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J Appl Physiol 102: 1170-1177, 2007. First published November 30, 2006; doi:10.1152/japplphysiol.00520.2006
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Developmental signals do not further accentuate nonuniform postpneumonectomy compensatory lung growth

Priya Ravikumar,1 Cuneyt Yilmaz,1 D. Merrill Dane,1 Robert L. Johnson, Jr.,1 Aaron S. Estrera,2 Connie C. W. Hsia1, (With the Technical Assistance of Richard T. Hogg and Deborah C. Hogg)

Departments of 1Internal Medicine and 2Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 8 May 2006 ; accepted in final form 22 November 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Mechanical forces imposed on lung tissue constitute major stimuli for normal lung development and postpneumonectomy (PNX) compensatory growth and remodeling. Superimposing developmental signals on PNX signals augments compensatory alveolar growth but exaggerates airway-parenchymal dissociation (i.e., dysanaptic lung growth); the latter tends to offset benefits derived from the former. In adult dogs after PNX, lobar expansion and growth of the remaining lobes were markedly non-uniform (Ravikumar et al. J Appl Physiol 97:1567–1574, 2004). We hypothesized that superimposing developmental and post-PNX signals further accentuates nonuniformity of lobar growth. We used high-resolution computed tomography (HRCT) to follow regional lung expansion and growth in foxhounds undergoing right PNX at 2.5 mo of age compared with litter-matched control (Sham) animals; scans were performed 4 and 10 mo following surgery, i.e., before and after somatic maturity. Air and tissue volumes were measured in each lobe; tissue volume estimated by HRCT includes air-free tissue and blood in small vessels <1 mm. Interlobar nonuniformity of tissue volume was absent at 4 mo but evident 10 mo after PNX; growth of the remaining left lower lobe gradually lagged behind other lobes. At maturity, nonuniformity of lobar growth in pneumonectomized puppies was similar to that previously reported in pneumonectomized adults. We conclude that superimposing developmental and post-PNX signals enhances some aspects of compensatory lung growth and remodeling without altering its nonuniform spatial distribution.

lung resection; high-resolution computed tomography scan; lung tissue volume; mechanical signal; dog

DURING DEVELOPMENT, mechanical force imposed on lung tissue by an enlarging rib cage is a major stimulus for postnatal lung growth and maturation (13); this stimulus ceases upon somatic maturity when the bony epiphyses close and both the rib cage and lungs reach their final dimensions. Following resection of one lung by pneumonectomy (PNX), the negative intrathoracic pressure causes the remaining lung to expand, deform, and eventually fill the empty hemithorax, creating a potent stimulus for triggering the pathways of compensatory alveolar growth and airway remodeling. Compensatory lung growth is more vigorous and functional restoration more complete in dogs undergoing PNX as puppies than as adults (29, 30). In adult dogs, compensatory lung growth is initiated only when more than ~50% of the lung is removed, suggesting the existence of a threshold of mechanical signals that must be exceeded before cellular growth is reinitiated (15, 16) as well as the possibility of additive effects of independent mechanical signals arising from different sources, i.e., maturation and PNX, on alveolar growth.

Mechanical signals from maturation and PNX are known to exert additive effects on airway compensation. Normal growth and remodeling of airways lag behind that of parenchyma (so called dysanaptic lung growth), and the lag is further exaggerated by PNX. In growing puppies pneumonectomized at 2.5 mo of age, we observed lengthening of the remaining airways without dilatation 4 mo post-PNX; dilatation became evident subsequently and significantly reduced airways resistance by 10 mo post-PNX (5). Dysnaptic growth offsets some of the benefit expected from alveolar growth; long-term compensatory increases in alveolar dimensions and diffusing capacity of the remaining lung were greater in animals pneumonectomized as puppies than as adults while the long-term compensatory reduction in work of breathing was similar in puppies and adults (5, 30).

In adult dogs after right or left PNX where lung resection imposed the only stimulus for compensatory lung growth or remodeling, lobar expansion and parenchymal growth of the remaining lung were nonuniform (28), likely reflecting the anatomical asymmetry of mediastinal structures and ligaments that differentially restrained expansion and growth of the remaining lobes. No previous study has longitudinally followed the pattern or time course of post-PNX regional lung growth during somatic maturation. We hypothesized that the additive effects from two sources of mechanical signals, maturation and PNX, further exaggerate nonuniformity of compensatory growth above and beyond that in post-PNX adult animals where there was only one source of signals. We performed high-resolution computed tomography (HRCT) at a constant transpulmonary pressure in growing foxhounds that had undergone right PNX at 2.5 mo of age compared with litter-matched control (Sham) animals. Scans were performed at two time points (4 and 10 mo after surgery corresponding to 6.5 and 12.5 mo of age, i.e., before and after somatic maturity). By identifying the lobar fissures we reconstructed each lobe and compared lobar air and tissue volumes between experimental groups and at the two ages. The main findings were as follows. 1) Regional compensatory growth of lung parenchyma was uniform at 4 mo but became nonuniform by 10 mo post-PNX; growth of the remaining left lower (caudal) lobe gradually lagged behind the other lobes. 2) At maturity, the pattern of regional nonuniformity was similar whether animals underwent PNX as puppies or as adults. We conclude that while superimposing developmental signals on post-PNX signals alters some aspects of compensatory lung growth it does not alter the nonuniform pattern of growth.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Experimental groups.   The Institutional Animal Care and Use Committee approved all the procedures. Foxhounds (2.5 mo of age) underwent either right PNX (55–58% lung removed, n = 9) or right thoracotomy without lung resection (Sham; n = 7) under general anesthesia by procedures previously described (29). The computed tomography (CT) scan was performed during the 4th mo following surgery (6.5 mo of age, n = 5 PNX, n = 6 Sham) and repeated 10 mo after surgery (~1 year of age, n = 9 PNX, n = 7 Sham).

HRCT.   Animals were fasted overnight, sedated with acepromazine (0.15 mg/kg sc) and atropine (0.023 ml/kg sc), anesthetized with propofol (4–8 mg/kg iv bolus for induction followed by infusion at 0.4 mg·min–1·kg–1), intubated with a cuffed endotracheal tube, placed in the supine position on the CT table, and mechanically ventilated (model 607, Harvard Apparatus, Holliston, MA) at a tidal volume (12–15 ml/kg) and respiratory rate sufficient to eliminate spontaneous breathing effort. Spiral CT scan was performed (GE high-speed CTI scanner) at 3 x 3 mm collimation, 120 kV, 250 mA, a pitch of 1.0, and a rotation time of 0.8 s. A scout image was first obtained to ensure the field of scan included the entire lung from the apex to the costophrenic angle. Prior to each imaging sequence, the lungs were hyperinflated with three tidal breaths, followed by passive expiration to functional residual capacity. Then the endotracheal tube was connected to a calibrated syringe set to deliver a volume of air previously determined to inflate the lungs of each animal to a transpulmonary pressure of 20 cmH20, equivalent to an inflation volume of ~45 ml/kg above functional residual capacity. This pressure was sufficient to prevent atelectasis and permit easy identification of interfaces among lung, rib cage, mediastinal structures, and the interlobar fissures; at the same time it is not too high to risk air leak around the endotracheal tube during scanning since the dog has a very wide trachea that becomes further dilated after PNX (5). The actual inflation volumes (in ml, mean ± SD) were: PNX-4 mo, 1,014 ± 195; Sham-4 mo, 1,036 ± 253; PNX-10 mo, 1,242 ± 210; Sham-10 mo, 1,133 ± 148. The breath was held for ~40 s while CT images were obtained, after which the animal was reconnected to the respirator. The images were reconstructed at consecutive 1 mm intervals using a 512x512 "standard" reconstruction algorithm resulting in ~300 images/animal.

Analysis of CT images.   Images were analyzed using the public domain software Object-Image v.1.6.2 with customized modification. The area occupied by lung tissue was outlined on each image using attenuation thresholding, which excluded conducting structures larger than 1–2 mm diameter. The trachea and next three generations of large conducting airways were excluded manually by marking them with the background color in each CT image in which they appear. Lung volume of each image is equal to the product of its area and thickness (1 mm); total lung volume was calculated from the sum of the volume of all images. Lobar fissures were identified by following serial images and used to partition the lobes of each lung.

The CT attenuation value [in Hounsfield units (HU)] of tracheal air and the muscle tissue was measured and the measurement used to partition the total lung volume into volume of air and tissue, since the average CT value of the lung is directly proportional to the ratio of tissue and air. During calibration of the scanner, the attenuation of air was arbitrarily set at –1,000 HU and water at 0 HU. Owing to beam-hardening artifacts and the dynamic range of the scanner, the CT attenuation value for air sampled inside the thorax is slightly lower than that sampled outside the thorax; therefore, the best index of CT value for air (CTair) is at the center of the tracheal air column within the chest. We averaged three regions (5 mm above the carina, 5 mm below the end of the endotracheal tube and half way between the two points) to obtain a mean CTair in each animal (–971 HU, range –961 to –997 HU). The so called "tissue volume" (Vtissue in ml) of a region estimated by HRCT includes the volume of alveolar septa as well as extraseptal tissue of structures (airways and vessels) <1–2 mm in diameter as well as the blood within these small vessels. We assumed the average CT value for air-free lung tissue and blood (CTtissue) to equal that of muscle and averaged three muscles in each animal (infraspinatus, supraspinatus, and pectoralis at the level just above the carina); the mean CTtissue values were relatively stable (56 HU, range 52–59 HU). The small variability in CT attenuation gradient causes little error and was neglected in further computation.

With the use of the approach described by others (3, 4, 11, 22, 33) as well as by us (23, 28, 32, 35), the total volume of each lobe (Vlobe in ml) was partitioned into tissue+blood volume (Vtissue) and air volume (Vair) as follows:

Formula 1(1)

Formula 2(2)
where CTlobe is average CT number (in HU) within a lobe. CT estimates of Vair and Vtissue has been shown to correlate with independent estimates by an acetylene rebreathing method (22, 23) and by quantitative histology (4, 28).

Statistical analysis.   Measurements were normalized by body weight and expressed as means ± SD. Measurements from PNX animals were expressed as a fraction of the corresponding lobar values in Sham controls. Comparison between groups was by ANOVA with post hoc Fisher multiple comparisons test. Longitudinal data between 4 and 10 mo following surgery were compared by repeated measures ANOVA. We used a commercial statistical package (STATVIEW v.5.0, SAS Institute, Cary, NC). A P value of 0.05 or less was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Representative images of three-dimensional lobar reconstruction from PNX and Sham groups at 4 and 10 mo after surgery are shown in Fig. 1. Following right PNX, mediastinal shift was prominent and all the remaining lobes expanded significantly but nonuniformly. The left cranial or upper lobe (LUL) and the left middle lobe (LML) expanded anteriorly across the midline; the left caudal or lower lobe (LLL) assumed a highly irregular shape as it expanded posteriorly across the midline behind the heart, esophagus, and great vessels. Within the grossly distorted LLL, the average CT attenuation value of the portion that herniated across the midline posterior to the esophagus (–810 ± 17 HU, ± SD) was slightly more positive but not significantly different from the CT values of the rest of the lobe (–839 ± 11 HU, P > 0.05).


Figure 1
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  		Fig. 1. Three-dimensional reconstruction of both lungs (A) and the left lung (B) alone in 1 control animal (SHAM) and the left lung in 1 animal after right pneumonectomy (PNX) at 4 and 10 mo after surgery, each shown in 2 views oriented by their coordinate axes: dorsal view and caudal view. Green, left cranial or upper lobe (LUL); red, left middle lobe (LML); blue, left caudal or lower lobe (LLL); gray, right cranial or upper lobe (RUL); yellow, right middle lobe (RML); magenta, right caudal or lower lobe (RLL); aqua, right infra-cardiac lobe (RCL).

 
The distribution of lobar volume 4 and 10 mo after surgery (6.5 and 12.5 mo of age) is shown in Table 1. At each time point after PNX, total lung air and tissue volumes were not different from that in lungs of both sham-operated controls. In control animals, air and tissue volumes of the right upper, middle, lower, and infra-cardiac lobes consisted of ~12%, 14%, 23%, and 9%, and the left upper, middle, and lower lobes 12%, 7% and 23%, respectively, of total air or tissue volume. These values compare reasonably well with the corresponding partition based on relative lobar weight reported in air-dried canine lungs by Rahn and Ross (26): 17%, 9%, 25%, and 8% for the right lung; 10%, 6%, and 26% for the left lung. In PNX animals, the remaining left upper middle and lower lobes constitute ~30%, 21%, and 49% of total lung air volume, and 27%, 18%, and 55% of total lung tissue volume, respectively. Body mass-specific lobar air volume did not change between 4 and 10 mo postsurgery in either group. Body mass-specific lobar tissue volume declined between 4 and 10 mo, reaching statistical significance in all lobes of the left lung in the Sham group and in the left lower lobe of the PNX group (Fig. 2).


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  		Table 1. Lobar air and tissue volume

 

Figure 2
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  		Fig. 2. Air and tissue volume of the left lung (per/kg body wt) 4 and 10 mo after surgery (SHAM: left; right PNX: right). Means ± SD. At each time point lobar values are significantly higher in the PNX group than the SHAM group. Compared with corresponding lobar values 4 mo after surgery, tissue volume is significantly lower at 10 mo in all the lobes of SHAM control animals and in the left lower lobe of PNX animals. P ≤ 0.05 by ANOVA: *vs. corresponding SHAM control, {dagger}vs. upper lobe and {ddagger}vs. middle lobe at the same time point, §vs. 4 mo after surgery.

 
Lobar tissue volume fraction (ratio of tissue volume to total volume) was significantly higher in the lower lobe than the upper or middle lobe in both experimental groups and both time points (Fig. 3). In both groups the ratio of tissue volume fractions at the two time points (4 mo/10 mo) increased similarly in all lobes, i.e., air volume fraction increased and tissue volume fraction declined as the animal matured (Fig. 3). As a result, the longitudinal change in overall tissue volume fraction of the whole left lung was similar between groups.


Figure 3
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  		Fig. 3. Tissue volume fraction (ratio of lobar tissue volume to total lobar volume) was higher in the left lower lobe than other lobes of the left lung in both groups (SHAM, top; right PNX, bottom), and declined between 4 and 10 mo after surgery, reaching statistical significance in all lobes of the SHAM control animals. Mean ± SD. P ≤ 0.05 by ANOVA: {dagger}vs. upper lobe and {ddagger}vs. middle lobe at the same time point; §vs. 4 mo after surgery.

 
The relative compensatory changes in air and tissue volume of the remaining lobes after PNX was expressed as ratios to the mean value of the corresponding control lobe in sham-operated animals (Fig. 4). At 4 mo post-PNX, air and tissue volumes increased to a similar extent (2.0- to 2.3-fold) among all remaining lobes, that is, no significant regional differences in compensatory growth. By 10 mo after PNX, the relative volume increase in the left lower lobe (2.0-fold) had significantly lagged behind those in the upper and middle lobes (2.5- and 2.8-fold), indicating nonuniform rates of lobar compensatory growth.


Figure 4
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  		Fig. 4. Relative change in lobar air and tissue volume of the remaining left lung following right PNX expressed as a ratio to the mean value in corresponding lobes of SHAM control animals at 4 and 10 mo after surgery (6 and 12 mo of age). Mean ± SD. All the ratios are significantly >1.0. At 10 mo after PNX, the relative change in lung tissue and air volume of the remaining left lower lobe lagged significantly. {ddagger}P ≤ 0.05 vs. left middle lobe by ANOVA.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Summary of results.   This is the first longitudinal examination of possible interactions between developmental and post-PNX signals on regional lung growth. In young dogs, growth rates among lobes were similar during maturation between 6.5 and 12.5 mo of age. Air volume increased faster than tissue volume in all regions, so that tissue volume fraction, which was normally higher in the lower lobe than in upper and middle lobes, declined similarly among lobes during this interval. In actively growing animals 4 mo after right PNX, lung tissue volume was higher to a similar extent (2.1- to 2.3-fold) in the remaining lobes relative to that in corresponding lobes of control animals. After reaching somatic maturity, i.e., 10 mo post-PNX, the relative compensatory increase in tissue volume of the remaining left lower lobe (2.0-fold) lagged behind that of the upper and middle lobes (2.5- and 2.8-fold, respectively). Therefore, nonuniform regional parenchymal growth was absent 4 mo post-PNX but developed subsequently. At maturity (10 mo post-PNX) the pattern of interlobar nonuniformity was similar to that previously reported in pneumonectomized adult dogs (28).

Critique of the methods.   CT attenuation has been used to estimate lung weight (a quantity equivalent to tissue plus blood volume), gas volume, surface-to-volume ratio, and airway dimensions in the quantitative assessment of the severity of emphysema and diffuse lung disease (24, 25). In patients studied by CT just before surgery for small lung tumors, the proportion of tissue to air obtained with CT in the resected lobe was similar to that obtained by morphometry (4). This technique has been used to follow parenchymal growth in children (6, 7). The gas volume per gram of lung tissue decreases from birth to 2 yr of age and then increases steadily to 17 yr of age (7), an observation consistent with the decrease in fractional tissue volume observed in the present study in growing dogs from 6.5 to 12.5 mo of age. The mean CT values we used for lung tissue+blood are relatively stable (average 56 HU, range 52–59 HU). Other investigators have assumed a lung CT value of 65 HU (4, 12, 22). If we recalculate our measurements based on their CT values, the maximum change in estimated tissue and air volumes is 1.3%.

Since Vtissue estimated by HRCT includes both tissue and blood volume within the gas exchange region, it is systematically larger than septal tissue volume estimated in the fixed lung by morphometry. However, these two estimates are significantly correlated in normal and post-PNX dog lungs with slopes of 0.91 for air volume and 1.06 for tissue volume (28). After resection of one lung, blood flow to the remaining lung increases immediately and then stabilizes. Although we could not partition the higher Vtissue in PNX animals into tissue or blood content, this limitation does not invalidate the use of HRCT for following longitudinal parenchymal changes post-PNX for several reasons. 1) Septal tissue and capillary blood volume increase in equal proportions during post-PNX compensation (29). 2) After the immediate post-PNX increase in blood flow stabilizes, subsequent increases in both tissue and blood volumes contribute equally to functional compensation, i.e., to an increased lung diffusing capacity that is attributable to about equal increases in membrane diffusing capacity and pulmonary capillary blood volume (29, 31, 32). Thus HRCT allows longitudinal follow-up of functionally relevant changes in lung parenchyma, which includes both tissue and blood.

Both stress and strain transduce mechanical signals for tissue growth and remodeling. Our study was not designed to separate stress from strain signals. Our previous data suggest that post-PNX strain and lung growth are correlated. After one lung is removed and the chest wall closed, a negative intrathoracic pressure causes the remaining lung to expand immediately, i.e., imparting three-dimensional strain. Minimizing lateral expansion of the remaining lung using a space-occupying inflatable silicone prosthesis is associated with blunted post-PNX lung expansion and tissue growth estimated by CT and morphometry as well as lower diffusing capacities for CO and O2 (20, 21, 35). However, post-PNX regional stress/strain has not been directly measured.

Normal lung development.   Mechanical signals are believed to stimulate and sustain developmental as well as post-PNX lung growth (27, 34). During maturation, the enlarging thorax, mediastinal structures, and lungs create opposing mechanical forces on lung tissue resulting in tissue strain and feedback interactions that sustain a balanced rate of cell growth among these components (13). The caudal lung region has higher vascular and interstitial conductance (1), larger capillary size and volume (9), and smaller air spaces (10) compared with other regions and may explain its higher tissue volume fraction. In addition to expansion of air spaces and generation of new gas exchange units, the growing lung undergoes progressive remodeling with parenchymal involution, thinning of the blood-gas diffusion barrier, and increase in alveolar surfaces (8). The double alveolar-capillary morphology with its abundant septal interstitial cells and connective tissue of the immature lung is gradually replaced by the adult morphology of single capillary profiles and pruned interstitium (36). The longitudinal decline in tissue volume fraction assessed by HRCT in control animals is consistent with the sequence of parenchymal remodeling that continues for months after birth; the rate of decline was similar among lobes and unaffected by prior lung resection. Thus HRCT accurately tracks the anatomical consequences and spatial distribution of lobar expansion as well as parenchymal growth.

Post-PNX compensatory response.   After PNX, the remaining lung becomes expanded and distorted. After stabilization of the initial increase in blood flow to the remaining lobes, we observed proportional changes in lobar air and tissue volumes by HRCT between 4 and 10 mo post-PNX consistent with parenchymal growth. The present results extend our earlier observations using conventional thoracic CT in foxhounds raised to maturity after undergoing right PNX as puppies, where compensatory increases in lung volume were greatest in the mid-lung zones (32). In addition, the distribution of compensatory increase in air and tissue volumes at maturity in the present study is almost identical to that previously reported by us in dogs pneumonectomized as adults and studied by HRCT 12 mo later (28), i.e., compensatory expansion and tissue growth was greater in the upper and middle lobes than in the lower lobe (Table 2).


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  		Table 2. Relative post-PNX compensation assessed by HRCT before or after somatic maturity

 
In previous animals pneumonectomized as puppies and then raised to maturity, alveolar septal volume (blood plus tissue) measured by morphometry in the remaining lobes increased to ~2.6- to 2.9-fold of control value, associated with a corresponding increase in lung diffusing capacity; the latter was estimated by both morphometric and physiologic methods (29). In the present animals the in vivo increases estimated by HRCT ranged from 2.1- to 2.8-fold. In animals pneumonectomized as adults the corresponding compensatory volume increase assessed by morphometry and a physiological method was more modest, ~1.8-fold of control values (16, 18). In both young and adult dogs, the fold change in alveolar septal tissue volume post-PNX obtained by morphometry was higher in the remaining left upper lung zone (upper and middle lobes combined) than in the left lower lobe (16, 29), similar to the present findings by HRCT. In separate studies where we minimized lung expansion in post-PNX adult dogs using custom-shaped inflated silicone prosthesis to replace the right lung (35), compensatory lung expansion was also reduced to a greater extent in the mid- and lower lung zone, suggesting that this region is very sensitive to changes in intrathoracic mechanical signals.

One likely explanation for the relatively restricted compensatory response in the lower lobe post-PNX is the presence of the heart and elevated right hemidiaphragm, which offered asymmetric resistance to the expansion of the adjacent lower lobe. The heart causes greater distortion to the left than the right lung. In anesthetized dogs, weight of the heart in the left lateral decubitus position imposed a greater reduction in volume of the left lung than the corresponding reduction in volume of the right lung imposed by the right lateral decubitus position (2). In addition, the right hemidiaphragm becomes elevated, stretched, and hypertrophied after right PNX (17), which increases the tension and decreases the compliance of the left hemidiaphragm, further impeding post-PNX expansion of the left lower lobe. Because the mediastinal ligaments are relatively thin in the dog, the lower lobe was still able to grow across the midline posterior to the heart, esophagus, and large vessels, leading to its irregular-shaped projection after PNX. Peripheral airways and blood vessels in the remaining lower lobe sometimes assume a direction 90° to 180° from the main stem bronchus and vessel. Such marked anatomical distortion raises important functional issues regarding effective distribution of ventilation and perfusion to the lower lobe as well as the contribution of regional anatomical distortion to the exponential increase in work of breathing observed during exercise post-PNX (14, 30). We did not detect significant abnormalities in global ventilation-perfusion distributions after PNX at rest or during exercise using the multiple inert gas elimination technique (19, 20) but have not examined regional ventilation-perfusion distributions. Additional studies using functional imaging techniques will be helpful in mapping the regional correspondence between anatomical distortion and ventilation-perfusion relationships.

In summary, we report that in actively growing animals, nonuniform distribution of lobar compensatory growth develops slowly between 4 and 10 mo post-PNX, with the remaining left lower lobe growing at a significantly slower rate compared with the upper and middle lobes. At maturity, the pattern of lobar nonuniformity was not significantly different from that seen in animals undergoing PNX as adults. Combined with our previous report in these animals that dilatation of conducting airways also developed slowly between 4 and 10 mo after PNX (5), these results show that progressive interactions between developmental and post-PNX signals alter some aspects of lung and airway growth and remodeling, such as enhancing the magnitude of compensatory alveolar growth and exaggerating airway-parenchymal dissociation in dysanaptic growth; however, superimposing these independent signals does not alter the pattern of nonuniform regional parenchymal growth.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
The National Heart, Lung, and Blood Institute Grants R01-HL-040070, HL-054060, HL-045716, and HL-062873 supported this research.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute or of the National Institutes of Health.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Daryn Clyburn for technical assistance; the staff of the Animal Resources Center for veterinary assistance; Cynthia Proper, Melanie Bishop, and Derek Lowe for technical assistance with CT scan; Dr. Roderick McColl for assistance with data transfer; and the Department of Radiology at the University of Texas Southwestern Medical Center at Dallas for making the facilities available.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Connie C. W. Hsia, Pulmonary and Critical Care Medicine, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9034

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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