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Department of Foods and Nutrition and * Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506
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 • monocrotaline • rats • right ventricular hypertrophy • type II pneumocytes
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). After monocrotaline administration, progressive changes
occur, with initial vascular remodeling and increased pulmonary
arterial pressure that eventually leads to cardiac right ventricular
hypertrophy
(RVH).3
Alterations in the structure of the pulmonary vessel walls include
thickening of the medial layer from smooth muscle cell hyperplasia with
increased extracellular matrix in airways associated with the pulmonary
arteries and increased thickness of the adventitial layer because of
edema and mononuclear inflammatory cell infiltrate. Parenchymal changes
include reduced alveolar size, thickened alveolar septa and
accumulation of alveolar inflammatory cells, mainly macrophages
(Molteni et al. 1989
, Pan et al. 1993
).
Monocrotaline also targets the type II pneumocytes, reducing their
population by ~80% and producing a hypertrophic response in the
remaining cells (Wilson and Segall 1990
). The importance
of this is not yet fully understood. Typically, type II pneumocytes act
as stem cells that have proliferative capabilities and can
differentiate into type I cells in the event of lung injury. In
addition, type II pneumocytes produce and release surfactant, which is
composed of phospholipids and proteins that reduce the surface tension
of water lining the alveoli and enable respiration.
Retinol has been suggested to have a role in the development of lungs,
from the late prenatal period to adulthood (Zachman 1995
). An active metabolite, retinoic acid, is involved in cell
differentiation and in maintaining the integrity of lung epithelial
cells. Retinol deficiency has been associated with the development of
bronchopulmonary dysplasia, which results in the loss of ciliated cells
and squamous metaplasia of the epithelial cells (Zachman et al. 1992
). In preterm infants, vitamin A levels correlate inversely
with the development of lung disease, particularly respiratory distress
syndrome (Hustead et al. 1984
). In the adult rat model,
pretreatment with all-trans-retinol has limited the amount
of pulmonary damage caused by the pneumotoxin 1-nitronaphthalene, and
retinol provided protection by inhibiting the inflammatory responses
associated with the progression of the toxic-induced injury
(Sauer et al. 1995
).
Morbidity and mortality of monocrotaline-treated rats are known to
be linked with vascular pathology (Pan et al. 1993
).
Epithelial injury by monocrotaline, specifically the type II cells,
also has been established (Molteni et al. 1986
,
Wilson and Segall 1990
). In addition, oxidative stress
also is involved in the monocrotaline-induced vascular pathology
(Aziz et al. 1995
, Prescott et al. 1990
)
and possibly is related to parenchymal pathology. Retinol possesses
some antioxidant function (Livrea and Packer 1994
) and
anti-inflammatory properties (Sauer et al. 1995
),
maintains epithelial cells and is implicated in epithelial cell repair.
This study was conducted to test the hypothesis that dietary
supplemental retinol protects the heart and lung from
monocrotaline-induced injury.
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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.
Monocrotaline (Trans World Chemicals, Rockville, MD) was dissolved in 0.1 mol/L HCl and neutralized with 0.1 mol/L NaOH. Rats were fed their respective diets for 1 wk and then injected subcutaneously with 60 mg monocrotaline/kg body weight or its vehicle.
Rats, weighing 150–170 g, were distributed randomly into three groups.
One group (MC) was injected with monocrotaline and fed the control
AIN-93G diet (Reeves et al. 1993
). The purified diets
were purchase from Dyets (Bethlehem, PA). Another group (MR) was
injected with monocrotaline and fed the control diet supplemented with
retinol palmitate. Total retinol palmitate in the diet was 17 mg/kg
diet which was equivalent to 8 times the content of the AIN-93G diet or
13 times the National Research Council recommendation (NRC
1995
). The dose selected was ~3 times the amount that
Edes and Gysbers (1993)
used to prevent hepatic retinol
depletion induced by benzopyrene. The third group (VC) was injected
with the monocrotaline vehicle and fed the control diet. Food intake
and body weights were determined.
Heart measurements.
Four weeks after monocrotaline injections, the rats were anesthetized, killed, and the hearts were weighed. The right ventricle (RV) was separated from the left ventricle (LV) plus septal wall (S), and both parts were weighed to assess RVH.
Protein analyses and phospholipid content of lung lavage.
Lavage of lungs was performed according to the procedures described by
Baybutt et al. (1993)
. In brief, the lungs were washed
three times with 10 mL aliquots of sterile saline. The lavage wash was
spun at 500 x g for 5 min to remove cellular
debris. The supernatant was harvested and stored at -70°C.
Phospholipids were extracted (Bligh and Dyer 1959
) and
quantified by phosphate analysis (Ames 1966
). Protein
was determined according to the method of Bradford (1976)
. After the lungs were lavaged, the tissues were
collected for histopathological analysis.
Histopathology.
Following gross necropsy examination, 4 wk after monocrotaline treatment, left and right lung lobes and heart were fixed in 10% neutral buffered formalin and processed routinely for light microscopy. Tissues were dehydrated in increasing concentrations of ethanol (70–100%), paraffin embedded, sectioned to 4–6 µm and mounted on glass slides. The tissue sections were rehydrated and stained with hematoxylin and eosin and examined by light microscopy. Two animals per group were used to evaluate the tissues. The same anatomical location was used for the respective lung and heart tissues. For the lung analysis, four sections of the lung were used and random areas of the section were evaluated. We selected a representative sample on which to report our findings for each group.
Isolation and culture 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 Company, St. Louis, MO) and supplemented with 2% penicillin
(100 mU/L)/streptomycin(100 mg/L), 5% fetal bovine serum
(Intergen, Purchase NY), and 3H-choline (1
kBq/µmol, New England Nuclear, Dupont, Wilmington,
DE). Cell yield was measured and viability determined by Trypan Blue
exclusion. The cells were allowed to adhere to six-well Corning
culture plates kept at 5% CO2/95% air and 37°C for
~20–22 h. The cultured cells were washed three times, and surfactant
synthesis was determined (~24 h). Surfactant secretion was determined
after a 3-h incubation in plain DMEM (Baybutt et al. 1993
). The [3H]-labeled phosphatidylcholine was
extracted by the procedure of Folch et al. (1957)
and
measured. The extracted [3H]-labeled lipid was used as a
well-established measure of surfactant synthesis (Baybutt et al. 1993
, Dobbs et al. 1982
). Surfactant
secretion was expressed as the percentage of the radioactivity of
[3H]-labeled lipid recovered in the medium over the sum
of the radioactivity found in the cells plus the medium. The purity of
the type II cell populations was assessed by tannic acid staining under
a light phase microscope (Mason et al. 1985
).
Statistical analysis.
When appropriate, data were expressed as means ± SEM.
Statistical differences among means were considered significant when
P < 0.05. Treatment-dependent changes were
analyzed using one-way ANOVA combined with the Duncan's multiple
range test. For heart weights (Table 1)
and total lung lavage (Table 2)
, we established equality of variance using the Hartley's
F-max test. For the right ventricular hypertrophy data
[RV/(LV+S), Table 1
], Levine's test, which is insensitive to
nonnormality, indicated equal variances. This was followed by a
nonparametric test, rank transform test along with rank transform
multiple comparisons to determine differences among mean values. The
statistical tests were carried out using the Statistical Analysis
System software program (SAS/STAT User's Guide, 1989, version 6, SAS
Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Light microscopy revealed the normal appearance of thin alveolar septa
with flattened lining epithelium in the VC group. The alveoli were also
clear of inflammatory exudate and proteinaceous fluid (Fig. 1A
). In the MC group, the injury was demonstrated by markedly
thickened alveolar septa with infiltrates of numerous mixed mononuclear
inflammatory cells and hyperplastic lining epithelium with increased
number of pulmonary arterioles (Fig. 1
B). The pulmonary
arterioles had walls thickened by medial smooth muscle hypertrophy that
obscured the vascular lumen. The alveoli were collapsed but clear of
inflammatory exudate and proteinaceous fluid. In the MR group, mild
thickening of the alveolar septa was visible with occasional mixed
mononuclear cells (Fig. 1
C). The alveoli were lined by
normal flattened epithelium and were clear of inflammatory exudate and
proteinaceous fluid. There were a greater number of arterioles observed
in the MC vs. the MR group.
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). The tunica media and adventitia displayed typical thickness with
adjacent thin alveolar septa and alveoli. The lungs from the MC group
had pulmonary arteritis (Fig. 2
B) with a tunica media
markedly thickened by medial smooth muscle hypertrophy. Foci of medial
necrosis and mixed mononuclear cell infiltrates were clearly evident.
The tunica adventitia was thickened with fibrosis and mixed mononuclear
inflammatory cell infiltrates that compressed and collapsed the
adjacent alveoli with thickened septa. The lungs from the MR group had
pulmonary arteries with a tunica media thickened by medial smooth
muscle hypertrophy. There was no evidence of the arteritis in the MR
group as was observed with monocrotaline alone (Fig. 2
C).
The tunica adventitia had normal thickness and was differentiated
easily from adjacent normal alveolar septa and alveoli.
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). Hearts from the MC group exhibited multiple foci of
myocardiocyte degeneration and necrosis along with increased connective
tissue stroma and infiltrates of mixed mononuclear inflammatory cells
in the interstitium (Fig. 3
B). The morphologic appearances
of myocardium from the MR group were improved, showing scattered foci
of only mild myocardiocyte degeneration, a mild increase in the
endomysial connective tissue and fewer mononuclear inflammatory cell
infiltrates than myocardial sections from the MC group (Fig. 3
C).
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). Retinol did not appear to alter the hypertensive response to
monocrotaline as indicated by the thickened arterial walls (Fig. 2
C) and unaffected RVH (Table 1)
.
To explore the monocrotaline toxicity at the level of cellular function
of the parenchyma, we isolated and cultured type II pneumocytes and
determined surfactant regulation. Lung lavage phospholipid content was
not significantly different among the VC, MC and MR groups (Table 2
). However, surfactant synthesis was significantly greater in the MC and
MR groups compared with the VC group. There was no difference in
surfactant synthesis between the MC and MR groups. Surfactant secretion
was significantly greater in the MC group compared with the VC group.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The beneficial effects of retinol were noted by using a high dose of
dietary retinol palmitate (17 mg/kg diet). The dose selected was ~3
times the amount that was used to prevent benzopyrene-induced
hepatic deficiency of vitamin A (Edes and Gysbers 1993
).
We did not observe any signs of toxicity (weight loss and exudate
around the eyes) throughout the 4-wk experiments. The observation that
the rat is resistant to retinol toxicity (Lotspeich and McCumbee 1987
) enabled us to use a high dose of retinol to evaluate its
effectiveness in protecting against the monocrotaline-induced
injury. The dose was effective in reducing injury in the heart and
lungs of monocrotaline-treated rats.
Monocrotaline increases inflammation in the lung, which is connected
with the oxidative generation of eicosanoids by inflammatory cells of
the alveoli (Stenmark et al. 1985
), synthesis of
platelet-activating factor (Ono and Voelkel 1991
)
and release of free radicals from polymorphonuclear leukocytes
(Prescott et al. 1990
). We recently have observed
protective effects of ß-carotene against the inflammatory response to
monocrotaline (Baybutt et al. 1998
). When rats were fed
the standard AIN93G diet with 52 mg ß-carotene/kg diet as their
source for vitamin A, the inflammatory response to monocrotaline was
abolished in the lung parenchyma. Nevertheless, the arteriolar walls
remained hypertrophied and the cardiac right ventricle was enlarged,
indicating that the pulmonary pressure was not reduced significantly,
similar to what we observed with retinol supplementation in this study.
The observed effects of ß-carotene likely were due to retinol,
because much of the ingested ß-carotene is converted to retinol in
the rat intestine (Wang 1994
). Dietary retinol used in
this study decreased the inflammatory responses within the alveolar
septa, the vasculature and the cardiac tissue, indicating a common
anti-inflammatory effect of retinol on the response to
monocrotaline toxicity. A similar anti-inflammatory role for
vitamin A was recently reported (Redlich et al. 1998
) in
which vitamin A reduced lung inflammation after thoracic radiation. In
addition, other studies have shown that high doses of retinol are
anti-inflammatory in the lung of rats treated with
1-nitronaphthalene (Sauer et al. 1995
) and bleomycin
(Habib et al. 1993
).
At present, the precise mechanism underlying the anti-inflammatory
effect of retinol is not known. However, one possible mechanism may
involve the neutrophil, an important mediator and promoter of
inflammation. Retinol has been shown to moderate the activity of the
neutrophil in a number of different ways. Retinol inhibits the release
of the superoxide anion (the oxygen free radical) that initiates the
inflammatory response (Camisa et al. 1982
, Sharma et al. 1990
). In addition, retinol inhibits the conversion of
arachidonic acid to leukotriene B4
(Randall et al. 1987
), which acts as a chemoattractant,
amplifying the inflammatory response through recruitment of other
neutrophils. Consistent with such a role of retinol, vitamin A
deficiency in rats resulted in a 43% increase in leukocytes, over half
of which were neutrophils (Wiedermann et al. 1996
).
Also, vitamin A–deficient mice exhibited an enhanced inflammatory
response to ozone (Paquette et al. 1996
). Some
investigators have found that inflammation accelerates depletion of
lung retinol, resulting in a localized deficiency (Kanda et al. 1990
). Dietary supplemental vitamin A may help prevent the
localized deficiency, thereby blunting the response of the neutrophils
and other inflammatory cells. The biochemical and cellular observations
cited above clearly suggest that retinol plays a critical role in
suppressing inflammatory responses. This suggestion is supported
further by the marked reduction in inflammation in both heart and lung
by dietary supplemental retinol observed in this study. Our finding is
the first to demonstrate histologically the anti-inflammatory
action of retinol in these tissues.
Despite its anti-inflammatory effect, supplemental dietary retinol
did not appear to alter function of the type II pneumocytes. It has
been demonstrated previously that there is a significant decrease in
the number of type II pneumocytes in the lungs of
monocrotaline-treated rats (Wilson and Segall 1990
).
Nevertheless, the amount of surfactant phospholipid recovered in the
lung lavage did not differ between monocrotaline-treated rats and
controls (Bummer et al. 1994
). Thus, the surviving type
II pneumocytes must compensate for the insufficient number of cells by
augmenting production and secretion of surfactant. Our data provide the
first evidence for this compensatory increase in surfactant
availability by the type II pneumocyte. Using isolated pneumocytes from
monocrotaline-treated rats, we observed an increase in cellular
production and secretion of surfactant in response to monocrotaline.
Additional dietary retinol in monocrotaline-treated rats did not
return surfactant production to control levels, suggesting that
supplemental retinol does not specifically affect the
monocrotaline-altered secretory function of the type II pneumocyte.
In conclusion, results of this study show that retinol supplementation mitigates monocrotaline injury to the lung and heart by decreasing the inflammatory response without correcting the cardiac right ventricular hypertrophy. Such an effect of supplemental retinol may prove to be significant in maintaining the structural integrity of the heart and lung when exposed to chemical injury. The noticeable anti-inflammatory effects of retinol, as observed by us and others, warrant further investigation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DMEM, Dulbecco's modified
Eagle's medium; LV, left ventricle; MC, monocrotaline control; MR,
monocrotaline with supplemented retinol; RV, right ventricle;
RV/(LV+S), right ventricle divided by the sum of the left ventricle
plus septal wall; RVH, right ventricular hypertrophy; S, septal wall;
VC, vehicle control.
Manuscript received December 3, 1998. Initial review completed February 22, 1999. Revision accepted April 5, 1999.
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