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,2
3
Discipline of Nutrition & Dietetics, Faculty of Medicine & Health Sciences, University of Newcastle, Callaghan, NSW 2308, Australia, and
Centre for Clinical Epidemiology & Biostatistics, Faculty of Medicine & Health Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • EPA • DHA • Lew • SSN rats • arthritis • dietary fat
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). This immunopotentiating activity
results from type-A bacterial species. The gram-positive
bacterial cell walls consist of peptidoglycan linked covalently to a
complex carbohydrate heteropolymer referred to as a peptidoglycan
polysaccharide complex (PG-PS) which is poorly degraded, persisting in
tissue for long periods of time.
Cromartie et al. (1977)
initially developed this model of streptococcal
cell wall (SCW) polymers and described it as the development of acute
erythema with swelling in peripheral joints, 24-h post-systemic
injection. This reaction peaked in severity at 3 d, then subsided.
Fourteen to 28 d later, a chronic phase of swelling developed that
persisted for months and ultimately destroyed the more severely
involved joints.
Diet-induced changes in tissue fatty acid composition may modify
inflammatory reactions. For example, in vitro studies have shown that
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) inhibit a
number of lymphocyte functions (Calder, 1997
). In vivo
studies in laboratory animals utilizing diets rich in (n-3)
polyunsaturated fatty acids (PUFA) (linseed, canola, fish oil) result
in suppressed lymphocyte proliferation and activity (Calder et al. 1995
). Direct comparisons of the effects of diets rich in
(n-3) fatty acids indicate that fish oil is more suppressive than
linseed or canola oil and (n-6) PUFA-rich diets appear to be less
suppressive than those containing (n-3) PUFA (Mantzioris et al. 1994
). Meta-analysis of clinical studies in rheumatoid
arthritis (RA) (James and Cleland 1997
) has shown that
fish oil has moderate therapeutic effects when given in large
quantities. Thus optimization of (n-3) PUFA treatment is essential for
the improvement of the efficacy of this treatment: for improvement in
compliance and to make it more practical.
There is little information concerning which (n-3) PUFA (EPA or DHA) is
immunosuppressive, or how much (n-3) PUFA in relation to (n-6) PUFA is
necessary to bring about these effects (Jeffery et al. 1997
). Thus, in this study, the effect of two diets with
different ratios of EPA and DHA were compared and contrasted with beef
tallow (BT)- and safflower oil (SFO)-based diets. We investigated the
effect of prefeeding these diets to weanling rats (prior to the
induction of arthritis) on plasma total fatty acids, plasma
phospholipids and macrophage phospholipids. We also investigated the
effects of the induced synovitis on hock circumference and footpad
thickness as evidence of inflammation and histological changes in hock
sections as evidence of arthritic activity in joints.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Weanling female (SPF) Lew/SSN rats (albino, a,h,c:RT1l) aged 3 wk, weighing between 30 to 50 g were obtained from the Animal Resources Center (Perth, WA, Australia). The rats were housed at the Faculty of Medicine and Health Sciences, University of Newcastle, in polypropylene cages with stainless steel wire tops for a period of 5 wk prior to induction of arthritis and then a further 5-wk post-induction (to observe the acute, chronic and remittive phases of the induced arthritis). The rats were housed individually in an open system with recycled paper-based bedding (Fibercycle, Mudgeerba, Australia) which was changed twice weekly. Free access to autoclaved water was provided via elongated waterspouts, and experimental diets were placed in special containers on the cage floor. Relative humidity ranged between 45 and 55% (humidity was measured but not regulated in the Medical Science Building animal facility). The environmental conditions included 23–25°C, (regulated at 23°C prior to arthritis induction and 25°C post-induction) 12:12 h artificial photoperiod and housing, handling, pain management and sample collection procedures conformed to the policies and recommendations of the University of Newcastle’s Animal Care and Ethics Committee.
Diets.
The four experimental diets were derived from a semipurified 20% corn
oil diet (without the corn oil) (Cat. No. 960245; ICN Nutritional
Biochemical Cleveland, OH). Each diet contained 200 g · kg
-1 lipid mixture to provide diets predominantly either BT
or SFO or DHA and EPA, BT and SFO were used as control diets.
(Table 1
). Proportions of the basal diet components and oil combinations used in
the ICN semipurified diet are listed in Table 2
. Formulation of these diets followed the protocol set out by the Ad Hoc
Committee (1977)
and Reeve et al. (1993)
. All diets were standardized
to contain 600 mg · kg–1 (racemic mix of RRR and SRR
isomers) 
-tocopherol acetate (ICN). DHA and EPA oils were provided
by Lube AS (Hadsund, Denmark). The vitamin E was necessary to
compensate for the vitamin E in the fish oil, to ensure that the
vitamin E concentration was the same in all diets. Diets were prepared
weekly, flushed with nitrogen, stored at -20°C and provided fresh to
the rats each day. There were five to seven rats allocated to each
diet, with two rats in the BT and DHA groups without arthritis. Four
rats were used as controls or as no disease (ND) rats for growth
comparison purposes. Oral buprenorphine was used for pain management.
Sublingual tablets (0.3 mg) dissolved in jelly were provided 12 hourly.
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Rats (n = 5–7) weighing 150 g and prefed
experimental diets were injected intraperitoneally with sterile
peptidoglycan group A polysaccharide (PG-APS) polymers produced from
Streptococcus pyrogenes (Lot No. 12202) from Lee
Laboratories (Grayson, GA) at a dose rate of 15 µg rhamnose · g
body-1. All rats displayed a marked acute onset of
arthritis followed by remission, prior to the development of the
chronic phase of this model of arthritis. Rat hock circumferences and
footpad thicknesses were measured prior to arthritis induction and at
4-d intervals until the termination of the experiment. Footpad
thicknesses (as a measure of edema and arthritis activity) were
measured using a specially adapted dial calliper, and hock
circumferences were measured using a modified rule tool calibrated to
gradations of 0.01 mm. An average of three measures was taken at each
stage. Rats were checked daily using an adaptation of the Morton and
Griffiths Adverse Effects Scoring Chart (Morton and Griffiths 1985
) (Table 3
). If the severity of the arthritis indicated the need for greater pain
management, a subcutaneous injection of buprenorphine (0.01 mg) was
given. Rats were routinely monitored until the termination of the
experiment.
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Three days before collection of elicited macrophages, anesthetized rats
were given an intraperitoneal injection of 50 g/L cornstarch solution
(20 mL · kg body weight-1). Cells were collected by
peritoneal lavage with 20 mL of warm PBS (Sigma Chemical Co., St.
Louis, MO). The total cell population from one animal was pelleted by
centrifugation at 400 x g for 10 min, resuspended
in Dulbecco’s modification of Eagle’s medium medium containing 5%
heat-inactivated fetal calf serum, plated in four 100 x 15 mm
sterile polystyrene culture dishes, incubated in 5% CO2
atmosphere at 37°C for 3 h to allow macrophage adherence.
Nonadherent cells and medium were then removed by aspiration and
culture dishes rinsed with a volume of warm PBS. This removed up to
50% of the total cell number but provided a macrophage population that
was >90% pure as indicated by morphology and staining with
naphthyl acetate esterase (Sigma Chemical Co.). Cell viability as
determined by phase contrast microscopy and trypan blue exclusion was
>95%.
Histology.
At the conclusion of the experiment, rats were killed by
CO2 inhalation, skinned hock joints were removed, fixed in
10% formalin, progressively decalcified with final fixing in amyl
acetate. Paraffin sections were then prepared and stained with
hematoxylin and eosin stain. The sections were then assessed
independently by a veterinary pathologist (Veterinary Pathology
Services, Cooparoo, Australia) who was unaware of the diets and diet
group of the rats. This laboratory was certified by the American
College of Pathologists. The rat hocks were graded by severity of
histological change overall and by seven aspects of joint change as
indicated in Table 4
.
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Blood was collected from anesthetized rats by cardiac puncture, plasma
was separated by centrifugation at 1300 x g and
stored at -20°C until analyzed. Freshly adhered macrophages were
harvested using a plastic scraper and lysed by sonication for 2 min
over ice with a cell disrupter in chloroform/methanol (2:1, v/v) with
0.002% of butylated hydroxytoluene and stored at -20°C until
analyzed. Plasma samples were transesterified for plasma fatty acid
analysis using the method by Lepage and Roy (1986)
. Lipids from plasma
samples were extracted using the method by Folch et al. (1957)
and
phospholipid fractions separated by TLC (Christie 1982
).
Heptadecanoic acid was added to the lipid extracts as an internal
standard and separation was carried out on silica gel plates by using
hexane/diethyl ether/acetic acid (85:15:1) as the solvent system. After
plates were dried and phospholipids identified, the phospholipids were
scraped from the plates and redissolved in hexane. Macrophage and
plasma phospholipids were then methylated using (14 g/100 g)
BF3-methanol reagent and heated for 1 h at 100°C
using a method of Metcalfe and Schmitz (1961)
. Analysis of methyl
esters was performed using capillary gas chromatography
(Hewlett-Packard HP6890, NSW, Australia). The column was a
30 m x 0.25 mm (DB-225) fused carbon-silica column coated with
cyanopropylphenyl (J&W Scientific, Folsom, CA), and a method modified
by Garg and Blake (1997)
was used to analyze the fatty acids. Methyl
esters were separated using ultra high purity hydrogen as the carrier
gas, injector and detector temperatures were maintained at 250°C,
column temperature was programmed for 170 to 220°C at a rate of
10°C per min up to 190°C and then a rate of 3°C per min up to
220°C. The total run time was 30 min, split ratio was 10:1 and a 5
µL injection volume was used. The chromatograph utilized a flame
ionizer detector and auto-sampler. Sample fatty acid methyl ester
(FAME) peaks were identified by retention time comparison of authentic
standard mixtures of FAME (Nu-Chek-Prep Inc., Elysian, MN), using
Chemstations version A.04.02 software for gas chromatographic analysis.
Statistical analysis.
Data are means ± SEM of five to seven rats fed each diet. Differences among blood lipids were determined using Kruskal Wallis test and footpad, and hock differences were determined using random intercept, normal model for each rat, with fixed time and group effects. For all comparisons, P < 0.05 was considered significant.
Usually, a one-way ANOVA test would be used to analyze continuous
variables such as blood lipids. However, ANOVA assumes that the outcome
is normally distributed. In this case, small numbers and a question
over the distribution of the outcomes mean that the nonparametric
analog of one-way ANOVA must be used to analyze blood lipid levels.
The analyses of footpad and hock differences over time, the repeated
nature of the measurements must be taken into account. Because there is
no reason to believe that a rat footpad or hock measurement changes
over time except for treatment differences, an ANOVA model with a
random intercept for each rat is an appropriate method of analysis in
the case of these measurements (Laird and Ware 1982
).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The diets used in this study were isocaloric, and there was no difference in food intake among rats fed the different diets (data not shown). Final body weights, and thus the total growth, were not different among rats fed the different diets. Rats displayed a marked acute onset of arthritis followed by remission, prior to the development of the chronic phase of this model of arthritis. All rats given an ip injection of PG-PS developed arthritis. Body weights and food intake decreased after the induction of arthritis in all groups. ND rats maintained a steady rate of growth and rats were more active and had a lower mean body weight (P < 0.05) than the arthritic rats.
Footpad and hock swelling.
Footpad inflammation of rats fed the four diets varied in intensity
(Fig. 1
). There was a significantly greater percentage change in footpad
thickness (adjusted for growth) in the BT diet-fed rats than in the
SFO, DHA and EPA diet-fed rats. Inflammation in DHA and EPA
diet-fed rats was significantly less than in those fed SFO diet
(P < 0.05), (Fig. 1)
. The percentage change in hock
circumferences (adjusted for growth) for the SFO, DHA and EPA
diet-fed rats did not differ significantly from that of the BT
diet-fed rats (data not shown).
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The histological sections of hock joints were assessed for severity of
change overall and a number of particular changes were related to the
effects of inflammation and arthritis (Table 4)
. The overall severity
of change suggested a trend (P = 0.09) that rats fed
the BT and DHA diets were the most severely affected and those
consuming EPA and SFO-based diets were less affected.
Modification of plasma and cellular lipids.
EPA [20:5(n-3)] was 1.5 g/100 g fatty acid in macrophage
phospholipids of rats fed the EPA diet, a level greater than in the
other three groups (P < 0.05), (Table 5). DHA in macrophage phospholipids of the EPA and DHA diet-fed rats
was significantly greater than in the BT and SFO diet-fed rats
(Table 5)
. The incorporation of EPA, docosapentaenoic acid (DPA)
[22:5(n-3)] and DHA in plasma phospholipids of the EPA and DHA
diet-fed rats was significantly different from those of the BT and
SFO diet-fed rats (Table 6
). The levels of palmitic acid (16:0) and 18:1(n-9) were lower in the
plasma of rats fed the SFO diet than in rats fed the other diets
(Table 7
). However, the 18:1(n-9) concentration in macrophage phospholipids did
not differ among groups (Table 5)
. Rats fed the SFO diet had plasma
concentrations of linoleic acid (LA) [18:2(n-6)] that were more than
twice that of other groups (P < 0.05) (Table 7)
, but
this difference was not evident in macrophage phospholipids where
levels were slightly (P < 0.05) greater in rats fed
SFO and BT diets than in rats fed EPA and DHA diets (Table 5)
. Plasma
concentrations of arachidonic acid (AA) [20:4(n-6)] in rats fed BT
and SFO diets were more than double those of the EPA and DHA
diet-fed rats (Table 7)
and these proportional differences were
similar in macrophage phospholipids (Table 5)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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, Kremer et al. 1995
). The purpose of this study was to examine the effect of
varying the dietary ratios of EPA/DHA on the pathogenesis of the
SCW-induced arthritis in female Lew/SSN rats. The characteristics
of the diets used in this study were selected so that they would be
relevant to humans with RA. All rat diets contained a mix of fatty
acids, the lipid content of which was 38% of energy, which is in
agreement with a previous human study (Volker et al. 1998
). EPA and DHA content of the diets provided 13 and 10% of
dietary energy, respectively, which is comparable with human
supplementation regimens. We compared differing ratios of EPA and DHA
to determine the optimal ratio for supplementation. A BT-based diet
was selected as the control diet and the SFO-based diet was used to
mirror the (n-6) fatty acid content of the Western diet.
Cromartie et al. (1977)
initially described this animal model of
arthritis. It is characterized by acute inflammation in peripheral
joints in 100% of susceptible strains within 24 h. Acute
inflammation is caused by SCW fragment deposition in the synovium. This
is a T cell-independent process, associated with complement
activation, which subsides in 3–5 d. Histologically, the rapid onset
early phase of the disease is characterized by synovial abnormalities
consistent with microvascular injury accompanied by perivascular
infiltrate of polymorphonuclear and mononuclear cells. The interstitial
spaces exhibit edema and fibrin deposits. The secondary, chronic
synovitis is T cell-dependent and includes pannus formation,
angiogenesis, erosions and joint destruction. The chronic phase is
characterized by synovial lining cell layer proliferation,
fibroblast-like cells in the sublining stroma and destructive
invasion of periarticular bone. In RA, the site of synovitis is in the
pannus, which is responsible for the characteristic erosions
(Chu et al. 1992
, Yanni et al. 1994
).
The extent of inflammation observed in the four diet groups, measured
from arthritis induction to peak of acute arthritic flare, varied.
Footpad thicknesses (a measure of inflammation and edema) were greater
in the rats fed the BT diet than in the EPA, DHA, and SFO diet-fed
rats (Fig. 1)
. All rats displayed a marked acute onset of arthritis
followed by remission, prior to the development of the chronic phase of
this model of arthritis. The immunomodulatory effects of these diets
are likely to be related to the changed availability of AA. Because
dietary AA was restricted, so too was the production of AA-derived
mediators of inflammation (Li et al. 1994
).
The histological grading of hock change overall in the dietary groups
did not mirror the results of the changes in footpad thicknesses and
hock circumferences (Table 4)
. The severity of arthritic change was
greatest in rats fed BT and DHA diets and least for the EPA and SFO
diet-fed rats. The severity of change in the rats fed the BT diet
was expected because SFA do not influence lipid mediators of
inflammation (Grimble 1994
). However, the severity of
arthritic change in rats fed the DHA diet suggested that it may have
been an efficient immunosuppressant, so that once the rat immune
systems were suppressed, the DHA diet did not modulate inflammatory
mediators. The degree of overall change in the rats fed EPA diets
provided further evidence of the immunosuppressive effect of the EPA
diet (Whelan 1996
). The ranking of the SFO diet-fed
rats with the EPA diet-fed rats was surprising. This could have
resulted from the high level of dietary LA which was responsible for a
negative feedback inhibition of LA conversion to AA and thus the
suppression of the production of AA-derived mediators of
inflammation (Whelan 1996
). This effect could be related
to the ratio of SFA to MUFA in the diet because this ratio can
influence the immunomodulatory effects of dietary lipids
(Jeffery et al. 1997
). These results could also indicate
that the SFO-based diet did not suppress the immune system activity of
the rats prior to induction of arthritis.
Fatty acid composition of rat plasma and macrophages generally
reflected those of the diets (Tables 5
, 6
and 7)
. The SFO diet had a
high proportion of LA but macrophage phospholipid levels in rats fed
that diet did not reflect the same proportions (Table 5)
. There is a
linear relationship between the proportion of DHA in the diet and the
proportion of LA in plasma (Petersen et al. 1998
) This
reflects the regulation of AA production via a feedback inhibition
(Garg and Li 1994
, Whelan 1996
). The high
proportion of LA in the SFO diet would suppress endogenous AA
production through an inhibitory feedback mechanism (Garg et al. 1988
). The proportion of AA was high in the plasma of SFO- and
BT-fed rats and low in the plasma of rats fed EPA and DHA diets
(Table 7)
.
The plasma of EPA diet-fed rats contained a high proportion of EPA
and DHA, whereas the plasma of DHA diet-fed rats contained a higher
proportion of DHA. In the plasma of EPA and DHA diet-fed rats, the
LA levels were low and also were low in macrophage phospholipids
(Tables 5
and 7)
. AA plasma levels in EPA and DHA diet-fed rats
were also low and remained low in macrophage phospholipids, which
reflected the ability of EPA and DHA to competitively inhibit AA
production (Calder 1998
, Garg et al. 1988
, Whelan 1996
). The (n-6) to (n-3) balance
of the EPA and DHA diets was manipulated to provide a comparison of the
immunomodulating effects of these diets.
In several animal models of autoimmune disease (Byleveld et al. 1998
, Leslie et al. 1985
,
Prickett et al. 1984
), an effect of dietary fish oil on
the severity of inflammation has been observed. Prickett et al. (1984)
and Leslie et al. (1985)
observed the effect of fish oil-based
diets in collagen-induced arthritis in Sprague-Dawley rats and
B10.RIII mice, respectively. Prickett and coworkers (1984) observed
that a 10% fish oil diet enhanced the susceptibility of rats to
induction of arthritis; however, the severity of arthritis was not
affected by diet. Leslie and colleagues (1985) reported that there was
a reduced incidence and severity of arthritis in a 5% fish oil diet
compared with a corn oil diet. Feeding diets to mice for 26 d
prior to induction of arthritis delayed the onset of arthritis, with
reduced incidence and severity compared with corn oil-fed mice.
Female mice fed a fish oil diet had a reduced incidence of arthritis
compared with males fed the same diet. Byleveld and colleagues
(1998) utilized a 20% fish oil diet in SPF male Swiss mice as
a model of respiratory infection. They observed that diets rich in
(n-3) fatty acids, which reduced the risk of cardiovascular disease and
inflammatory diseases, are unlikely to compromise the outcomes of
infection or clearance of infection. RA clinical studies in humans
(Cleland et al. 1988
, Kremer et al. 1990
,
1995
) have utilized pharmacological doses of EPA and DHA
(1.0 to 7.1 g/d), in as much as 16 g d of fat without any
increases in immunomodulatory effects.
The current study indicates that changing the lipid characteristics of the diet has an immunomodulatory effect in this animal model of arthritis. Fish oil may influence the pathogenesis of SCW-induced arthritis and that (n-3) fatty acids found in fish oil may elicit an effect. However, the total PUFA content of the diet and the balance of (n-6) to (n-3) fatty acids are important in determining the overall effect. The ratio of EPA/DHA can be fine-tuned to optimize this immunoregulatory effect. Further research is necessary to determine the exact effects in more lengthy trials.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Dianne Volker was the recipient of an Australian Postgraduate Award.
4 Abbreviations used: AA, arachidonic acid; BT, beef tallow; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid;
EPA, eicosapentaenoic acid; i.p., intraperitoneal injection; LA, linoleic acid; LNA, -linolenic acid; MUFA, monounsaturated fatty acids; ND, no disease; PG PS, peptidoglycan polysaccharide; PUFA, polyunsaturated fatty acids; RA, rheumatoid arthritis; SCW, streptococcal cell wall; SFO, safflower oil; SPF, specific pathogen-free.
Manuscript received July 22, 1999. Initial review completed August 12, 1999. Revision accepted October 28, 1999.
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