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J Appl Physiol 102: 200-206, 2007. First published August 31, 2006; doi:10.1152/japplphysiol.00400.2006
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Age-dependent changes of airway and lung parenchyma in C57BL/6J mice

Kewu Huang, Richard Rabold, Brian Schofield, Wayne Mitzner, and Clarke G. Tankersley

Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, Baltimore, Maryland

Submitted 4 April 2006 ; accepted in final form 15 August 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
In the current study, we hypothesize that senescent-dependent changes between airway and lung parenchymal tissues of C57BL/6J (B6) mice are not synchronized with respect to altered lung mechanics. Furthermore, aging modifications in elastin fiber and collagen content of the airways and lung parenchyma are remodeling events that differ with time. To test these hypotheses, we performed quasi-static pressure-volume (PV) curves and impedance measurements of the respiratory system in 2-, 20-, and 26-mo-old B6 mice. From the PV curves, the lung volume at 30 cmH2O pressure (V30) and respiratory system compliance (Crs) were significantly (P < 0.01) increased between 2 and 20 mo of age, representing about 80–84% of the total increase that occurred between 2 and 26 mo of age. Senescent-dependent changes in tissue damping and tissue elastance were analogous to changes in V30 and Crs; that is, a majority of the parenchymal alterations in the lung mechanics occurred between 2 and 20 mo of age. In contrast, significant decreases in airway resistance (R) occurred between 20 and 26 mo of age; that is, the decrease in R between 2 and 20 mo of age represented only 29% (P > 0.05) of total decrease occurring through 26 mo. Morphometric analysis of the elastic fiber content in lung parenchyma was significantly (P < 0.01) decreased between 2 and 20 mo of age. To the contrary, increased collagen content was significantly delayed until 26 mo of age (P < 0.01, 2 vs. 26 mo). In conclusion, our data demonstrate that senescent-dependent changes in airway and lung tissue mechanics are not synchronized in B6 mice. Moreover, the reduction in elastic fiber content with age is an early lung remodeling event, and the increased collagen content in the lung parenchyma occurs later in senescence.

senescence; lung mechanics; elastic fiber content; collagen deposition; airway resistance

SENESCENCE is associated with important structural and physiological changes in the lung. In aging humans, the lung elastic recoil decreases (9, 17, 33), which is likely attributable to structural and functional alterations in the extracellular matrix (ECM) of the lung parenchyma and loss of alveolar surface area (1, 32). Although mice have been frequently used to model the mechanisms of lung biology and disease in humans, senescent-dependent changes in the mouse lung have not been studied extensively. Previous studies have examined senescent changes in lung mechanics of the mouse lung and have demonstrated changes of static compliance (26, 32). These previous studies did not partition lung mechanical properties into components representing the airways and lung parenchyma separately, which is important in understanding the mechanisms of aging leading to a senile lung. It is also unclear how senescent-dependent changes in ECM affect altered lung mechanics with respect to the airways and lung parenchyma. Previous studies (3, 20, 21, 29) have suggested that decreases in elastin-containing fibers account for increased lung compliance occurring in the normal breathing range, whereas collagen, a nondistensible connective tissue element, accounts for the lung volume limitations. It is likely, therefore, that these two lung remodeling events are influenced differently by the effects of senescence.

In the present study, we measured volume-dependent airway and tissue impedances in C57BL/6J (B6) mice at 2, 20, and 26 mo of age to search for specific signals associated with senescent-dependent mechanical changes in the airway and lung parenchyma. The quantification of collagen and elastic fiber content of these two regions of the lung were conducted to implicate the importance of changes in the ECM as the origin of senescent changes in the lung. We found senescent-dependent alterations in the mechanical properties of the lung parenchyma that did not coincide with age-dependent changes in the airway. Furthermore, decrements on elastin-fiber content of the lung parenchyma differed in time from the subsequent lung remodeling events involving collagen deposition. These changes in ECM composition were unique to the lung parenchyma and did not have a similar effect on the airways.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals.   Three groups of male B6 mice, aged 2 mo (n = 8), 20 mo (n = 7), and 26 mo old (n = 9), were purchased from either Jackson Laboratories or the National Institute of Aging. The animals were housed in a facility at the Johns Hopkins University, Bloomberg School of Public Health. The temperature of the facility was maintained at ~21.5°C, and the light-dark cycle varied every 12 h, beginning at 0700. The animals were housed in microisolation cages and were fed ad libitum with a pelleted stock diet. The study was approved by the Johns Hopkins University Animal Care and Use Committee and complied with the American Physiological Society Guidelines.

Respiratory impedance measurements.   Animals were anesthetized with intraperitoneal injections of pentobarbital sodium at a dose of 80 mg/kg body wt. After the trachea was cannulated, the mouse, while in a supine position, was connected via the tracheal cannula to a computer-controlled small animal ventilator (FlexiVent, Montreal, Canada). All mice were mechanically ventilated with 100% O2 at 150 breaths/min and a tidal volume of 10 ml/kg. After 10 min of mechanical ventilation, each animal was paralyzed with an intraperitoneal injection of 0.05 ml succinylcholine (9 mg/ml). A computer-generated volume signal composed of 19 mutually primed sinusoids ranging from 0.25 to 19.625 Hz was applied to the airway opening. Five minutes after a deep inspiration at an airway pressure of 30 cmH2O, the impedance of the respiratory system was measured at four different positive end-expiratory pressures (PEEP) of 2, 5, 10, and 15 cmH2O and then fitted by Flexivent software to a constant phase model as described by Hantos and colleagues (13) to provide measures of airway resistance (R), tissue damping (G), tissue elastance (H), and tissue hysteresivity ({eta}).

Pressure-volume curve.   After the impedance measurements, mice were mechanically ventilated with 100% O2 at a PEEP of 2 cmH2O for 1 min, and the cannula was sealed with a stopcock for 3 min to degas the lung. Quasi-static pressure-volume (PV) curves were then performed in situ. The rate of inflation and deflation was standardized by a dual infusion-withdraw pump (model 900–610, Harvard Apparatus, Dover, MA), and the airway pressure was measured by using a differential pressure transducer (model 8510B-2, Endevco). The initial inflation rate was controlled at ~0.75 ml/min to ensure that all lung regions opened before being switched to a rate of 2 ml/min for the remaining inflation-deflation maneuvers. The pressure limits of the inflation and deflation airway pressures were 30 and –10 cmH2O, respectively. The volumes on deflation at 0 (V0) and 30 cmH2O (V30) were considered to represent functional residual capacity (FRC) and total lung capacity (TLC), respectively. Compliance of the intact respiratory system was computed from the slopes of the PV relationships between 5 and 0 cmH2O (Crs5–0) and between 15 and 10 cmH2O (Crs15–10) on deflation.

Mean chord length of alveoli.   After the PV curve was completed, the tracheal cannula was connected to a 10-cmH2O column of Zenker's fixative (mercuric chloride-acetic acid fixative, EM Science, Gibbstown, NJ) for 4 h. To more consistently control the selection of sample sections, only the left lungs were processed and analyzed. We selected lung sections by a standardized procedure as described by Soutiere et al. (30). From the left lung, the top 3-mm section was removed and discarded, and then three serial 2-mm sections were removed and processed for histology. Blocks were washed in 70% alcohol twice followed by 80% alcohol preservation and then embedded in paraffin in methacrylate. For the measurement of mean chord length (MCL), 5-µm-thick sections were cut and stained with 0.05% toluidine blue. From each section, seven nonoverlapping 676 µm x 505 µm fields were sampled, deliberately avoiding the large airways and blood vessels. Each of these regions was photographed for digital analysis, and conventional morphometric methods were used to determine MCL of alveoli using NIH Image software (ImageJ version 1.62). For consistency with previous studies (30), chord lengths <8 µm or >250 µm were excluded.

Quantification of elastic fiber and collagen content.   From these same tissue blocks, additional 5-µm sections were analyzed for elastic fiber and collagen content in lung parenchymal tissue. Sections were stained with acid orcein alcoholic solution for elastic fiber content, and additional sections were stained with 0.05% fast green FCF and picrosirius red for collagen content. Seven nonoverlapping 676 µm x 505 µm fields were sampled, deliberately avoiding the large airways and blood vessels.

Airway samples were randomly selected from these same lung sections used to assess elastic fiber and collagen content in the lung parenchyma. It was difficult to select airway samples from known generations of the airway tree and standardize the location of these samples among the three age groups. Instead, airway samples were selected based on their internal perimeter (Pi) to directly compare the age-dependent changes in elastic fiber and collagen content between the parenchymal tissue and airways. To this end, all complete airways were contained within a x20 field of view, with Pi < 1.0 mm (ranging from 0.50 to 0.81 mm; see Table 3). The selected airways were obtained from six mice per age group (187 total samples); i.e., 90 samples were analyzed for elastic fiber (31 at 2 mo, 27 at 20 mo, and 32 at 26 mo), and 97 samples were analyzed for collagen (34 at 2 mo, 27 at 20 mo, and 36 at 26 mo).


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  		Table 3. Tissue density, inner airway perimeter, and airway wall area of B6 mice

 
To quantify elastic fiber and collagen content in the lung parenchyma and airways, we performed color thresholding using Image-pro Plus 5.1 software as described elsewhere (8, 25, 27). In the current study, color thresholding was used to separate the histological samples into pixels associated with different tissue staining procedures. Each image, stained for either collagen or elastic fibers, was composed of contrasting pixels representing the color of interest (i.e., collagen or elastic fibers) against a background color (i.e., other tissue or air space). For the lung parenchyma, the areas of elastic fiber (ELP) and collagen (CLP) in the tissue samples were determined by computing the percentage as normalized to the total area of the tissue in the 676 µm x 505 µm fields (8). The parenchymal tissue density (TD) was computed as the percentage of the lung tissue occupied by total area of the field. Like the MCL measurements, 21 histological samples were obtained from each animal and averaged for a given animal.

For the airways, the outer border was determined by digitally removing the parenchymal attachments, and when necessary, this border was extrapolated through regions adjacent to blood vessels. The resulting image was manually segmented by different colors representing elastin, collagen, epithelial cell lining, and airway lumen, and Pi was quantified by the computer. The areas of elastic fiber and collagen in the airway wall were also quantified by computer software, which determined the proportion of these areas relative to the total airway wall area, including the area of the epithelial cell lining. The total area of the airway wall was normalized to the inner perimeter squared (Pi2) as described by Kovar et al. (19). For each histological parameter, multiple airway samples obtained from each animal were averaged to represent a given animal.

Statistical analysis.   One-way ANOVA was performed to compare values among different age groups. Two-way ANOVA was performed to compare the impedance coefficients at different PEEP levels among the age groups. Mean comparisons between groups were further tested by Bonferroni post hoc test. Statistical significance was established at P < 0.05. Results in figures and tables are expressed as means ± SE.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The body weight and lung volume parameters are shown in Table 1. Body weight was significantly (P < 0.01) greater at 20 and 26 mo of age compared with the 2-mo-old group. The V30 increased significantly (P < 0.01) from 0.97 ± 0.08 ml at 2 mo to 1.36 ± 0.02 ml at 20 mo (P < 0.01) and then increased further to 1.46 ± 0.02 ml at 26 mo of age; that is, 80% of total increase in V30 occurred between 2 and 20 mo. Likewise, the V0 increased from 0.27 ± 0.03 ml at 2 mo to 0.35 ± 0.02 ml at 20 mo and then increased further to 0.44 ± 0.03 ml at 26 mo of age; that is, 47% of total increase occurred between 2 and 20 mo. The changes in Crs5–0 were consistent with the age-dependent changes in lung volumes; that is, 84% of total increase in Crs5–0 had occurred between 2 and 20 mo of age (Table 1).


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  		Table 1. Body weight and lung volume parameters of aging B6 mice

 
In Fig. 1, the average R is shown for the different age groups at increasing levels of PEEP. With increasing PEEP, R progressively decreased in each age group. At each PEEP level, there was also a consistent age-dependent decrease in R, which was significant (P < 0.01) between 2 and 26 mo of age. For example, at the PEEP level of 2 cmH2O, R was slightly decreased from 0.82 ± 0.05 cmH2O.s/ml at 2 mo to 0.74 ± 0.06 cmH2O·s/ml at 20 mo (P > 0.05) and then significantly decreased to 0.54 ± 0.06 cmH2O·s/ml at 26 mo (P < 0.01 vs. 2 mo; P < 0.05 vs. 20 mo); that is, only 29% of total decrease in R had occurred before 20 mo, whereas 71% of the total decrease occurred after 20 mo of age.


Figure 1
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  		Fig. 1. Airway resistance as a function of increasing levels of positive end-expiratory pressure (PEEP) in different aged B6 mice. *P < 0.01, §P < 0.05 compared with 2-mo age group; {dagger}P < 0.05 compared with 20-mo age group. Data are expressed as means ± SE.

 
The corresponding lung impedance parameters at different PEEP levels are reported in Table 2. At a PEEP level of 2 cmH2O, G and H were both significantly (P < 0.01) decreased between 2 and 20 mo, and thereafter, no significant change occurred at 26 mo of age. The {eta} increased slightly with age from 2 to 26 mo (P < 0.05), with no detectable increase at 20 mo.


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  		Table 2. Respiratory impedance parameters of B6 mice at different PEEP levels

 
Figure 2 shows the alveolar MCL in different age groups of B6 mice. The alveolar MCL was significantly (P < 0.05) increased with age from 35.0 ± 0.9 µm at 2 mo to 39.6 ± 1.1 µm at 26 mo. There was no detectable difference (P > 0.05) between 2- and 20-mo-old mice.


Figure 2
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  		Fig. 2. Mean chord length of alveoli in different aged B6 mice. §P < 0.05 compared with 2-mo age group. Data are expressed as means ± SE.

 
Figure 3 shows the distribution of elastic fiber and collagen in sections of airways and lung parenchyma. Representative airways sections are shown for 2-, 20-, and 26-mo-old mice, highlighting elastic fiber (Fig. 3, A–C) and collagen content (Fig. 3, D–F). Similarly, lung parenchyma sections are also shown for 2-, 20-, and 26-mo-old mice, highlighting elastic fiber (Fig. 3, G–I) and collagen content (Fig. 3, J–L).


Figure 3
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  		Fig. 3. The contribution of elastic fiber and collagen in peripheral airway and lung parenchyma. A–C: elastic fiber in airway at 2 mo (A), 20 mo (B), and 26 mo (C). D–F: collagen in airway at 2 mo (D), 20 mo (E), and 26 mo (F). G–I: elastic fiber in lung parenchyma at 2 mo (G), 20 mo (H), and 26 mo (I). J–L: collagen in lung parenchyma at 2 mo (J), 20 mo (K), and 26 mo (L). The elastic fiber was stained blue, and the collagen was stained red. The objective power was x20.

 
Table 3 shows the TD, Pi, and airway wall area normalized by Pi2 for the three age groups of B6 mice. There were no significant (P > 0.05) differences among the three age groups or between the two staining procedures for elastic fiber and collagen content.

Figure 4 shows the average percentage of elastic fiber and collagen content in airways of B6 mice from the three age groups. There were no significant differences (P > 0.05) observed among three age groups.


Figure 4
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  		Fig. 4. The percentage of elastic fiber (A) and collagen (B) content in airways in the 3 age groups of B6 mice. There were no significant differences detected among the age groups. Data are expressed as means ± SE.

 
Figure 5 shows ELP and CLP as normalized to the lung parenchymal area in the three age groups. ELP was significantly (P < 0.01) decreased at 20 and 26 mo of age compared with 2-mo-old mice, and there was no significant (P > 0.05) difference between 20 and 26 mo of age. In contrast, CLP was significantly increased at 26 mo of age compared with 2- and 20-mo-old mice (P < 0.01 vs. 2 mo, P < 0.05 vs. 20 mo).


Figure 5
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  		Fig. 5. The percentage of elastic fiber (A) and collagen (B) content as normalized for the lung parenchyma in the 3 different aged groups of B6 mice. * P < 0.01 compared with 2-mo age group; {dagger}P < 0.05 compared with 20-mo age group. Data are expressed as means ± SE.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Aging effects on lung function and mechanics in humans have been investigated in several previous reports. For example, it is well established that vital capacity is reduced and FRC is increased with age, although the TLC remains relatively constant (7). It should be noted though that TLC is an effort-dependent volume, so even if the lung were more compliant with age, the TLC might not increase if the pleural pressure at maximal effort did not stay constant. There have also been several studies that have investigated the effect of age on lung mechanics in rodent models. In Sprague-Dawley rats, a leftward and upward shift in the PV curve was observed, and lung elastance was reduced at high lung volume in the aged group (22). Using another rodent model of aging (SAMR1 mice), Hirai and colleagues (14) showed an age-dependent increase in static compliance, dynamic compliance, and TLC. However, when the compliances were normalized to lung volume, the age differences were eliminated. Neither of these laboratories (14, 22) separated the aging effects on airway mechanics and parenchymal mechanics with age, as was done in B6 mice in the current study.

The results from the present study are consistent with previous investigations (8, 14) by showing the V30, V0, Crs, and alveolar MCL to be significantly increased in aged mice. Although our results showed that about 80–84% of the aging effects on lung volume (i.e., V30 and Crs5–0) occurred from 2 to 20 mo (Table 1), this might have been expected if there was a fairly constant change with age over this more prolonged time period. Although little detail is known about the rate of change in the intervening months between our selected measurement time points, a constant rate of change with age appeared to occur with respect to parenchymal mechanics. The timing of these changes in lung volume was reflected by the impedance measurements, specifically G and H. There were significant decreases in G and H between 2 and 20 mo of age (Table 2), but there were no further changes observed between 20 and 26 mo, suggesting that early aging effects on lung mechanics appear to target the lung parenchyma.

In contrast to these age-dependent changes in parenchymal mechanics, the aging effects on R were delayed. That is, only 29% of the total decrease in R occurred between 2 and 20 mo of age (Table 2), whereas the majority of the aging effects in R occurred after 20 mo. This difference suggests that the aging effects on the airways do not parallel the aging effects on the lung parenchyma in B6 mice. Briscoe and Dubois (5) had observed that airway R measured at low flow close to FRC was, on average, similar in childhood and old age and concluded that the major factor determining R in normal subjects was lung size. A recent study has shown that the resistance of respiratory system measured by forced oscillation technique in healthy elderly subjects aged 65–100 yr was slightly lower than in younger adults (12). The results from the current study appear to demonstrate a similar decreased R in extremely senescent mice.

To the extent that the aging effects mimic emphysema, it is puzzling why the mice should exhibit larger airways (decreased resistance) with age. In humans with emphysema, the loss of support for airways generally leads to a narrowing of the airways, especially on expiration (15, 23). At the present time, we can offer several speculative reasons for the observed decrease in R at lower levels of PEEP in the 26-mo-old mice. The first explanation suggests that the aging lung is not really emphysemic. Although even aged human lungs show substantial airspace enlargement with age (17), these anatomic changes are not routinely correlated with clinical manifestations of emphysema. Perhaps one needs pathological destruction in the parenchyma to weaken the specific structures that support the airways. Another possible explanation for the age-dependent decrease in R may relate to the central airway caliber, which is the likely source of lung resistance in mice as it is in humans (11, 34). It is possible that a minute thinning of the inner lining of the larger airway wall could contribute to a modestly enlarged lumen with a concomitant amplified decrease in R between 20- and 26-mo-old B6 mice. However, this would be very difficult to observe anatomically in vivo.

A final possibility may be the effect of changes of lung volume on R. If the mice breathe at higher lung volumes, this would serve to dilate the airways and reduce resistance. Indeed, other investigators (10, 12) have suggested that the age-dependent decrease in R is inversely correlated to changes in FRC. Although we did not measure FRC in vivo, we did measure V0 postmortem. The measurement of V0 is the lung volume in a closed chest with transpulmonary pressure equal and opposite to transthoracic pressure, thus comparable to FRC in vivo. If we consider V0 as an index of FRC, then the change in FRC from 2 to 26 mo of age is 0.17 ml; that is, 47% of that change occurs between 2 and 20 mo, whereas 53% occurs during 20 and 26 mo. Likewise, if we consider the changes in R at 2 cmH2O PEEP in the same way, then the change from 2 to 26 mo of age is 0.28 cmH2O·s/ml; that is, 29% of that change occurs between 2 and 20 mo, whereas 71% of the change occurs during 20 and 26 mo of age. Therefore, the age-dependent changes in R are not entirely volume dependent. The current results support the hypothesis that decrements in the elastic recoil of the airway lead to increases in airway caliber and decreases in R later in senescence. This loss of elastic recoil of the airways is not balanced by opposing parenchymal tissue forces. A similar hypothesis has been suggested by Gibson and colleagues (10). In contrast, the current results in B6 mice suggest that the loss of airway elastic recoil follows the earlier decline in parenchymal elasticity.

Collagen and elastin are the ECM proteins that make up the framework of the alveolar structure and are most important in determining the mechanical properties of lung parenchyma (31). The interstitium of the lung parenchyma contains mostly types I and III collagen, which provide the structural framework for the alveolar wall. Elastic fibers of the lung are composed of elastin and other microfibrils, including primarily fibrillin and fibullin (18). Several studies have demonstrated that changes of volume-dependent lung mechanics are associated with structural changes of the lung ECM (20, 29). These studies have suggested that elastic fibers primarily influence lung compliance at the lower pressure range or at low lung volumes near FRC. In contrast, collagen fibrils become more important at high lung volumes where inflation becomes limited. Mercer and Crapo (21) have conducted elegant morphometric studies examining the configuration of collagen and elastic fibers in the alveolar duct and wall. These investigators concluded that at low levels of strain, collagen fibers have a "wavelike" configuration and are readily extensible, and stress is borne by adjacent elastic fibers. At higher levels of strain, collagen fibers act to limit further distension.

Although age-related changes in the elastin and collagen content of human and animal lungs have been reported (2, 4, 17, 24, 26), the results have varied widely, and the conclusions have been equivocal. This may be due to issues related to the variety of materials and methods used. In addition, to our knowledge, it is unknown whether age-dependent changes of elastic fiber and collagen in lung parenchyma occur differently with time during senescence.

In the current study, the morphometric results suggest that the changes in elastin and collagen content of the lung parenchyma are not synchronized with age. Specifically, the elastin fiber content decreased between 2 and 20 mo of age, whereas the collagen content was significantly increased in 26-mo-old B6 mice (Fig. 5). These changes in the quantity of elastin and collagen content were especially evident in the lung parenchyma, and similar changes were not detectable in the peripheral airways (Fig. 4). The lung parenchymal changes in elastic fiber and collagen content did not result from changes in TD (Table 3). Although it is difficult to link the age-dependent changes in lung mechanics to variation in ECM collagen and elastin content, several possibilities exist from these data. One hypothesis suggests that an increase in collagen content in the lung parenchyma leads to a reduced lung compliance (28). However, the increase in collagen content from 20 to 26 mo of age in the present study is associated with an increase in static lung compliance over this same time period (Table 1). The age-dependent increase in static compliance is complex and likely attributable to a variety of volume-dependent and volume-independent factors. On the other hand, the increased collagen content in B6 mice with senescence is either abnormal (16) or did not appear to play an obvious role in the age-dependent changes in lung mechanics. The decrease in elastin fiber content in the lung parenchyma observed between 2 and 20 mo of age is associated with an increase in compliance and a loss of elastance (Table 2). However, this age-dependent association requires more rigorous investigation, especially when other changes in lung architecture such as the increase in alveolar size (Fig. 2) are considered. Investigating the contribution of other ECM components, such proteoglycans, on lung mechanical changes with age is also important (6).

In conclusion, we have measured the respiratory mechanics in adult and senescent B6 mice and demonstrated that the lung of B6 mice is altered with age. It is obvious from the results that the changes of airway and lung tissue mechanics were not synchronous. The early aging changes (i.e., those events that occur between 2 and 20 mo) include increased lung volume (V30) and static compliance and a loss of elastic fiber content in the lung parenchyma. The later aging events that occur after 20 mo involve a notable change in R, a significant increased alveolar size, and greater collagen content in the lung parenchyma. In this aging model, the early changes that target the lung parenchyma are ultimately followed by age-associated changes in the airways.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institute of Aging Grant AG-21057 and National Heart, Lung, and Blood Institute Grant HL-010342.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. G. Tankersley, Div. of Physiology, Bloomberg School of Public Health, The Johns Hopkins Univ., 615 N. Wolfe St., Baltimore, MD 21205 (ctankers{at}jhsph.edu)

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
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 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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