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Am J Physiol Lung Cell Mol Physiol 290: L866-L870, 2006. First published December 16, 2005; doi:10.1152/ajplung.00396.2005
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Estrogen receptor regulation of pulmonary alveolar dimensions: alveolar sexual dimorphism in mice

Donald Massaro1 and Gloria DeCarlo Massaro2

Lung Biology Laboratory, Departments of 1Medicine and 2Pediatrics, Georgetown University School of Medicine, Washington, District of Columbia

Submitted 24 August 2005 ; accepted in final form 15 December 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Female rats and mice have smaller and, per body mass (BM), more alveoli and alveolar surface area (Sa) than males of their respective species. This sexual dimorphism becomes apparent about the time of sexual maturity. It is prevented in rats (not tested in mice) by ovariectomy at age 3 wk. In female mice, estrogen receptor (ER)-{alpha} and ER-beta are required for formation of alveoli of appropriate size and number. We now report the average volume of an alveolus (va) and the number of alveoli per body mass (Na/BM) were not statistically different between ER-{alpha}–/– and wild type (wt) males. However, the combination of a larger value for va and a smaller value for Na/BM, though neither parameter achieved a statistically significant intergroup difference, resulted in a statistically significant lower Sa/BM in ER-{alpha}–/– males compared with wt males. In ER-beta–/– males, va was bigger and Na/BM and Sa/BM were lower compared with wt males. Wt males had larger alveoli and lower Na/BM and Sa/BM than wt females. The wt sexual dimorphism of va, Na/BM, and Sa/BM was absent in ER-{alpha}–/– mice. Alveolar size did not differ between ER-beta–/– females and males but Na/BM and Sa/BM were greater in ER-beta–/– females than in ER-beta–/– males. The results in male mice, with prior findings in female mice, 1) demonstrate estrogen receptors have a smaller effect on alveolar dimensions in male than female mice, 2) show ER-{alpha} and ER-beta are required for the sexual dimorphism of alveolar size, and 3) show ER-{alpha} is needed for the sexual dimorphism of body mass-specific alveolar number and surface area.

lung function; hormone replacement therapy; chronic obstructive pulmonary disease; mutant mice

ESTROGEN (18) and estrogen receptor (ER)-{alpha} and ER-beta (15), the only known mammalian estrogen receptors (9), are required for the formation and maintenance of a full complement of alveoli in female mice. The absence of ER-beta, but not of ER-{alpha}, diminishes lung elastic tissue recoil in female mice (15). In adult mice, ovariectomy leads to loss of alveoli, estrogen replacement induces alveolar regeneration (15).

With the onset of sexual maturity, pulmonary alveolar sexual dimorphism becomes apparent in mice and rats (19) (we are unaware of similar studies on the lung of other species). Adult virgin female mice and rats have smaller alveoli and, per body mass, more alveoli and alveolar surface area, than same-age males of their respective species (19). These differences occur without a difference of body mass-specific O2 consumption between virgin females and males (19). That and the clear linear inverse relationship between body mass-specific O2 consumption and alveolar size (31) led to the proposal (19) that the smaller alveoli and greater body mass-specific gas-exchange surface in females were selected for evolutionarily because they help females meet the marked increase of O2 consumption during pregnancy and lactation, without adding to it the energy cost of forming additional alveoli (1, 12). This notion of "preparation" for reproduction by lung at the onset of sexual maturity in female mice and rats (19) is similar to packing, at puberty, mechanically excessive mineral into human female bones for reproductive needs, e.g., for subsequent use to help provide calcium for the skeleton in the fetus and calcium-rich milk for the newborn (10, 11).

We now report ER deletion in male mice had a much smaller effect on lung volume and alveolar dimensions than in female mice, that ER-{alpha} and ER-beta are required for sexual dimorphism of alveolar size, whereas ER-{alpha} mediates the sexual dimorphism of body mass-specific alveolar number and surface area.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. We purchased adult female and male wild-type (wt) C57BL/6 mice and ER-{alpha}–/– and ER-beta–/– mice on a background of C57BL/6 from Taconic Farms. Rodent Lab Chow 5001 (Ralston Purina) and tap water were allowed ad libitum. All mice were housed in the Department of Comparative Medicine at 21°C on a 12:12-h light-dark cycle. We killed mice by cutting large vessels in the abdomen after establishing a surgical level of anesthesia with xylazine (~10 mg/kg) plus ketamine (~75 mg/kg). All procedures were approved by the Georgetown University Animal Care and Use Committee and comply with the National Institutes of Health guidelines.

Morphometry. We anesthetized mice, intubated the trachea, punctured the diaphragm, and instilled 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.4, into the trachea at a transpulmonary pressure of 20 cmH2O. The trachea was ligated, the lungs were removed from the chest, and fixation was continued for 2 h at 0–4°C. We measured lung volume by volume displacement (28), cut lungs into blocks, and selected blocks for further processing by a systematic sampling technique (6). The selected blocks were washed with cacodylate buffer, postfixed at 4°C for 1 h in 2% osmium tetroxide in 0.1 M sodium cacodylate buffer, dehydrated, and embedded in epoxy resin (15–20).

Serial sections were cut at ~0.8 µm thickness, to a depth of 150–250 µm, from three blocks per mouse. Alveolar air spaces were identified by following gas-exchange structures through a complete set of prints of serially sectioned lung (15–20). An alveolus was defined as a gas-exchange structure with a mouth, which communicates with a common air space, that was designated an alveolar duct.

The selector method (5), which allows alveoli to be chosen based on number, uninfluenced by size, shape, or orientation, was used to select alveoli for analysis. The average volume of an alveolus was determined by the point-sample intercepts method as previously described in detail (16), and the number of alveoli was calculated from the average volume of an alveolus and the total volume of alveolar air.

Alveolar surface area was determined by point and intersection counting (35). Sections ~0.8 µm thick were cut from each of 10 tissue blocks to obtain 10 sections/mouse. The sections were stained with toluidine blue and photographed. Final prints for point and intersection counting were at a magnification of x160.

Statistical analysis. For each parameter measured or calculated, the value for individual animals in each group was averaged, and the mean and SD were calculated. We conducted a one-way ANOVA and post hoc a priori comparisons using the Student-Newman-Keuls test (29).

Previously published data. We added to the data on male mice in this manuscript data we previously reported on female mice (15), as well as a small amount of additional data on female mice not reported. The previously published data, clearly identified in each of the tables, were added to facilitate intersex comparisons.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Estrogen receptors, body size, and lung volume in female mice. Others have found crown-rump length was not different among 60-day-old wt, ER-{alpha}–/–, and ER-beta–/– female mice (8, 14). However, we found nose-rump length of 8- to 10-wk-old female ER-{alpha}–/– mice was greater than same age female wt mice (Table 1). Female ER-{alpha}–/– mice are heavier and have a greater mass of adipose tissue than wt and ER-beta–/– female mice (8, 33). We found the same effect of genotype on body mass among our female mice (Table 1); we did not weigh adipose tissue.


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  		Table 1. Body length, mass, and lung volume: female-male comparison among wild-type, ER-{alpha}–/– and ER-beta–/– adult mice

 
Absolute lung volume was greater in female ER-{alpha}–/– and ER-beta–/– compared with wt females (Table 1). Body mass-specific lung volume was the same in wt and female ER-{alpha}–/– mice but was larger in female ER-beta–/– mice than in females of each other genotype (Table 1). The greater body mass-specific lung volume in female ER-beta–/– compared with female wt mice (Table 1), at the same transpulmonary pressure, indicates lung tissue elastic recoil is less in the mutant. The diminished elastic tissue recoil in the absence of ER-beta is consistent with the evidence estrogen increases synthesis of extracellular matrix protein via ER-beta (2).

Estrogen receptors, body size, and lung volume in male mice. Nose-rump length was not different between wt and ER-{alpha}–/– males, but nose-rump length was greater in ER-beta–/– males than in wt males (Table 1). This differs from a reported lack of a difference of crown-rump length between male ER-beta–/– and male wt mice (33). With age, male ER-{alpha}–/– mice become increasingly heavier than male wt mice (32), but we did not find a difference of body mass among 8–10 wk male wt, ER-{alpha}–/–, or ER-beta–/– mice (Table 1). Among males, only ER-beta–/– mice had a larger absolute lung volume than wt mice. However, body mass-specific lung volume did not differ among the different male genotypes (Table 1).

Estrogen receptors, body size, and lung volume: female-male comparisons. Male wt and ER-beta–/–, but not ER-{alpha}–/– males, were longer than female mice of the same genotype. Wild-type and ER-beta–/– males, but not ER-{alpha}–/– male mice, weighed more than females of the same genotype (Table 1). Absolute lung volume was greater in wt males compared with wt females but did not exhibit intersex differences between mutant mice of the same genotype (Table 1). Body mass-specific lung volume was lower in wt male than in wt female mice and in ER-beta–/– male than in ER-beta–/– female mice but did not differ between sexes in ER-{alpha}–/– mice (Table 1). These data indicate the sexual dimorphism of lung volume/body mass is mediated via ER-{alpha}. The greater body mass-specific lung volume in female ER-beta–/– mice than in either other female group and the absence of a difference in body mass-specific lung volume among the male groups indicate ER-beta exerts a measurable female-specific effect on lung tissue elastic recoil (Table 1).

Estrogen receptors and alveolar dimensions in female mice. As reported (15), female ER-{alpha}–/– and ER-beta–/– mice have 1.7-fold and 1.9-fold, respectively, larger alveoli than wt female mice (Table 2). In female mice, the body mass-specific number of alveoli was equally low in ER-{alpha}–/– and ER-beta–/– compared with wt females (Table 2). Body mass-specific alveolar surface area was lower in ER-{alpha}–/– than in either other female group. Body mass-specific alveolar surface area did not differ between wt and ER-beta–/– female mice (Table 2). However, the absence of a difference of body mass-specific alveolar surface area between wt and ER-beta–/– female mice, despite the larger and fewer alveoli in ER-beta–/– females, is due to the larger lung size of ER-beta–/– female mice that, in turn, reflects diminished elastic tissue recoil in ER-beta–/– female mice.


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  		Table 2. Alveolar size, number, and surface area: female-male comparison among wt, ER-{alpha}–/–, and ER-beta–/– adult mice

 
Estrogen receptors and alveolar dimensions in male mice. Unlike females, in which both mutant genotypes had larger alveoli than wt type mice, in males only ER-beta–/– mice had alveoli larger than wt males (Table 2). Also unlike females, in which the size of alveoli did not differ among the mutant groups, male ER-beta–/– mice had larger alveoli than ER-{alpha}–/– males. The body mass-specific number of alveoli was not different between wt male and ER-{alpha}–/– male mice (Table 2), but ER-beta–/– male mice had, per body mass, fewer alveoli than wt or ER-{alpha}–/– males (Table 2). Alveolar surface area per body mass was lower in ER-{alpha}–/– and in ER-beta–/– males than in wt males (Table 2).

Estrogen receptors and alveolar dimensions: female-male comparisons. Confirming prior findings with a different strain of mice (19) and consistent with results in rats (19), we found wt female mice had smaller, more numerous alveoli and a larger body mass-specific alveolar surface area than wt males (Table 2). The absence of ER-{alpha}, or ER-beta, eliminated the female-male sexual dimorphism of alveolar size (Table 2). Thus both receptors are required for the smaller alveoli of female compared with male mice. In the absence of ER-{alpha}, the intersex difference in body mass-specific alveolar number present in wt mice did not develop (Table 2). By contrast, deletion of ER-beta did not prevent development of the sexual dimorphism of body mass-specific number of alveoli (Table 2). These results indicate ER-{alpha} mediates the sexual dimorphism of alveolar number.

Lack of ER-{alpha} eliminated the female-male difference of body mass-specific alveolar surface area (Table 2). Although ER-beta deletion did not prevent the greater body mass-specific number of alveoli present in wt female compared with wt male mice (Table 2), part of the maintained intersex difference was due to the lower lung recoil (greater body mass-specific lung volume) in ER-beta–/– female than ER-beta–/– male mice (Table 1).

Volume density and volume of gas-exchange air space and alveolar wall in female mice. The volume density (fraction) of gas-exchange region air space (alveolar duct plus alveolar air) was greater in each female mutant genotype than in female wt mice (Table 3). Similarly, each female mutant group had a larger absolute volume of gas-exchange air space than wt females (Table 3). When corrected for body mass, gas-exchange air volume was the same in female wt and female ER-{alpha}–/– mice but was larger in female ER-beta–/– mice than in each other female group (Table 3).


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  		Table 3. Volume density and volume of gas-exchange region air: female-male comparison among wt, ER-{alpha}–/–, and ER-beta–/– adult mice

 
Alveolar wall volume density was lower in female ER-beta–/– mice than in female wt mice (Table 4). Absolute alveolar wall volume was greater in female ER-{alpha}–/– mice than in wt or ER-beta–/– female mice. However, when corrected for body mass, the alveolar wall volume was lower in ER-{alpha}–/– females than in wt females.


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  		Table 4. Volume density and volume of alveolar wall: female-male comparison among wild type (wt), ER-{alpha}–/–, and ER-beta–/– adult mice

 
Volume density and volume of gas-exchange air space and alveolar wall in male mice. Volume density of gas-exchange air space was not different between male wt type and either group of male mutants but was greater in ER-{alpha}–/– males than in ER-beta–/– males (Table 3). The absolute volume of gas-exchange air was not significantly larger, at the P < 0.05 level, in male ER-{alpha}–/– compared with wt males but was significantly larger in ER-beta–/– than in wt males. The gas exchange air volume per body mass was not different among the male genotypes. Neither the volume density, absolute volume, nor body mass-specific volume of the alveolar wall differed among wt, ER-{alpha}–/–, and ER-beta–/– males (Table 4).

Volume density and volume of gas-exchange air space and alveolar wall: female-male comparisons. The volume density of gas-exchange air was lower in ER-{alpha}–/– female than ER-{alpha}–/– male mice (Table 3). The absolute volume of gas-exchange air did not exhibit an intersex difference within the same genotype (Table 3). ER-beta–/– females had a greater body mass-specific gas-exchange air volume than ER-beta–/– males. Wt females had a greater volume of gas-exchange region walls (Vwall)/body mass than wt males. Female ER-{alpha}–/– mice had a larger volume density of gas-exchange walls, Vwall, and Vwall/body mass than ER-{alpha}–/– males (Table 4).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Sexual dimorphism of alveolar architecture: proposed relationship to reproductive need for O2. Meeting energy needs and efficient use of body space are important determinants of survival in organisms singly and as a species (1, 7, 12). Tenney and Remmers (31), in a seminal publication, provided clear evidence that the different body mass-specific O2 requirements among organisms are met by interorganism differences in alveolar size. Thus small organisms with a high body mass-specific O2 consumption have smaller alveoli and a higher body mass-specific alveolar surface area than larger organisms with a lower body mass-specific O2 consumption (31). In functional terms, smaller alveoli have a higher surface-to-volume ratio, thereby increasing their diffusing capacity for O2 (24, 26).

Although they have the same body mass-specific O2 consumption, wt female rats and mice have smaller and, per body mass, more alveoli and a greater alveolar surface area than same-age males of their respective species (19). Our present data (Table 2) confirm this in a second strain of mice. These differences, which become apparent about the time sexual maturity is achieved (19), should provide females with alveoli that have a higher diffusing capacity for O2 than alveoli in males (26). The demonstration that adult female swine have a higher PaO2 than males at moderate and very high altitude (21) is consistent with the notion females have more effective gas-exchange units than males.

Oxygen consumption, a reflection of energy need, increases markedly as pregnancy progresses, e.g., on the last day of gestation in rats (gestation day 22), and on the 14th day of lactation, O2 consumption is twofold higher than in same-aged virgin female rats (19). This twofold increase in O2 consumption occurs without a change in alveolar dimensions (19). Therefore, considering that wild female animals spend, and until recent times women spent, a substantial amount of their adult lives pregnant or lactating, the larger lung per body mass (Table 1, Ref. 19) and the more efficient gas-exchange units in females were probably selected for as evolutionarily advantageous to reproduction, assisting females to meet the energy burden of reproduction (12, 18), and without adding to it the energy requirement of forming new alveoli.

Ovariectomy at weaning (age 21 days) prevents development of alveolar sexual dimorphism in rats; estrogen replacement from the time of ovariectomy allows alveolar sexual dimorphism to develop (18). The latter indicates that, among the ovarian hormones, estrogen is responsible for alveolar sexual dimorphism. Our present study shows the sexual dimorphism of lung size per body mass and alveolar size are mediated through both estrogen receptors (summarized in Table 5). Deletion of either estrogen receptor diminishes, or eliminates, the sexual dimorphism of absolute lung volume (Table 1) and alveolar size (Table 2). However, the receptors may act by different means. The absence of ER-{alpha} diminishes subdivision (septation) of the gas-exchange saccules present at birth, as shown by the greater volume of an average alveolus in ER-{alpha}–/– females than in wt females (Table 2), in the absence of a difference in lung tissue elastic recoil. The latter is indicated by the lack of a difference of body mass-specific lung volume between female wt and female ER-{alpha}–/– mice (Table 1). By contrast, the absence of ER-beta in female mice results in diminished septation and lower lung tissue elastic recoil; both consequences of ER-beta deletion contribute to the large alveoli in ER-beta–/– females compared with wt females and to the sexual dimorphism of alveolar size in ER-beta mutants (Tables 1 and 2). The conclusion that the large alveoli in ER-beta–/– female mice compared with wt mice is due, in part, to less septation is supported by the lower body mass-specific number of alveoli in ER-beta–/– compared with wt females (Table 2). The lower lung elastic recoil in ER-beta–/– females compared with wt females (Table 1), by resulting in larger lungs in ER-beta–/– females, allows the sexual dimorphism of body mass-specific alveolar surface area to be maintained even though alveolar size is not different between ER-beta–/– male and female mice (Table 2).


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  		Table 5. Summary of lung volume and estrogen receptor-mediated alveolar sexual dimorphism

 
Aging, lung function, chronic obstructive pulmonary disease, and estrogen. Diffusing capacity, an indicator of alveolar surface area (24, 27), diminishes with age in never smokers (23). The fall of diffusion capacity in male never smokers is linear with age and is more rapid than the decline in female never smokers (23). However, in female never smokers, the rate of decline accelerates after menopause, approaching that of men (23). That this menopause-related accelerated decline of diffusing capacity is due to a fall in the concentration of estrogen is supported by the observations that ovariectomy in adult mice results in alveolar loss and estrogen replacement in alveolar regeneration (15).

The forced timed vital capacities reflect resistance to airflow in the conducting airways and lung tissue elastic recoil. Increased resistance to airflow is present in airways that are excessively narrow during expiration, which can, in part, be due to the loss of the tethering effect of alveolar attachments caused by alveolar destruction.

Elderly women receiving hormone replacement (estrogen plus progesterone) have a higher forced expiratory volume at 1 s (FEV1) than similar age women not receiving hormone replacement; this difference is not explained by lower rates of smoking or by other health factors (3). Administration of estrogen plus progesterone (4, 13), estrogen alone (25), or an estrogen-like compound (25) to postmenopausal women increases their forced vital capacity and FEV1. Even in women age 24–35 yr, use of an oral contraceptive containing estradiol and a progestin increases forced expiratory flow rates, especially flow rates at low lung volumes (30). Expiratory airflow at low lung volumes reflects the patency of small conducting airways, which depend substantially on the tethering effect of alveolar attachments. Hence, these findings in young women point to the alveolar maintaining effect of ovarian hormones. The loss of alveoli in mice after ovariectomy and their regeneration during estradiol replacement (15) suggest estrogen is the ovarian hormone responsible for maintaining alveolar structural stability.

Low concentrations of ovarian hormones may play a role in the development and progression of chronic obstructive pulmonary disease (COPD). Women constitute ~75% of never smokers above age 55 yr with clinical and lung function evidence of COPD (22, 34). The standardized mortality rate is almost twice higher in women than men among individuals with COPD who participated in a survey in which the average age upon entry was 56.6 yr (27). Thus evidence is growing to indicate estrogen may delay the loss of, and improve, those lung functions that reflect maintenance of alveolar structure (3, 4, 13, 25, 30) and, as a consequence, the number of alveolar attachments to small conducting airways.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-37666, HL-20366, and HL-073558.


   ACKNOWLEDGMENTS
 
D. Massaro is Cohen Professor of Medicine. We thank Dr. Linda B. Clerch for a critical review of the manuscript and Zofia Opalka for excellent technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Massaro, Lung Biology Laboratory, Box 571481, Preclinical Science Bldg., GM-12, Georgetown Univ. School Medicine, 3900 Reservoir Rd., NW, Washington, DC 20057-1481 (e-mail: massarod{at}georgetown.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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 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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