magnification by using a microscope connected to a high-resolution video camera (3 CCD XP007P; Sony, Tokyo, Japan). Images of microscopic fields were digitized (Image-Pro Plus; Media Cybernetics, Silver Spring, Md). Just as Gould et al (8) have recommended 35 microscopic fields for microscopic measurement of pulmonary emphysema in humans, we too performed measurements on five fields from each of the seven lung slices obtained from each lung. When a bronchus was present in a field, another field was considered. With the optical system used, the field area measured 2.024 mm2.

Histomorphometry was performed through two types of measurements (6), each performed by using custom-written software installed on a personal computer. First, the diameter of the alveoli and alveolar ducts was estimated as follows: Seven lines (three horizontal and four vertical) were drawn by the computer, and the distances between the intersections of these lines with the alveoli and duct walls were measured on 35 microscopic fields per lung specimen (ie, 70 fields per animal). This measurement was averaged and named the mean interwall distance (MIWD). Second, the perimeter of the alveoli and alveolar ducts was measured on the same 70 fields. This measurement was averaged and named the mean perimeter per field (MP). For both types of measurements, results originally expressed in pixels were converted into micrometers, where 1 pixel corresponded to 2.22 µm. The whole procedure for microscopic measurements was conducted by one of the investigators (C.O.).

Statistical Analysis
Quantitative variables are expressed as mean ± standard error of the mean.

MIWD, MP, and PFT findings were compared between groups of animals by using a Kruskal-Wallis test followed by Mann-Whitney tests in case of statistical significance. Statistical significance was set at a P value of less than .05.

Relative areas of lung with attenuation coefficients lower than each threshold, as well as each percentile, were correlated to microscopic measurements. We calculated Spearman correlation coefficients between each set of CT data obtained with the nine thresholds and eight percentiles with both MIWD and MP and considered that the higher this coefficient (for a given set of data), the more appropriate that threshold in quantifying emphysema.

We evaluated the potential added value of each PFT, the most appropriate threshold, and the most appropriate percentile in predicting microscopic measurements. Two stepwise multiple regressions were performed, with those variables as explained variables and respectively with MIWD and MP as dependent variables.

The statistical software used was SPSS for Windows (release 13.0; SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Examples of microscopic slices for saline- and elastase-exposed rats are shown in Figure 1.


Figure 1
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  		Figure 1a: Histologic lung sections of rats after (a) tracheal injection of 200 µL normal sterile saline, (b) single injection of 300 IU elastase, and (c) two injections of 300 IU elastase, 8 weeks apart. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 1
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  		Figure 1b: Histologic lung sections of rats after (a) tracheal injection of 200 µL normal sterile saline, (b) single injection of 300 IU elastase, and (c) two injections of 300 IU elastase, 8 weeks apart. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 1
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  		Figure 1c: Histologic lung sections of rats after (a) tracheal injection of 200 µL normal sterile saline, (b) single injection of 300 IU elastase, and (c) two injections of 300 IU elastase, 8 weeks apart. (Hematoxylin-eosin stain; original magnification, x50.)

 
Microscopic Measurements
MIWD (Fig 2) was significantly higher in groups 2 and 3 than in group 1 (P < .001) and was also significantly higher in group 3 than group 2 (P < .001).


Figure 2
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  		Figure 2: Graph shows that MIWD is significantly higher in animals that received two tracheal injections of elastase (group 3) than in those that received one injection of elastase (group 2) and in control animals (group 1). Error bars = standard error of the mean.

 
MP (Fig 3) was significantly lower in groups 2 and 3 than in group 1 (P < .001) and was also significantly lower in group 3 than group 2 (P < .001).


Figure 3
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  		Figure 3: Graph shows that MP is significantly lower in animals that received two tracheal injections of elastase (group 3) than in those that received one injection of elastase (group 2) and in control animals (group 1). Error bars = standard error of the mean.

 
The Spearman correlation (Fig 4) coefficient between MIWD and MP was –0.984, which indicated a significant correlation (P < .001).


Figure 4
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  		Figure 4: Plot shows the significant negative correlation between MP and MIWD. bullet = Control group (group 1), {circ} = one injection of elastase (group 2), {blacktriangleup} = two injections of elastase (group 3).

 
Thresholds
The highest Spearman correlation coefficients were obtained for –940 HU for both microscopic measures (Spearman coefficient, rs = 0.676, P < .001 for MIWD; rs = –0.720, P < .001 for MP) (Table 1). The relationship between the threshold of a relative surface area with attenuation coefficients less than –940 HU (RA940) and MIWD and that between RA940 and MP are illustrated in Figures 5 and 6, respectively.


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  		Table 1. Relative Area of Lung with Attenuation Coefficients Lower than the Tested Thresholds and Spearman Correlation Coefficient between Relative Areas and Microscopic Measurements

 

Figure 5
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  		Figure 5: Plot shows the significant positive correlation between RA940 and MIWD. bullet = Control group (group 1), {circ} = one injection of elastase (group 2), {blacktriangleup} = two injections of elastase (group 3).

 

Figure 6
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  		Figure 6: Plot shows the significant negative correlation between RA940 and MP. bullet = Control group (group 1), {circ} = one injection of elastase (group 2), {blacktriangleup} = two injections of elastase (group 3).

 
Percentiles
The highest Spearman correlation coefficient was obtained for the 3rd percentile (rs = –0.647, P < .001 for MIWD; rs = 0.701, P < .001 for MP) (Table 2). The relationship between 3rd percentile and MIWD and that between 3rd percentile and MP are illustrated in Figures 7 and 8, respectively.


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  		Table 2. Attenuation Coefficients Corresponding to Tested Percentiles and Spearman Correlation Coefficient between Percentiles and Microscopic Measurements

 

Figure 7
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  		Figure 7: Plot shows the significant negative correlation between 3rd percentile (p3) and MIWD. bullet = Control group (group 1), {circ} = one injection of elastase (group 2), {blacktriangleup} = two injections of elastase (group 3).

 

Figure 8
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  		Figure 8: Plot shows the significant positive correlation between 3rd percentile (p3) and MP. bullet = Control group (group 1), {circ} = one injection of elastase (group 2), {blacktriangleup} = two injections of elastase (group 3).

 
PFT Measurements
Dynamic resistance was not significantly different between groups, whereas dynamic and static compliance were significantly higher in groups 3 and 2 than in group 1 but were not significantly different between groups 2 and 3 (P = .340 and P = .967, respectively) (Fig 9).


Figure 9
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  		Figure 9: Bar graph shows that dynamic resistance (white bars), dynamic compliance (black bars), and static compliance (gray bars) are significantly higher in animals who received tracheal injections of elastase (groups 2 and 3) than in control animals (group 1). Data are mean ± standard error of the mean.

 
Comparisons between CT Indexes and PFTs
To determine whether CT provides any added value over PFTs, we separately considered MIWD and MP as microscopic references (Table 3). Stepwise multiple regressions showed that dynamic compliance was the most highly correlated variable (for MIWD, r = 0.674, P < .001; for MP, r = 0.702, P < .001), with RA940 yielding a significant additional contribution (for MIWD, multiple r = 0.792, P < .001; for MP, multiple r = 0.782, P < .001) or with 3rd percentile yielding a significant additional contribution (for MIWD, multiple r = 0.762, P < .001; for MP, multiple r = 0.786, P < .001).


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  		Table 3. Dynamic Resistance, Dynamic and Static Compliance, and Spearman Correlation Coefficients between These Parameters and Microscopic Measurements

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Results of this animal study show that among all considered CT indexes, RA940 and the 3rd percentile best reflect the extent of elastase-induced emphysema on 1-mm-thick CT sections. In addition, RA940 and the 3rd percentile are complementary to PFTs (dynamic compliance) for the prediction of microscopic extent of pulmonary emphysema. However, RA940 and the 3rd percentile are not the only indexes to demonstrate this extent, as correlation coefficients are very close each other.

All considered thresholds—from –900 to –980 HU—show significant correlations with both microscopic measurements. Those thresholds proposed in humans, such as –950 HU proposed by Gevenois et al (6) for incremental thin-section CT and –960 and –970 HU proposed by Madani et al (13) for helical thin-section CT, are also associated with significant correlations. For practical purposes, –940 HU appears as the most appropriate threshold, because it had the strongest correlation with both MIWD and MP, but all thresholds ranging from –920 to –950 HU could be reasonably acceptable, since they are associated with P values of less than .001.

Various percentiles have been previously used, but only the 5th percentile has been validated through correlations against a microscopic measurement reflecting the diameter of distal air spaces (8). Therefore, we have investigated the correlations between percentiles ranging from the 1st percentile to the 18th percentile and microscopic measurements reflecting this diameter. All these percentiles are significantly correlated with these measurements, but the strongest correlation suggests that the 3rd percentile is the most appropriate. Nevertheless, all percentiles ranging from the 3rd to the 12th could be acceptable, since they are associated with P values of less than .001.

As elastase-induced pulmonary emphysema is associated with an increase in lung compliance (3,14), we have investigated the correlations between PFTs and microscopic measurements. Considering that these correlations exist, together with correlations between the most appropriate CT indexes (ie, RA940 and 3rd percentile) and microscopic measurements, we have investigated the possible complementary roles of these parameters in predicting microscopic measurements. Stepwise multiple regressions have revealed that together dynamic compliance and RA940 or 3rd percentile are sufficient for prediction of both the microscopic measurements and that all other PFTs do not yield any additional information, suggesting that in practice, RA940 or 3rd percentile might be the only CT indexes to consider.

In agreement with the findings of earlier studies on the effect of elastase in rodents (2,3,11,14,15), in our findings we have observed an increase in MIWD in elastase-treated rats in comparison with control rats, without any sign of alveolar or bronchial inflammation after an 8-week delay. Two successive tracheal injections of elastase induce progressive emphysema-like lesions (16). MIWD values observed in this study were lower than the diameter of normal alveoli usually reported. This difference could be explained by our method of measurement, which was based on a computer-generated calculation of the ratio of the length of a test line randomly drawn on the microscopic field divided by the number of intercepts of this line with alveolar walls, rather than a physical measurement of the actual diameter of the alveoli. As pointed out by Müller and Thurlbeck (17), MIWD corresponds to the average transection distance between walls of alveoli, alveolar ducts, and alveolar sacs considered together and not to the average alveolar diameter. This difference could also be explained by the fact that we did not correct our measurements for shrinkage, as our purpose was not to measure precisely the diameter of emphysematous enlarged air spaces but to rapidly measure the size of alveoli, alveolar ducts, and alveolar sacs on a high number of fields.

Our study has limitations. First, we do not have any information on the amount of elastase that reached each lung and the alveolar tissue. Therefore, CT data were collected from both lungs and were correlated to microscopic measurements also obtained from both lung specimens. Second, we have used a CT scanner designed for human examinations. With this system, 1 pixel corresponds approximately to 0.1 mm (50 mm divided by 512), which is the same order of magnitude as the MIWD in most emphysematous animals (group 3). Theoretically, a CT scanner specifically designed for rat size might have had a higher spatial resolution, but the scanning time would have been much longer, (ie, from 1 to 5 minutes, depending on the requested image quality), which would not have been compatible with animal survival.

In conclusion, RA940 and 3rd percentile demonstrate the extent of elastase-induced pulmonary emphysema in rats and are complementary to dynamic compliance for the prediction of microscopic measurements, which suggests that they can be used in longitudinal animal studies.

Practical application: As a basis for future works investigating therapeutic interventions on animal models, this study shows that the extent of elastase-induced pulmonary emphysema can be measured with CT in rats.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors thank J. F. Parotte for programming morphometric software, G. Keesemaecker for help during all the experiments, A. Thiry, MD, PhD, for technical support, M. Belleflamme for the animal maintenance, and A. Van Muylem, PhD, for figure preparation.


   FOOTNOTES
 

Abbreviations: MIWD = mean interwall distance • MP = mean perimeter per field • PFT = pulmonary function test • RA940 = relative surface area with attenuation coefficients less than –940 HU

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, C.O., P.A.G.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, C.O., P.G., P.A.G.; experimental studies, C.O., P.A.G.; statistical analysis, V.D.M.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

  1. The definition of emphysema: report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases Workshop. Am Rev Respir Dis 1985;132:182–185.[Medline]
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  3. Snider GL, Lucey EC, Stone PJ. Animal models of emphysema. Am Rev Respir Dis 1986;133:149–169.[Medline]
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  5. Gevenois PA, Yernault JC. Can computed tomography quantify pulmonary emphysema? Eur Respir J 1995;8:843–848.[Abstract]
  6. Gevenois PA, De Vuyst P, de Maertelaer V, et al. Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1996;154:187–192.[Abstract]
  7. Morgan MD. Detection and quantification of pulmonary emphysema by computed tomography: a window of opportunity. Thorax 1992;47:1001–1004.[Medline]
  8. Gould GA, MacNee W, McLean A, et al. CT measurements of lung density in life can quantitate distal airspace enlargement: an essential defining feature of human emphysema. Am Rev Respir Dis 1988;137:380–392.[Medline]
  9. Bergin C, Müller N, Nichols DM, et al. The diagnosis of emphysema: a computed tomographic-pathologic correlation. Am Rev Respir Dis 1986;133:541–546.[Medline]
  10. National Research Council. Guide for the care and use of laboratory animals. 7th ed. Washington, DC: National Academy Press, 1996.
  11. Busch RH, Lauhala KE, Loscutoff SM, McDonald KE. Experimental pulmonary emphysema induced in the rat by intratracheally-administered elastase: morphogenesis. Environ Res 1984;33:497–513.[Medline]
  12. Khuenl-Brady KS, Koller J, Mair P, Puhringer F, Mitterschiffthaler G. Comparison of vecuronium- and atracurium-induced neuromuscular blockade in postpartum and nonpregnant patients. Anesth Analg 1991;72:110–113.[Abstract/Free Full Text]
  13. Madani A, Zanen J, de Maertelaer V, Gevenois PA. Pulmonary emphysema: objective quantification at multi–detector row CT—comparison with macroscopic and microscopic morphometry. Radiology 2006;238:1036–1043.[Abstract/Free Full Text]
  14. Kimmel EC, Winsett DW, Diamond L. Augmentation of elastase-induced emphysema by cigarette smoke: description of a model and a review of possible mechanisms. Am Rev Respir Dis 1985;132:885–893.[Medline]
  15. Kirschvink N, Vincke G, Fievez L, et al. Repeated cadmium nebulizations induce pulmonary MMP-2 and MMP-9 production and emphysema in rats. Toxicology 2005;211:36–48.[CrossRef][Medline]
  16. Tepper J, Pfeiffer J, Aldrich M, et al. Can retinoic acid ameliorate the physiologic and morphologic effects of elastase instillation in the rat? Chest 2000;117(5 suppl 1):242S–244S.
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