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Effects of Parenteral Fish-Oil Emulsion (Omegaven) on Cutaneous Wound Healing in Rats Treated With Dexamethasone
Arzu Gercek, MD*,
Ozlem Yildirim, MSc ,
Deniz Konya, MD ,
Suheyla Bozkurt, MD ,
Serdar Ozgen, MD,
Turker Kilic, MD,
Aydin Sav, MD and
Necmettin Pamir, MD
From the * Department of Anesthesiology and
Reanimation, Division of Molecular Biology,
Department of Neurosurgery, and
Department of Pathology, Institute of
Neurological Sciences, Marmara University, Maltepe, Istanbul, Turkey
Correspondence: Arzu Gercek, MD, Marmara University Institute of Neurological
Sciences, Anesthesiology and Reanimation, Yaliboyu cad Emanet sok Emek No:
2/28, Bostanci, Istanbul 34744, Turkey. Electronic mail may be sent to
arzugercek{at}yahoo.com.
Background: The aim was to assess wound healing when parenteral
fish-oil emulsion is given to rats receiving dexamethasone. Methods:
For 5 days after skin wounding, group S (control; n = 7) received saline 1
mL/kg intraperitoneal (IP); group D (n = 7), dexamethasone 0.2 mg/kg IP; and
group DO (n = 9), dexamethasone 0.2 mg/kg IP plus 1 mL/kg Omegaven (Fresenius
Kabi, Austria). Wound specimens were assessed for hydroxyproline level, wound
depth, histology (epidermal/dermal regeneration, granulation tissue thickness,
and angiogenesis), and expression of transforming growth factor-β
(TGF-β) and platelet-derived growth factor-AA (PDGF-AA).
Results: Compared with D and DO specimens, controls had higher
hydroxyproline (p < .01), deeper wounds (p < .05), and
better histologic scores (p < .01 angiogenesis; others p
< .05). There were no significant differences between the group D and DO
means for hydroxyproline level, wound depth, or histologic scores (p
> .05 for all). Controls had higher TGF-β expression scores than the
other groups (p < .01 for both) and a higher PDGF-AA expression
score than group DO (p < .01). Groups D and DO had statistically
similar TGF-β scores, but group D had a higher PDGF-AA score (2.71
± 0.75 vs 1.55 ± 0.72, respectively; p <
.05). Conclusions: According to the parameters we studied, adding
parenteral  -3 and -6 fatty acids to the nutrition regimen of
rats treated with dexamethasone does not seem to have adverse effects on wound
healing, and effects on wound healing may not need to be considered when
determining if these agents should be supplemented in nutrition support
regimens.
Wound healing is a complex programmed sequence of cellular and molecular
processes that includes inflammation, cell migration, angiogenesis, synthesis
of provisional matrix, collagen deposition, and
reepithelialization.1,2
The most important stage of wound healing is the initial inflammatory phase,
which is characterized by increased vascular permeability, cells undergoing
chemotaxis from circulation into the wound milieu, local release of cytokines
and growth factors, and migration of polymorphonuclear neutrophils and
monocytes.3
Corticosteroids have anti-inflammatory and immunosuppressive properties and
have been used to treat various diseases for >50 years. Studies have shown
that corticosteroids have negative effects on wound healing. Specifically,
they reduce inflammation, which, in turn, affects cell migration, cell
proliferation, and
angiogenesis.4 These
agents also decrease collagen
synthesis.5,6
Besides anti-inflammatory effects of -3 and -6 fatty acids,
it is presumed that they have immune enhancing benefits, (ie, -3 fatty
acids enhance cell-mediated
immunity,7 increase
resistance to
infection,8,9
but also inhibit platelet function and reduce
thrombosis10).
These data indicate that these fatty acids have potential clinical benefit for
patients undergoing treatment in intensive care. However, there are questions
about how these substances affect cutaneous wound
healing.2,11
Dexamethasone takes place at the treatment regimen of the patients with
acute adrenal
insufficiency,12
intracranial
pathology,13 spinal
cord compression,14
acute respiratory distress
syndrome,15
inflammatory bowel
disease,16 etc. It
was thought that anti-inflammatory and immunomodulatory effects of -3
and -6 fatty acids could also be beneficial for these
patients.17,18
Besides surgery, some of the wound types frequently seen in intensive care
units are trauma-related injury, catheter's site, tracheotomy, percutaneous
gastrostomy, and pressure sores. Delay in wound healing may result in
infection, bacteremia/sepsis, and second-time surgery. As a result of these
complications, patient's quality of life becomes poor, duration of
hospitalization gets longer, and financial cost is increased. Therefore, as
intensivists, we have to take wound healing into consideration where patients'
nutrition support regimens are concerned.
We postulate that adding parenteral fish oil (-3 and -6 fatty
acids) to the therapeutic regimen of patients receiving dexamethasone could
further delay cutaneous wound healing according to competing mechanisms of
action. In particular, we are interested to know whether including parenteral
fish-oil emulsion in these patients' nutrition protocol affects cutaneous
wound healing. The aim of this animal-model study was to assess wound healing
when rats treated with dexamethasone are also given parenteral fish-oil
emulsion.
 |
MATERIALS AND METHODS
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The experimental protocol was approved by the Animal Care and Use Committee
at Marmara University. Twenty-three adult male Sprague-Dawley rats weighing
approximately 250–300 g were housed 2 animals per cage at the Marmara
University Institute of Neurologic Sciences. They were fed a standard rodent
chow diet and water ad libitum and were kept at a constant
temperature (22°C) on 12-hour cycles of light and dark.
The rats were randomly allocated to 1 of 3 treatment groups:
Group S (saline-only control; n = 7): for 5 days after dorsal skin wounding
(method detailed below), each rat received a daily intraperitoneal (IP)
injection of 1 mL/kg physiologic saline.
Group D (dexamethasone only; n = 7): for 5 days after wounding, each rat
received a daily IP injection of 0.2 mg/kg dexamethasone (Dekort, Deva,
Turkey). Group DO (dexamethasone plus parenteral fish oil; n = 9): for 5 days
after wounding, each rat received a daily IP injection of 0.2 mg/kg
dexamethasone plus 1 mL/kg Omegaven (Fresenius Kabi Austria GmbH, Graz,
Austria; see formula for IV product below).
Wounding was carried out as described below, and all rats were killed by
decapitation 14 days later. At the time of death, an intracardiac blood sample
was collected and the animal's white blood cell count was recorded. Also, a
3x1-cm strip of skin was excised from the wound site on the dorsum, and
this piece was divided into 2 parts. A 2x1-cm portion was immersed in
phosphate-buffered formalin solution (PBS) and sent for histologic and
immunohistochemical analysis, and the remaining 1x1-cm portion was
freeze-dried, weighed, and stored at –169°C in liquid nitrogen until
hydroxyproline assay was carried out.
Cutaneous Wounding Technique
Each rat was anesthetized with an IP injection of ketamine 90 mg/kg and
then placed on a board in the prone position. The hair on the dorsum was
closely shaved with an electric razor, and the surgical field was disinfected
with povidone-iodine and draped with sterile towels. A dorsal-midline skin
incision approximately 3 cm long was made, exposing the muscular fascia. The
margins of this wound were then apposed with nonabsorbable interrupted
sutures.
Omegaven Formula
The Omegaven fish-oil emulsion used for the study was a 10% formulation.
One hundred milliliters of this product contains the following components:
eicosapentaenoic acid (1.25–2.82 g), docosahexaenoic acid
(1.44–3.09 g), myristic acid (0.1–0.6 g), palmitic acid
(0.25–1.0 g), palmitoleic acid (0.3–0.9 g), stearic acid
(0.05–0.2 g), oleic acid (0.6–1.3 g), linoleic acid (0.1–0.7
g), linolenic acid (<2 g), octadecatetraenoic acid (0.05–0.4 g),
eicosanoic acid (0.05–0.3 g), arachidonic acid (0.1–0.4 g),
docosanoic acid (<0.15 g), docosapentanoic acid (0.15–0.45 g),
D- -tocopherol (0.015–0.0296 g), glycerol (2.5 g), and
purified egg phosphatide (1.2 g). According to the manufacturer, the
osmolality of this emulsion is 308–376 mOsm/kg and the pH is
7.5–8.7.
Hydroxyproline Assay
The tissue samples for hydroxyproline assay were washed with physiologic
saline and dried in a 100°C oven for 72 hours. Hydroxyproline levels were
determined spectrophotometrically using the method described by
Woessner.19
Initially, each specimen was weighed and hydrolyzed in 12-N HCl at 130°C
for 3 hours. Then each sample was adjusted to a final volume of 1 mL and
centrifuged at 3000 x g for 15 minutes. The supernatant was
separated off and an equal volume of isopropanol was added. Then this mixture
was centrifuged at 2500 x g for 10 minutes. Serial dilutions of
pure hydroxyproline were used as standards, and the concentration of
hydroxyproline in each sample was calculated using the
absorbance-concentration curve for the standard hydroxyproline solutions.
Histology and Immunohistochemistry
The wound specimen from each rat was fixed in formalin and embedded in
paraffin. A microdermatome was used to cut five 5-µm sections from the
block and these were mounted on slides. The slides were placed in an oven at
60°C overnight and then deparaffinized in xylene and immersed in 10%
ethylenediaminetetraacetic acid (EDTA) buffer for 2 minutes.
Histologic Features
Two slides from each wound specimen were stained with hematoxylin-eosin,
rinsed in distilled water, and then dehydrated. For each specimen, the depth
of the wound was recorded and specific histologic features (epidermal and
dermal regeneration, granulation tissue thickness, degree of angiogenesis)
were scored. This scoring system is outlined in
Table I.
Immunohistochemical Analysis
Three slides from each specimen were used for immunohistochemical testing.
Endogenous peroxidase was quenched by submersing the sections in 3% hydrogen
peroxide in methanol for 20 minutes at room temperature. After a thorough
washing in PBS, blocking solution (Lab Vision Ultra V Block TA-125-UB; Santa
Cruz Biotechnologies, Santa Cruz, CA) was applied to block nonspecific
antibody binding. The sections were washed in PBS again and then incubated
with primary antibody (Santa Cruz Biotechnologies) diluted in PBS for 2 hours
at room temperature. After another thorough washing in PBS, the sections were
incubated with streptavidin peroxidase solution for 20 minutes at room
temperature. A final PBS washing was done, and the sections were incubated in
diaminobenzidine (Lab Vision DAB Substrate TA-125-HD; Santa Cruz
Biotechnologies) for 5 minutes at room temperature. They were then rinsed in
distilled water, counterstained with hematoxylin-eosin, rinsed in distilled
water again, dehydrated, and mounted.
Levels of expression of transforming growth factor (TGF)-β and
platelet-derived growth factor (PDGF)-AA were assessed semiquantitatively by a
blinded pathologist using a 5-point scale. In this system, a score of 0
indicated no staining at all, 1 indicated scattered staining in the dermis but
not in the epidermis, 2 indicated intense staining throughout the dermis but
none in the epidermis, 3 indicated intense staining throughout the dermis and
scattered staining in the epidermis, and 4 indicated intense staining
throughout both the dermis and epidermis.
Statistical Analysis
All data were evaluated in blinded fashion and expressed as mean ±
SD. Group data were statistically compared using one-way analysis of variance
(ANOVA). If a statistical difference was identified using ANOVA, Dunn's
multiple comparison test was performed. Probability values < .05 were
considered to indicate significant difference.
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RESULTS
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There were no significant differences among the mean white blood cell
counts in groups S (5.70 ± 1.95 cells/mm3), D (5.50 ±
2.50 cells/mm3), and DO (5.80 ± 2.00 cells/mm3;
p > .05). There were also no significant differences among the
groups with respect to mean percentages of neutrophils, lymphocytes, and
monocytes (p > .05 for all).
The mean hydroxyproline level in the specimens from group S (152 .85
± 6.36 µg/g) was significantly higher than the corresponding means
in groups D (99.25 ± 0.677 µg/g) and DO (99.78 ± 1.87
µg/g; p < .01 for both). There was no significant difference
between the mean hydroxyproline levels in groups D and DO (p >
.05).
The mean wound depth in group S (110.71 ± 9.90 µm) was
significantly greater than the mean depths in both other groups (102.14
± 17.52 µm in group D and 98.00 ± 12.12 µm in group DO;
p < .05 for both). There was no significant difference between the
mean depths in groups D and DO (p > .05).
Table II shows the results
for scoring of wound histologic features. Compared with group S, groups D and
DO had significantly lower mean scores for epidermal and dermal regeneration,
granulation tissue thickness, and angiogenesis. There was no significant
difference between the mean scores for epidermal and dermal regeneration,
granulation tissue thickness, and angiogenesis in groups D and DO (p
> .05).
Figures 1 and
2 show the results for
TGF-β and PDGF-AA expression in the wounds. The mean TGF-β score in
group S was significantly higher than that in group D (3.85 ± 0.37
vs 2.85 ± 0.37, respectively; p < .01); however,
the mean PDGF-AA score in group S was not significantly different from the
corresponding value in group D (3.00 ± 0.57 vs 2.71 ±
0.75, respectively; p > .05). The mean scores for TGF-β
expression and PDGF-AA expression in group S were both significantly higher
than the corresponding means in group DO (3.85 ± 0.37 vs 2.88
± 0.60, respectively, for TGF-β and 3.00 ± 0.57 vs
1.55 ± 0.72, respectively, for PDGF-AA; p < .01 for both).
There was no significant difference between the mean TGF-β scores in
groups D and DO (p > .05); however, the mean PDGF-AA score in
group D was significantly higher than the corresponding value in group DO
(2.71 ± 0.75 vs 1.55 ± 0.72, respectively; p
< .05).
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FIGURE 1. Immunoreactivity for TGF-β at 14 days after wounding. Note the
localization of this factor in the active granulation tissue in all groups and
the intense epidermal staining in group S (arrow A). A, Group S. B, Group D.
C, Group DO. Original magnification, 200x.
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View larger version (104K):
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FIGURE 2. Immunoreactivity for platelet-derived growth factor (PDGF)-AA at 14 days
after wounding. Note the localization of PDGF-AA in the active granulation
tissue in all groups. Also note the scattered epidermal staining in group D
(arrow B) and the intense epidermal staining in group S (arrow A). A, Group S.
B, Group D. C, Group DO. Original magnification, 200x.
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DISCUSSION
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Wound repair involves several main elements: growth factors, cell-cell and
cell-matrix interactions, and synthesis of extracellular matrix and collagen.
Healing of a clean surgical incision with approximated margins involves an
orchestrated sequence of events. After the injured tissue is infiltrated by
neutrophils, epithelial basal cells begin to show mitotic figures and
epithelial closure takes place within 24–48 hours. Granulation tissue
appears on day 3, and over the next few days the incision space fills with
this tissue. By day 5, revascularization is maximal, collagen fibrils begin to
appear, and epithelial proliferation
peaks.20 Collagen
continues to accumulate in week
2.21
The level of hydroxyproline in tissue is an indirect and objective
indicator of collagen
production.22
Hydroxyproline levels have been used to assess tissue collagen synthesis in
many experimental
studies.23,24
Corticosteroids are known to decrease collagen
synthesis.25,26
In our study, we observed no significant difference in the mean hydroxyproline
levels in wound tissues from groups D and DO, which indicates similar levels
of collagen synthesis. This result suggests that Omegaven had no additive
negative impact (ie, in addition to dexamethasone effects) on collagen
production.
As noted above, revascularization reaches maximum by the 5th day of wound
healing.20
Development of more mature capillary vessels near a wound allows for good
tissue nutrition and is directly related to better wound
healing.21 In our
study, histologic scoring revealed no significant difference between the
degrees of angiogenesis in the wound tissues from groups D and DO. This
indicates that Omegaven had no additive negative effect on revascularization
and vascular growth during wound healing.
Albina et al27
assessed how an -3 fatty acid-enriched diet affected wound healing in
rats. They compared results in groups of animals that were fed complete diets
that differed only in fat composition. The findings suggested that a diet rich
in -3 fatty acid might negatively affect quality of wound healing by
altering the fibroblastic or maturational phases. Other work by Cardoso et
al18 investigated
how topical administration of -3 and -6 essential fatty acids
affected wound closure in mice. Their results indicated that -3 fatty
acid treatment significantly delayed the wound closure process. Our results
conflict with the findings of these 2 studies as we observed no significant
differences between groups D and DO with respect to wound depth, epidermal and
dermal regeneration, granulation tissue thickness, or degree of
angiogenesis.
TGF-β and PDGF-AA are the most potent stimulators of
healing.28 In
addition to hydroxyproline levels and histology, we analyzed expression of
these growth factors in our wound-tissue specimens. TGF-β is produced by
platelets, T cells, endothelium, and macrophages. This factor is a growth
inhibitor that stimulates fibroblast chemotaxis, stimulates collagen
production, and inhibits collagen degradation. Thus, TGF-β promotes
fibrogenesis. It also deactivates macrophages. This factor is known to have a
stimulatory effect on dermal wound healing and has been implicated as the
primary causative agent in
fibrosis.29 Cromack
et al30 studied
TGF-β levels in subcutaneous wound chambers during the natural healing
process in rats. They aspirated material from these sites from day 3 through
day 16 after wounding and assessed TGF-β levels and cytology. Theirs was
the first study to show that tissue levels of TGF-β change throughout the
healing process. Specifically, the results revealed that tissue levels of
TGF-β on days 6 through 14 postwounding in rats were significantly higher
than baseline levels. The authors also found that TGF-β levels peaked
during the fibroblast proliferation and collagen synthesis phase of healing in
this species. Glucocorticoids such as dexamethasone normally inhibit wound
healing and are capable of antagonizing the fibrotic effect of
TGF-β.5,11
Further, Nakayama et
al31 showed that
low-dose eicosapentaenoic acid (an -6 polyunsaturated fatty acid)
inhibits the exaggerated growth of vascular smooth muscle cells in rats with
spontaneous hypertension and that it does so by suppressing TGF-β. We
observed no significant difference in staining intensity for TGF-β
between the wound specimens from group D and those from group DO.
PDGF-AA is released from platelets and is thought to have 2 main functions
in wound healing: to attract fibroblasts, neutrophils, monocytes and smooth
muscle cells (endothelial and intimal) to a clot and then induce proliferation
of these cells. In addition, PDGF-AA stimulates matrix metalloproteinase
production by fibroblasts and myofibroblasts. This enzyme leads to contraction
of matrix collagen and also potentiates vascular endothelial growth factor,
which causes budding of new capillaries in the wound
(angiogenesis).29
Thus, PDGF-AA has stimulatory effects on dermal wound healing through
promotion of angiogenesis, production of matrix, and collagenization. Kaminski
et al32
investigated mRNA expression of PDGF in mononuclear cells and granulocytes
in vivo in human volunteers who were prescribed a diet rich in
-3 fatty acids. They observed that dietary -3 fatty acids
down-regulated gene expression of PDGF-AA to 33% of normal and identified this
as the likely mechanism for the antifibrotic and antiatherosclerotic actions
of -3 fatty acids. In our study, group DO exhibited significantly lower
PDGF-AA expression than group D. Considered together, our immunohistochemical
results indicate that, compared with dexamethasone, Omegaven has more
significant negative impact on PDGF-AA expression than on TGF-β
expression.
In conclusion, we observed that adding parenteral fish-oil emulsion to the
nutrition regimen of rats treated with dexamethasone led to decreased
expression of PDGF-AA in experimental wound tissues. Otherwise, according to
hydroxyproline level, wound depth, histology (epidermal/dermal regeneration,
granulation tissue thickness, and angiogenesis), and expression of TGF-β,
the fish emulsion had no adverse effects on wound healing; that is, we
observed no aggravation of the dexamethasone effects. These results in rats
suggest that it may be safe to add -3 and -6 fatty acids to the
nutrition regimen of patients being treated with dexamethasone.
Received for publication August 8, 2006.
Accepted for publication November 21, 2006.
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161-166 (2007)
DOI: 10.1177/0148607107031003161
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MATERIALS AND METHODS
RESULTS