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Am J Physiol Lung Cell Mol Physiol 294: L991-L997, 2008. First published March 14, 2008; doi:10.1152/ajplung.00013.2008
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Apoetm1Unc mice have impaired alveologenesis, low lung function, and rapid loss of lung function

Donald Massaro1 and Gloria DeCarlo Massaro2

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

Submitted 7 January 2008 ; accepted in final form 11 March 2008


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Diminished lung function, indicated by a low forced expiratory volume in one second (FEV1), and short physical stature, predict early mortality from all causes, including cardiovascular, among smokers and never smokers. The basis for these associations is unclear, and, it is not known if there is a pulmonary morphological component to the relationship between low FEV1 and early death in a general population. Some apolipoprotein E genotypes also predict atherosclerosis and early mortality. These considerations led us to examine the Apoetm1Unc (Apoe) mouse, in which the apolipoprotein E gene is deleted, and that develops dyslipidemia, atherosclerosis at an early age, and has a shorter life span than the founder wild-type (wt) strain. We asked if Apoe mice have a morphological or functional pulmonary phenotype. We measured the size, number, and surface area of pulmonary gas-exchange units (alveoli) and mechanical properties of the lung. Compared with wt mice, Apoe mice had: 1) diminished developmental alveologenesis, 2) increased airway resistance in early adulthood, 3) high lung volume and high dynamic and static compliance in later adulthood, 4) more rapid loss of lung recoil with age, and 5) were less long than wt mice. These findings in mice indicate the association of a low FEV1 with early death in humans may have developmental, and accelerated ageing, related pulmonary components, and that dietary, genetic, or dietary and genetic influences, on lipid metabolism may be an upstream cause of inflammation and oxidative stress, currently considered to be major risk factors for COPD.

FEV1; predict early death; atherosclerosis; short stature; diet; genetics; cholesterol

EPIDEMIOLOGICAL STUDIES INDICATE that in a general population of never smokers or smokers, a low forced expiratory volume in one second (FEV1), compared with its expected value, is a predictor of early mortality from all causes, including cardiovascular (3, 33). Why FEV1 has this predictive capacity in a general population, especially among never smokers, is unclear. A putative factor linking a low for expected FEV1 to cardiovascular disease is evidence of the presence of chronic systemic inflammation, based on finding elevated concentrations of markers of systemic inflammation, in individuals with a low FEV1 (31), and in those with cardiovascular disease (34). Oxidative stress is also considered a risk factor for cardiovascular disease (34), for a low FEV1 in a general population (26), and for chronic obstructive pulmonary disease (COPD), which is a cause of a low FEV1 (27). However, in COPD, there are morphological abnormalities associated with, and indicative of, a low FEV1 (10). In contrast, it is not known if in a general population without COPD, or without other identified pulmonary diseases, a pulmonary morphological abnormality accompanies a low FEV1. It is also unknown if impaired pulmonary development contributes to a low FEV1 in a general population. A related, equally unclear, association is that of short stature, a low for predicted FEV1, and early death (2).

Apolipoprotein E has an important role in triglyceride and cholesterol metabolism, but substantial evidence links it to biological processes other than lipid transport (18–20), and certain apolipoprotein genotypes are associated with early death (15). The Apoetm1Unc (Apoe) mouse, which lacks a functional apolipoprotein E gene (38), develops atherosclerosis at an early age and has a shorter life span than its founder wild-type (wt) mouse (25). These considerations led us to test the hypothesis that Apoe mice have a pulmonary morphological and functional phenotype consistent with the presence of a low FEV1 in humans, and that lung function diminishes with age at a more rapid rate in Apoe mice than in wt mice. We found Apoe mice 1) were shorter than wt mice, 2) had diminished formation of pulmonary gas-exchange units (diminished developmental alveologenesis), 3) exhibited high airways resistance as young adults consistent with a low FEV1 in humans, and 4) had a more rapid loss of mechanical lung function with age compared with wt mice. Thus, this model of atherosclerosis and early death has a pulmonary phenotype of impaired developmental alveologenesis, low lung mechanical function, a rapid decline of lung function with age, and low body length.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
RESULTS
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Animals. We purchased wt C57BL/6J and B6.129P2-Apoetm1Unc male mice from Jackson Laboratory. The mutant mice were originally generated by inactivation of the apolipoprotein E gene (38). The C57BL/6J was produced by Jackson Laboratory by back crossing the Apoetm1Unc mutation 10 times to C57BL/6J mice (Jax Mice Data Sheet, The Jackson Laboratory). All mice were housed in the Department of Comparative Medicine at Georgetown University School of Medicine, maintained on a 12:12-h light-dark cycle, and allowed Rodent Chow 5001 and tap water ad libitum. Mice were killed by cutting great vessels in the abdomen after achieving a surgical level of anesthesia (indicated by failure to withdraw from a toe pinch) 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. Lungs were fixed at a transpulmonary pressure of 20 cmH2O. This was achieved by inserting a cannula into the trachea and instilling 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.4. The trachea was then ligated, the lungs excised from the chest, and fixation was continued for 2 h at 0–4°C. Lung volume was measured by volume displacement (29). Lungs were then cut into blocks, and blocks were selected for further processing by a systematic sampling technique (7). Fixation was continued as previously described (22, 24). Serial sections of lung were cut, and alveolar air spaces were identified by following gas-exchange structures through a complete set of prints (22, 24). The selector method was used to select alveoli for analysis; the volume of an average alveolus was determined by the point-sample intercepts method (4) as previously described in detail (22, 24); 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 estimated by point and intersection counting (35).

Measurement of lung mechanical properties. We achieved a surgical level of anesthesia as described above, then shaved the ventral side of the neck, made a skin incision, identified the trachea by blunt dissection, made a small incision between two tracheal rings, and inserted and tied an 18-gauge cannula into the trachea. The mouse was placed in a supine position and connected via the tracheal cannula to a computer-controlled small animal ventilator (flexiVent, Scireq Scientific Respiratory Equipment). Mice were ventilated at 150 breaths/min with room air at a volume of 10 ml/kg body mass. After 3 min of ventilation, we initiated the computer-generated program to measure lung compliance (C) and the impedance of the respiratory system. The latter was measured 2 min after an inflation of 30 cmH2O and was then fitted by flexiVent software to a constant-phase model to provide measures of airway resistance (RN), tissue damping (G), tissue elastance (H), and the ratio of G to H (tissue hysteresivity). For measurement of impedance, the flexiVent software provides a computer-generated volume signal made up of 19 mutually primed sinusoids ranging from 0.25 to 19.5 Hz that was applied to the airway opening.

Statistical methods. For each parameter measured or calculated from measurements, the values for individual animals were averaged per experimental group, and the standard deviation of the group mean was calculated. A one-way analysis of variance was used for multiple group comparisons, and the statistical significance of the difference between two groups was obtained by an unpaired two-tailed t-test (StatMost3).


   RESULTS
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Body mass, nose to rump length, and lung volume. Apoe mice weighed less than wt mice at ages 1 and 3 mo; both groups weighed the same at age 8 mo (Fig. 1A). The nose-rump distance was less in Apoe than in wt mice at 1 and 3 mo of age (not measured at 8 mo) (Fig. 1B).


Figure 1
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  		Fig. 1. Body mass (A), nose-to-rump length (B), pulmonary alveolar surface-to-volume ratio (C), and alveolar surface area (D). Means ± SD are given. Values within the bars give the number of mice. A: ANOVA = 5.1E-019; *P = <0.001 vs. 3-mo-old wild-type (wt); {dagger}P < 0.001 vs. 3-mo-old Apoe. B: ANOVA = 7.5E-008; *P < 0.002 vs. 3-mo-old wt; {dagger}P < 0.0002 vs. 3-mo-old Apoe. C: ANOVA = 7.8E-005; *P < 0.005 vs. 3-mo-old wt; {dagger}P < 0.3 vs. 3-mo-old Apoe. D: ANOVA = 2.9E-0.005; *P < 0.001 vs. 3-mo-old wt; {dagger}P = 0.001 vs. 3-mo-old Apoe.

 
Alveolar dimensions. One-month- and 3-mo-old Apoe mice had gas-exchange units with a smaller surface-to-volume ratio (Fig. 1C) and lower surface area (Fig. 1D) than wt mice. This indicates their gas-exchange units are larger than those of wt mice. To further document the differences in alveolar dimensions between wt and Apoe mice, we measured alveolar dimensions from serial sections of lung of 3-mo-old mice. Three-month-old Apoe mice had larger and fewer alveoli than same-age wt mice (Table 1), confirming the surface-to-volume measurements. Thus, alveoli in Apoe mice were larger, fewer, and had a smaller surface area than alveoli in wt mice. Some of these differences can be appreciated by examination of histological sections (Fig. 2).


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  		Table 1. Volume of an average alveolus (va), alveolar number (Na), and body mass-specific number of alveoli (Na/kg)

 

Figure 2
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  		Fig. 2. Light microscopic view of the lung of 1-mo-old wt (A) and Apoe (B) mice and 3-mo-old wt (C) and Apoe (D) mice. Scale bars, 100 µm.

 
Lung volume and mechanical properties in wt and Apoe mice. Lung volume at a transpulmonary pressure of 30 cmH20 was the same in 3-mo-old wt and Apoe mice, but at age 8 mo, it was greater in Apoe compared with wt mice (Fig. 3A). Dynamic (Fig. 3B) and static (Fig. 3C) compliance of the lung were the same in Apoe and wt mice at age 3 mo, but were higher (less recoil) in Apoe compared with wt mice at age 8 mo (Fig. 3, B and C). Resistance to airflow in the conducting (bronchial) airways was greater in Apoe than in wt mice at age 3 mo, but there was not an intergroup difference in airway resistance at age 8 mo (Fig. 3D). Tissue damping, a reflection of energy dissipation in lung tissue, was the same in both groups of mice at both ages (Fig. 4A). Tissue elastance, an indicator of energy conservation, was higher in Apoe mice compared with wt mice at ages 3 and 8 mo (Fig. 4B). Tissue hysteresivity, the ratio of G/H, did not differ among groups (Fig. 4C).


Figure 3
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  		Fig. 3. Lung volume (A), dynamic compliance (B), static compliance (C), and airway resistance (D). Means ± SD are given. Values within the bars give the number of mice. A: ANOVA = 3.5 E-005; *P < 0.01 vs. 8-mo-old wt; {dagger}P < 0.0003 vs. 8-mo-old Apoe. B: ANOVA = 8.9 E-005; *P < 0.02 vs. 8-mo-old wt; {dagger}P = 0.0004 vs. 8-mo-old Apoe; C: ANOVA = 0.001; *P < 0.005 vs. 8-mo-old wt; {dagger}P < 0.01 vs. 8-mo-old Apoe; D: ANOVA = 4.9 E-006; *P < 0.002 vs. 8-mo-old wt; {dagger}P < 0.0002 vs. 8-mo-old Apoe. RN, airway resistance.

 

Figure 4
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  		Fig. 4. Tissue damping (A), elastance (B), and hysteresivity (C). Means ± SD are given. Values within the bars give the number of mice. A: ANOVA = <0.009; *P < 0.02 vs. 8-mo-old wt; {dagger}P < 0.003 vs. 8-mo-old Apoe, and because this is the second comparison, the Bonferroni method indicates the intergroup difference is not statistically significant. B: ANOVA = 4.9E-007; *P = 0.0004 vs. 8-mo-old wt; {dagger}P < 0.0001 vs. 8-mo-old Apoe. C: there were no differences among the group means.

 
Comparison of ageing-related changes in lung function. Between ages 3 and 8 mo, there was a 2.5-fold greater percentage increase of lung volume in Apoe than in wt mice (Fig. 5A). Over the same period, lung compliance increased about twice as much in Apoe mice as in wt mice (Fig. 5B), and resistance in the conducting airways fell 25% in wt mice and 42% in Apoe mice (Fig. 5C). An age-related fall of airways resistance in wt mice, as we found, was reported earlier by others (11). The basis for the decline is not clear. However, airway resistance measured with the flexiVent is measured in inspiration and expiration. Therefore, it is possible bronchial smooth muscle, as other muscles, atrophies with age resulting in loss of tone of the conducting airways, with consequent greater widening of the conducting airways during inspiration in older mice. Tissue damping declined in both groups of mice, but the decline did not differ to a statistically significant degree between wt and Apoe mice (Fig. 6A). Tissue elastance fell twice as much in Apoe as in wt mice, between ages 3 and 8 mo (Fig. 6B). Although the absolute values for hysteresivity did not differ among groups, when calculated as a percentage change with age, the percent increase of hysteresivity between age 3 mo and age 8 mo was greater in Apoe compared with wt mice (Fig. 6C). An increase of hysteresivity is thought to signify alteration in the properties of tissues, increased heterogeneity of tissue, or a combination of the two events (12, 16).


Figure 5
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  		Fig. 5. Change of lung volume (A), compliance (B), and airway resistance (C) with age. Means ± SD are given.

 

Figure 6
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  		Fig. 6. Change of tissue dampening (A), tissue elastance (B), and tissue hysteresivity (C) with age. Means ± SD are given.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Apolipoprotein E has a major role in triglyceride and cholesterol metabolism, and differences in Apoe genotype frequencies are associated with increased mortality (19). Compared with wt, Apoe mice die sooner (25), have earlier onset and more severe atherosclerosis (25), and have hyperlipidemia (9), increased circulating levels of LDL cholesterol (9), very low density lipoprotein cholesterol (9), triglycerides (25), and total cholesterol (20).

The lung is not widely considered an organ that suffers the ill effects of dyslipidemia, including hypercholesterolemia. However, in animals, a diet high in cholesterol produces atheromatous changes in the pulmonary vasculature (5, 6, 8, 13, 30). Providing rabbits with a diet high in cholesterol results in "senile emphysema" and has led to the suggestion that disordered lipid metabolism results in abnormal pulmonary alveoli (14). This latter notion is supported by our present findings, and, on a more mechanistic level, by the demonstration that a high cholesterol diet in rabbits induces in the lung a several hundred-fold elevation of 15-lipoxygenase activity (1); the latter has a pro- as well as an anti-inflammatory effect, and may have a proathrogenic effect (for review, see Ref. 36).

The biological basis of the epidemiological link between atherosclerosis and COPD, among never smokers and smokers (32), is not understood, but it is thought that systemic inflammation present in COPD may foster atherosclerosis (17, 33). However, our study with Apoe knockout mice, which have disordered lipid metabolism including hypercholesterolemia (38), earlier work by others indicating hypercholesterolemia in rabbits results in senile emphysema (14), and the marked increase of 15-lipoxygenase in lung and heart in mice fed a high cholesterol diet (1), suggest the influence of diet, genetics, or both on lipid metabolism, is the more upstream mediator of the concurrence of COPD and cardiovascular disease than is inflammation and oxidative stress (17, 33).

The formation of mature pulmonary gas-exchange units (alveoli) is, in part, by subdivision (septation) of gas-exchange saccules present at birth. This subdivision results in gas-exchange structures (alveoli) that are smaller, more numerous, and with a greater surface area than the gas-exchange saccules present at birth (23). Thus, subdivision of the saccules present at birth produces gas-exchange units with a higher surface-to-volume ratio than those present at birth. The lung's gas-exchange surface area per lung volume is also larger at age 14 days than at birth. Compared with 1-mo-old wt mice, septation is impaired in Apoe mice, and by age 3 mo, there is not "catch-up" septation, i.e., the impairment of septation persists into adulthood. The presence of fewer alveoli in Apoe mice would result in fewer alveolar attachments to, and hence less tethering of, small bronchial airways, resulting in their premature and excessive narrowing, during expiration, and therefore in elevated airway resistance (28). Similar findings in humans would result in a low FEV1. Thus, to the extent that our morphometric findings in the Apoe mouse are a model for humans, the low FEV1 in humans would have, at least in part, a pathogenic alveolar developmental component.

Compared with its predicted value, a low FEV1 is a marker for increased all-cause mortality (3, 33). Short stature is also associated with a low for predicted FEV1 and early death (2). Thus, finding Apoe mice are not as long as wt mice indicates the association between body length and early death is present in these mice, as in humans. The basis for these associations is unclear in mice and in humans, but is generally ascribed to "ageing." However, because of diminished formation of alveoli, Apoe mice not only age faster than wt mice, but begin age-related alveolar loss from a lower starting point. This lower starting point, and the more rapid rate of loss of lung function with age in Apoe mice, would, if similar events occurred in humans, result in a lower FEV1 than predicted. More broadly, humans with impaired developmental alveologenesis from any of many potential causes (21), begin ageing-related loss of lung function from a low starting point. Therefore, even loss at a rate not different from that of a general population, would be more apparent compared with the general population; the consequences of alveolar loss due to lung disease would also be more apparent and result in earlier onset of symptoms.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
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REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grants HL-020366, HL-073558, and HL-037666.


   ACKNOWLEDGMENTS
 
We thank Zofia Opalka for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Massaro, Lung Regeneration Laboratory, Georgetown Univ. School of 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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 ABSTRACT
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 RESULTS
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  1. Bailey JM, Makheja AN, Lee R, Simon TH. Systemic activation of 15-lipoxygenase in heart, lung, and vascular tissues by hypercholesterolemia: relationship to lipoprotein oxidation and atherogenesis. Atherosclerosis 113: 247–258, 1995.[CrossRef][Web of Science][Medline]
  2. Batty GD, Gunnell D, Langenberg C, Smith GD, Marmot MG, Shipley MJ. Adult height and lung function as markers of life course exposures: associations with risk factors and cause-specific mortality. Eur J Epidemiol 21: 795–801, 2006.[CrossRef][Web of Science][Medline]
  3. Beaty TH, Newill CA, Cohen BH, Tockman MS, Bryant SH, Spurgeon HA. Effects of pulmonary function on mortality. J Chronic Dis 38: 703–710, 1985.[CrossRef][Web of Science][Medline]
  4. Cruz-Orive LM. Particle number can be estimated using a disector of unknown thickness: the selector. J Microsc 145: 121–142, 1987.[Web of Science][Medline]
  5. Bollack C, Klein M, Fontaine R. Lesions of the pulmonary arteries and parenchyma during experimental arteriosclerosis in the rabbit. Presse Med 75: 2217–2220, 1967.[Medline]
  6. Chile GV, Thurlbeck WM, Weigensberg BI. Severe pulmonary atherosclerosis in hypercholesterolemic rabbits. Arch Pathol 98: 47–50, 1074.
  7. Cruz-Orive LM, Weibel ER. Sampling designs for stereology. J Microsc 122: 235–257, 1987.
  8. Eckert H. Lung changes by experimentally induced cholesterol atheromatosis. Z Erkr Atmungsorgane 145: 202–207, 1976.[Medline]
  9. Guo Y, Zhang C, Du X, Nair U, Yoo TJ. Morphological and functional alterations of the cochlea in apolipoprotein E gene deficient mice. Hear Res 208: 54–67, 2005.[CrossRef][Web of Science][Medline]
  10. Hogg JC, Senior RM. Chronic obstructive pulmonary disease-part 2: pathology and biochemistry of emphysema. Thorax 57: 830–834, 2002.[Abstract/Free Full Text]
  11. Huang K, Mitzner W, Rabold R, Schofield B, Lee H, Biswal S, Tankersley CG. Variation in senescent-dependent lung changes in inbred mouse strains. J Appl Physiol 102: 1632–1639, 2007.[Abstract/Free Full Text]
  12. Kaczka DW, Ingenito EP, Israel E, Lutchen KR. Airway and lung tissue mechanics in asthma. Effects of albuterol. Am J Respir Crit Care Med 159: 169–178, 1999.[Abstract/Free Full Text]
  13. Kamimura R, Suzuki S, Miura N, Miyahara K. Pulmonary atherosclerosis and pulmonary arterial pressure in cholesterol-fed New Zealand white rabbits. J Vet Med Sci 63: 647–653, 2001.[CrossRef][Web of Science][Medline]
  14. Klimenko ED, Pozdniakov OM. Structural changes in the pulmonary vessels and parenchyma in experimental hypercholesterolemia and atherosclerosis. Biull Eksp Biol Med 100: 103–106, 1985.[Medline]
  15. Lee JH, Tank MX, Schupf N, Stern Y, Jacobs DM, Tycko B, Mayeux R. Mortality and apolipoprotein E in Hispanic, African-American, and Caucasian elders. Am J Med Genet 103: 121–127, 2001.[CrossRef][Web of Science][Medline]
  16. Lutchen KR, Hantoa Z, Petak F, Adamicza A, Suki B. Airway inhomogeneities contribute to apparent lung tissue mechanics during constriction. J Appl Physiol 80: 1841–1849, 1996.[Abstract/Free Full Text]
  17. Maclay JD, McAllister DA, Macnee W. Cardiovascular risk in chronic obstructive pulmonary disease. Respirology 12: 634–641, 2007.[CrossRef][Web of Science][Medline]
  18. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240: 622–630, 1988.[Abstract/Free Full Text]
  19. Mahley RW, Huang Y. Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond. Curr Opin Lipid 10: 207–217, 1999.[CrossRef][Web of Science][Medline]
  20. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1: 507–537, 2000.[CrossRef][Web of Science][Medline]
  21. Massaro D, Massaro GD. Developmental alveologenesis: longer, differential regulation and perhaps more danger. Am J Physiol Lung Cell Mol Physiol 293: L568–L569, 2007.[Free Full Text]
  22. Massaro GD, Massaro D. Formation of alveoli in rats: postnatal effect of prenatal dexamethasone. Am J Physiol Lung Cell Mol Physiol 263: L37–L41, 1992.[Abstract/Free Full Text]
  23. Massaro GD, Massaro D. Formation of pulmonary alveoli and gas-exchange surface area: quantitation and regulation. Annu Rev Physiol 58: 73–92, 1996.[CrossRef][Web of Science][Medline]
  24. Massaro GD, Mortola JP, Massaro D. Sexual dimorphism in the architecture of the lung's gas-exchange region. Proc Natl Acad Sci USA 92: 1105–1107, 1995.[Abstract/Free Full Text]
  25. Moghadasian MH, McManus BM, Nguyen LB, Shefer S, Nadji M, Godin DV, Green TJ, Hill J, Yang Y, Scudamore CH, Frohlich JJ. Pathophysiology of apolipoprotein E deficiency in mice: relevance to apoe-related disorders in humans. FASEB J 15: 2623–2630, 2001.[Abstract/Free Full Text]
  26. Ochs-Balcom HM, Grant BJ, Muti P, Sempos CT, Freudenheim JL, Browne RW, Trevisan M, Iacoviello L, Cassano PA, Schunemann HJ. Oxidative stress and pulmonary function in the general population. Am J Epidemiol 162: 1137–1145, 2005.[Abstract/Free Full Text]
  27. Panettieri RA Jr, Kotlikoff MI, Gerthoffer WT, Hershenson MB, Woodruff PG, Hall IP, Banks-Schlegel SP. Airway smooth muscle in bronchial tone, inflammation, and remodeling: basic to clinical relevance. Am J Respir Crit Care Med 177: 248–252, 2008.[Abstract/Free Full Text]
  28. Saetta M, Finkelstein R, Cosio MG. Morphological and cellular basis for airflow limitation in smokers. Eur Respir J 7: 1505–1515, 1994.[Abstract]
  29. Scherle W. A simple method for volumetry of organs in quantitative stereology. Mikroskopie 26: 57–60, 1970.[Medline]
  30. Schwenke DC. Comparison of aorta and pulmonary artery: 1. Early cholesterol accumulation and relative susceptibility to atheromatous lesions. Circ Res 81: 338–345, 1997.[Abstract/Free Full Text]
  31. Shaaban R, Kony S, Driss F, Leynaert B, Soussan D, Pin I, Neukirch F, Zureik M. Change in C-reactive protein levels and FEV1 decline: a longitudinal population-based study. Respir Med 100: 2112–2120, 2006.[CrossRef][Web of Science][Medline]
  32. Sin DD, Paul Man SF. Systemic inflammation and mortality in chronic obstructive pulmonary disease. Can J Physiol Pharmacol 85: 141–147, 2007.[CrossRef][Web of Science][Medline]
  33. Sin DD, Wu L, Paul Man SF. The relationship between reduced lung function and cardiovascular mortality. A population-based study and a systematic review of the literature. Chest 127: 1952–1959, 2005.[CrossRef][Web of Science][Medline]
  34. Trevisan M, Browne R, Ram M, Muti P, Freudenheim J, Carosella AM, Armstrong D. Correlates of markers of oxidative status in the general population. Am J Epidemiol 154: 348–356, 2001.[Abstract/Free Full Text]
  35. Weibel ER. Stereological Methods. New York: Academic, p. 9–196, 1979.
  36. Wittwer J, Hersberger M. The two faces of the 15-lipoxygenase in atherosclerosis. Prostaglandins Leukot Essent Fatty Acids 77: 67–77, 2007.[CrossRef][Web of Science][Medline]
  37. Young CG, Knight CA, Vickers KC, Westbrook D, Madamanchi NR, Runge MS, Ischiropoulos H, Ballinger SW. Differential effects of exercise on aortic mitochondria. Am J Physiol Heart Circ Physiol 288: H1683–H1689, 2005.[Abstract/Free Full Text]
  38. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258: 468–471, 1992.[Abstract/Free Full Text]




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