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Department of Human Nutrition, Kansas State University, Manhattan, KS 66506 and * Department of Pathology and Pharmacology, University of Missouri, Kansas City, MO 64108
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • retinol deficiency • emphysema • rats • inflammation • pneumocyte function
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Several studies have defined the role of vitamin A in
the tracheal epithelial cells (Klann and Marchok 1982
,
Lancillotti et al. 1992
, McDowell et al. 1984
and 1987
), suggesting that regeneration of the tracheal epithelium
after injury requires vitamin A–dependent mucous cell proliferation.
In vitamin A–deficient rats, the proliferation of these mucous cells
is inhibited, which leads to the development of a pathologic condition
called squamous metaplasia (Lancillotti et al. 1992
,
McDowell et al. 1984
and 1987
). Little information is
available on the effect of vitamin A deficiency in distal epithelial
cells and the resulting tissue pathologies.
In cultured tracheal cells, retinoic acid
(RA),3
an active metabolite of vitamin A, stimulated cell growth and
proliferation (Klann and Marchok 1982
,
Lancillotti et al. 1992
). Less information is available
concerning the role of vitamin A in the alveolar epithelium, the distal
epithelial cells of the lung. The mechanism responsible for maintaining
alveolar integrity stems in part from vitamin A–directed proliferation
of type II pneumocytes in response to injury (Takahashi et al. 1993
). When type II pneumocytes are cultured, RA stimulates
both cell proliferation (Nabeyrat et al. 1998
) and
polyamine synthesis (Heger and Baybutt 1999
). Polyamines
are organic polycations necessary for cell proliferation (Pegg 1986
).
The type II pneumocyte plays a critical role in the lung by producing surfactant, a mixture of phospholipids and protein that reduces surface tension in the air spaces and maintains alveolar patency. Additionally, the type II cell serves as a progenitor for the type I pneumocyte, which is the major resident of the alveolar wall and is therefore important for normal lung maintenance. In lung injury, precise regulation of type II pneumocyte functions is critical because their proliferation and differentiation into type I cells are necessary for repair of the injury.
The purpose of this study was to determine the effect of vitamin A deficiency on lung tissue morphology and on type II pneumocyte function. To evaluate the effect of vitamin A deficiency on the two important functions of the type II pneumocyte, maintaining alveolar patency and lung cell repair, we measured surfactant synthesis and ornithine decarboxylase (ODC) activity, respectively. Ornithine decarboxylase is the initial rate-limiting enzyme for synthesis of polyamines (a marker for cell growth and differentiation). Because the majority of vitamin A is stored in the liver, we also evaluated the histologic appearance of livers from vitamin A–deficient rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) were housed in stainless steel cages at ~24°C with a 12-h light:dark cycle. Animal care and use were approved by the Institutional Animal Care and Use Committee of Kansas State University. Rats were cared for in an animal facility approved by the American Association for the Advancement of Laboratory Animal Care.
Male weanling rats (35–40 g) were assigned randomly to two groups. The
vitamin A–adequate (control) group was fed the standard AIN-93G diet
(Reeves et al. 1993
), and the vitamin A–deficient group
was fed the standard AIN-93G diet without vitamin A. The rats were fed
ad libitum and the purified diets were purchased from Dyets Inc.
(Bethlehem, PA). Food intake and body weights were determined. The rats
were fed the vitamin A–adequate or –deficient diet for 6 wk. The rats
were anesthetized and blood was collected from the abdominal aorta. The
rats were killed by exsanguination.
Organ collection for histologic studies.
Liver and lungs were collected for chemical and histologic studies. The right lung from each rat was inflated with 10% buffered formalin and then placed in the same solution and fixed for 1 wk. Sagittal sections were embedded in paraffin, and 4-µm thick sections were stained by hematoxylin and eosin for light microscopy. Masson’s trichrome staining for collagen and Weigert’s staining for elastin were performed on representative samples from rats from each group.
A lobe of liver from each rat also was collected at necropsy, immediately placed in 10% buffered formalin and fixed for 1 wk. Hematoxylin and eosin and Masson’s trichrome staining were performed on 4-µm thick sections of this tissue.
Semiquantitative evaluation of lung damage.
A semiquantitative evaluation of the histologic damage to the lung
induced by vitamin A deficiency was accomplished by scoring its degree
of severity according to previously published methods (Baybutt and Molteni 1999
, Cohen et al. 1996
). The scorer
was unaware of the treatment. The presence and the degree of alveolar
and bronchial inflammation, the presence and extent of collagen
deposition in the septal walls, the presence and severity of emphysema
and the extent of elastin deposition were evaluated by the scorer by
subjective comparisons with the normal tissue. The changes were
quantified by scores ranging from "10" (presence of inflammation,
collagen, emphysema or elastin) to "40" (extensive amounts of
inflammation, collagen, emphysema or elastin). A score of "5"
indicated that there were some areas of the sections with the specific
parameter and some without. Tissue with normal appearance or no
detectable amounts of elastin/collagen received a score of 0. The
assigned values for each group of treated rats were averaged.
Analysis of retinol content of tissues.
Serum, liver, lung and type II pneumocytes were analyzed for total
retinol contents. For retinol measurements of serum and type II
pneumocytes, 100 µL of serum or cell suspension (1–2
x 109 cells/L) was saponified with 10 vol of KOH
solution (95% ethanol, 5% KOH and 1% pyrogallol) at 60°C for 20
min. The samples were cooled to room temperature and washed in 20 vol
of hexane and 10 vol of deionized water. The upper hexane layer was
collected and all-trans-retinyl acetate (Sigma Chemical,
St. Louis, MO) in methanol was added as an internal standard (100
µL). The solvent was evaporated under N2
and the sample dissolved in 200 µL of methanol before
retinol analysis by HPLC according to the method of Ross (1986)
.
For tissue analysis of retinol contents, minced whole liver (600 mg)
and minced lung (200 mg) were extracted by the method of Folch et al. (1957)
. Final lipid extract volume was 5 mL. An aliquot
of the lipid extract (100 µL) was saponified and
prepared for HPLC analysis as described above.
The concentration of retinol was determined using a reverse-phase
HPLC column (Alltima C18, 5 µm, 4.6 x 150 mm,
Alltech Associates, Deerfield, IL) and Beckman System Gold software
(Beckman Instruments, Fullerton CA) according to a previously published
procedure (May and Koo 1989
). Methanol/water (99:1) was
used as the mobile phase with a flow rate of 1 mL/min. Detection was
monitored at 325 nm (Model 166, Beckman Instruments, San Ramon, CA).
Under these conditions, retinol and retinyl acetate were eluted at
~3.5 and 4.7 min., respectively. The linear range was from 0.17 to
0.87 nmol. The average percentage of recovery for the internal standard
was 97% (liver), 98% (lung), 93% (serum) and 98% (type II
pneumocytes).
Biochemical analysis of serum.
The following analytes relevant to the rats’ general metabolic state were measured from serum collected at the time of killing. We used a Dade Dimension XL analytical instrument (Dade Chemistry Systems, Newark, DE) to measure total bilirubin, cholesterol, alkaline phosphatase, alanine aminotransferase, aspartic transaminase, albumin, blood urea nitrogen, lactate dehydrogenase, creatinine and triglycerides.
Isolation of type II pneumonocytes.
Isolation of type II pneumocytes was carried out according to the
procedure of Dobbs et al. (1986)
for each group. Cells
were resuspended in Dulbecco’s modified Eagle’s medium (DMEM; Fisher
Scientific, St. Louis, MO), and the freshly isolated cells were used to
determine surfactant synthesis or ODC activity. Cell yield was measured
and viability determined by trypan blue exclusion. The purity of the
type II cell populations of our isolation procedure was assessed by
tannic acid staining under a light-phase microscope (Mason et al. 1985
). Purity and viability were typically ~90%.
Surfactant phospholipid synthesis.
The freshly isolated cells in serum-free DMEM were distributed into
15-mL sterile plastic tubes with screw caps (Falcon, Becton, Dickinson,
Franklin Lakes, NJ). Cell suspension (1 mL) was pipetted into each tube
at a concentration of 2 x 106 cells/mL, and
3H-choline (37kBq/µmol, New England
Nuclear, Dupont, Wilmington, DE) was added to each tube. With screw
caps loosened, the tubes were incubated in an environment of 5%
CO2/95% air at 37°C for various lengths of time. The
cells were harvested at 0, 1, 4 and 24 h to determine surfactant
phospholipid (PL) synthesis. Surfactant synthesis was determined by
previously published methods (Baybutt et al. 1993
). The
[3H]-labeled phosphatidylcholine (PC) was extracted by
the procedure of Folch et al. (1957)
, and the extracted
labeled lipid was used as a well-established measure of surfactant
synthesis (Baybutt et al. 1993
, Dobbs et al. 1982
). Radioactivity was measured using 2 mL of scintillation
cocktail (ScintiVerse, SX18–4, Fisher Scientific, Fairlawn, NJ) and a
Beckman LS 8000 (Beckman Instruments, Fullerton, CA) scintillation
counter. Surfactant PL synthesis was expressed as pmol labeled
lipid/106 cells.
ODC assay.
Activity of ODC enzyme was determined using methods previously
described (Heger and Baybutt 1999
). The ODC assay buffer
was prepared (50 mmol/L Tris buffer + 0.1 mmol/L EDTA, 100 mmol/L
dithiothreitol, 2 mmol/L pyridoxal phosphate, 500 µmol/L
phenylmethylsulfonyl fluoride, 30% solution Brij 35, 500
mmol/L NaF). Freshly isolated cells (~2 x 106) were
harvested with 0.6 mL of ODC assay buffer. The cell suspension was
vortexed, the extract was centrifuged at 45,000 x g, and the resulting supernatant of soluble protein was
assayed for ODC activity. Each sample was tested in triplicate. The
extract was incubated with 20 µL of
[14C]ornithine cocktail (92.5 Bq
[14C]ornithine, 5 mmol/L ornithine, distilled water).
During the 2-h incubation at 37°C, the released
14CO2 was captured by a filter paper spotted
with 2 mol/L NaOH and located in a center well suspended above the
enzyme reaction mixture. Released 14CO2 was
measured after placing the filter paper in 2 mL of ScintiVerse and
counted in a Beckman LS 8000 scintillation counter. Enzyme activity was
expressed as pmol/(min·106 cells).
Statistical analysis.
When appropriate, data were expressed as means ± SEM. Statistical differences among means were considered significant at P < 0.05. Treatment- and time-dependent differences were analyzed using the t test in the statistical program PSI-Plot Version 5.50a for Windows (Poly Software International, Sandy, UT).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). There was also no difference in body weight between the two groups
throughout the experiment (Fig. 2
).
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). The concentration of retinol in the liver and lung of vitamin
A–deficient rats was 61 and 49% less than in controls, respectively.
The concentration of vitamin A in the type II pneumocyte was 22% less
than in controls.
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Representative sections of the lungs of rats fed both diets are shown
in Figure 3
. The lungs of control rats (Fig. 3A
) did not show any
significant pathology, and only at a larger magnification were a few
red cells and a few inflammatory cells (mostly polymorphonucleated
neutrophils) seen in the lumen of some alveoli as well as in the septa
forming the alveolar walls. Some minimal thickening of a few of these
septa also was observed.
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and
C); some areas show marked and extensive thinning of the
alveolar septa with disappearance of the parenchyma, so that emphysema
(increased size of air spaces distal to the terminal bronchiole, with
thinning and partial or total destruction of septal wall) becomes
prominent (Fig. 3B
), whereas the salient feature in other
areas is the presence of a severe interstitial pneumonitis (Fig. 3C
), with thickening of the alveolar walls and infiltration
of inflammatory cells. An inflammatory process is also evident in many
small bronchi, which also show a partial disepithelization. There was
thinning of the septal walls, the merging of the alveoli and septal
thickening with the prominent infiltration of mostly chronic
inflammatory cells.
Trichrome staining showed more collagen in the lungs of rats fed a
vitamin A–deficient diet. Essentially all of the increased collagen
was found in the areas of interstitial pneumonitis with the virtual
disappearance of collagen in the emphysematous areas. Peribronchial
collagen was present in a normal amount even in the rats fed vitamin
A–deficient diets. The same rats also had a lower content of elastin,
especially in the lung arteries. Semiquantitative evaluations of the
histologic changes of the lung are summarized in Table 2
. For the histologic analysis, there was either no within-treatment
variation or that variation was contributed by only one or two samples
in the control group; therefore, a statistical analysis was not
appropriate to evaluate these data. However, differences in averages
between the vitamin A–deficient and –adequate rats were quite evident
for all of the variables listed.
|
). No notable histologic changes from the normal appearance of the liver
were seen in the controls (Fig. 4A
).
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). The lower rate (P < 0.05) of synthesis was evident
as early as 1 h and persisted to 24 h. The ODC activity also
was significantly lower (P < 0.05, n = 6) in the type II pneumocytes of vitamin A–deficient rats [0.09
± 0.017 pmol/(min x 106 cells)]
compared with the controls [0.12 ± 0.011 pmol/(min x
106 cells)].
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To our knowledge, this is the first time that lung histologic data have
been presented to show that vitamin A deficiency results in emphysemic
lungs. The development of emphysema observed in the lungs of vitamin
A–deficient rats is consistent with previous reports. Emphysema is
characterized by a decreased number of alveoli due to the thinning and
destruction of the septal wall, creating larger air spaces in the
lungs. In an elastase-induced model of emphysema in rats,
Massaro and Massaro (1997)
found that development of
emphysema could be prevented by administration of
all-trans-retinoic acid. In addition, these investigators
found that postnatal treatment with RA increased the number of alveoli
relative to those in the lungs of control rats (Massaro and Massaro 1996
).
Cigarette smoking is known to increase the risk for developing
emphysema. Edes and Gysbers (1993)
reported that feeding
rats benzopyrene, a constituent in cigarette smoke, induced lower
levels of vitamin A in the lungs and liver. Our results show that
vitamin A deficiency per se induces emphysema; therefore, the emphysema
resulting from cigarette smoke could be the result of a localized
vitamin A deficiency of the lungs.
Another characteristic of emphysema is a decreased elastic recoil after
exhalation because of a decrease in the amount of the matrix protein
elastin. We detected fewer elastic fibers in the lungs of vitamin
A–deficient young rats (Table 2)
. Decreased elastin staining also was
observed in the lungs of rat fetuses from vitamin A–deficient mothers
(Antipatis et al. 1998
). This decrease was paralleled by
decreased mRNA content for elastin in the fetal lung. In contrast, the
levels of RA, RA receptor and cellular retinol binding protein mRNA
were highest in lung interstitial fibroblasts during the time of
maximal elastin synthesis, when extensive enlargement of the alveolar
surface area occurred (McGowan et al. 1995
).
Furthermore, RA has been found to stimulate elastin synthesis in chick
embryonic fibroblasts, increasing both elastin mRNA and protein
(Tajima et al. 1997
). The increased elastin synthesis
appears to be specific to RA, because retinol failed to increase
elastin mRNA levels. The decrease in lung content of elastin in vitamin
A–deficient rats likely was due to a decrease in production rather
than increased degradation because vitamin A deficiency does not
significantly alter neutrophil elastase activity (Twining et al. 1996
).
Vitamin A is known to preserve and maintain the integrity of the lung
epithelium (Takahashi et al. 1993
). During lung
epithelial cell injury, the type II pneumocyte proliferates and then
differentiates into a type I pneumocyte that replaces the injured cell
and restores the alveoli. Vitamin A is thought to be necessary for this
process. The precise mechanism of action of vitamin A is not known, but
RA and polyamines appear to be involved. Retinoic acid prevented the
decreased number of alveoli in elastase-induced emphysema
(Massaro and Massaro 1997
) and increased the number of
alveoli when administered postnatally (Massaro and Massaro 1996
). Furthermore, in cultured type II pneumocytes, we found
that RA increased the activity of ODC, the rate-limiting enzyme in
the synthesis of polyamines (Heger and Baybutt 1999
).
Vitamin A not only affects cellular polyamine content, but also
initiates cell proliferation of type II pneumocytes (Nabeyrat et al. 1998
). In contrast, vitamin A deficiency prevents the
increased pneumocyte proliferation in ozone-treated rats
(Takahashi et al. 1993
). In this study, we found that
the lungs of vitamin A–deficient rats had fewer alveoli as indicated
by the areas of emphysema. This coincided with a decreased ODC activity
in the type II pneumocytes, and is reported for the first time. These
results also are consistent with others that found slightly decreased
ODC activity in the whole lungs of rats fed a vitamin A–deficient diet
(Savoure et al. 1993
).
The type II pneumocyte not only serves to maintain lung epithelial
cells, but also provides surfactant to reduce surface tension of the
water lining the alveoli and enabling respiration. Vitamin A appears to
play an important role in regulating surfactant synthesis. When
pregnant rats were administered either retinyl palmitate or RA, fetal
surfactant PL was increased (Fraslon and Bourbon, 1994
).
With vitamin A deficiency, however, bronchoalveolar lavage PL content
was decreased (Iakovleva et al. 1987
). In addition, in
this study, we observed that PC synthesis was reduced significantly in
freshly isolated cells from vitamin A–deficient rats.
The other lesion detected in the lungs of vitamin A–deficient rats was
interstitial pneumonitis. We demonstrated previously that both vitamin
A and ß-carotene prevented inflammation when rats were administered
monocrotaline (MCT), a proinflammatory pneumotoxin and hepatotoxin
(Baybutt and Molteni 1999
, Swamidas et al. 1999
). We also found significantly lower vitamin A levels in
the lungs and liver of MCT-treated rats (data not shown). In
addition, vitamin A has been shown to prevent inflammation in
irradiated rat lungs (Redlich et al. 1998
) and in lungs
treated with either 1-nitronaphthalene (Sauer et al. 1995
) or bleomycin (Habib et al. 1993
).
The role of vitamin A in preventing inflammation is related in part to
its interaction with the leukocytes. Inflammation occurs in the
microcirculation and can be characterized by the movement of fluid and
leukocytes from the blood to the extravascular tissue. Vitamin A
appears to be most effective against the most prevalent proinflammatory
leukocyte, the neutrophil. There are several mechanisms for the
anti-inflammatory role of vitamin A, including inhibition of
neutrophil superoxide anion production (Camisa et al. 1982
, Sharma et al. 1990
), decreased release of
lysosomal enzymes by neutrophils (Camisa et al. 1982
)
and decreased synthesis of leukotriene B4, a
chemoattractant for neutrophils (Randall et al. 1987
).
In contrast, in vitamin A deficiency, circulating leukocytes are
increased (Wiedermann et al. 1996
) and ozone-induced
inflammation exacerbated (Paquette et al. 1996
). In this
study, we found that vitamin A deficiency induced inflammation in the
distal airways of lungs of rats apart from a proinflammatory agent.
Numerous vacuoles of the hepatocytes were observed in the liver of
vitamin A–deficient rats. Such vacuolization often is considered an
index of steatosis. Azais-Braesco et al. (1997)
reported
that steatosis and portal inflammation also were observed in
3,4,3',4'-tetrachlorobiphenyl–treated rats; these rats had
significantly lower vitamin A content in their livers. In a previous
study, we also noticed hepatocyte vacuole formation in MCT-treated
rats that was not observed when the rats were fed the standard AIN93G
diet supplemented with provitamin A, ß-carotene, along with MCT
(Baybutt and Molteni 1999
). Similar vacuole formation
has been noted in vitamin A–deficient livers of both alcoholic humans
and alcohol-treated rats (Leo et al. 1983
).
In conclusion, results of this study show that vitamin A deficiency induced emphysema and inflammation in the lungs and vacuole formation in the hepatocytes of rats. Surfactant synthesis and ornithine decarboxylase activity were significantly lower in type II pneumocytes isolated from vitamin A–deficient rats. These findings underscore the important role of vitamin A in maintaining lung and liver parenchyma and functioning of the type II pneumocytes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DMEM, Dulbecco’s modified
Eagle’s medium; MCT, monocrotaline; ODC, ornithine decarboxylase; PC,
phosphatidylcholine; PL, phospholipid; RA, retinoic acid.
Manuscript received November 1, 1999. Initial review completed December 10, 1999. Revision accepted February 7, 2000.
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