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*
Department of Medicine, University of Toronto, Toronto, Ontario M5G-2C4, Canada and
St. Joseph’s Health Centre, Toronto, Ontario, M6R 1B5 Canada
2To whom correspondence should be addressed. E-mail: johane.allard{at}uhn.on.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-tocopherol acetate, 49 mg/kg); diet + iron (iron, 3000 mg/kg); diet + vitamin E (dl--tocopherol acetate, 2000 mg/kg) and the diet + both iron and vitamin E, each at the same concentrations as above. Body weight change, rectal bleeding, histological scores, plasma and colonic lipid peroxides (LPO), plasma 8-isoprostane, colonic glutathione peroxidase (GPx) and plasma vitamin E were measured. Iron supplementation increased disease activity as demonstrated by higher histological scores and heavier rectal bleeding. This was associated with an increase in colonic and plasma LPO and plasma 8-isoprostane as well as a decrease in colonic GPx. Vitamin E supplementation decreased colonic inflammation and rectal bleeding but did not affect oxidative stress, suggesting another mechanism for reducing inflammation. In conclusion, oral iron supplementation resulted in an increase in disease activity in this model of colitis. This detrimental effect on disease activity was reduced by vitamin E. Therefore, the addition of vitamin E to oral iron supplementation may be beneficial.
KEY WORDS: • iron • vitamin E • colitis • dextran sulfate sodium • oxidative stress
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). This is because oral iron is poorly absorbed in the upper gastrointestinal tract and most of it ends up in the colonic lumen. Iron can then react with superoxide (O2
) and hydrogen peroxide (H2O2), from activated neutrophils, to produce the hydroxyl radical (OH·) via the Fenton reaction: 1. O2 + Fe3+ 
O2 + Fe2+; 2. H2O2 + Fe2+ Fe3+ + OH- + OH·.
Hydroxyl radicals are extremely reactive and can attack any cell components and cause oxidative damage (2
). These radicals can also lead to the formation of other reactive oxygen species (ROS) (3
). The pro-oxidative imbalance created by this overproduction of ROS can directly enhance intestinal injury (4
). Furthermore, ROS can attack the polyunsaturated fatty acids of the cell membranes and induce lipid peroxidation (5
). This is a deleterious process that can affect cell function (6
). ROS can also increase mucosal and vascular permeability, recruit neutrophils and activate such transcription factors as nuclear factor-
B (NF-B), which up-regulates the transcription of adhesion molecules, cytokines and enzymes, all involved in the inflammatory responses (7
).
If this oxidative stress is sustained, such as during colitis, it will progressively weaken the antioxidant defense system. Indeed, patients with IBD and colitis are deficient in antioxidant vitamins, such as vitamin E, vitamin C and carotenoids, as well as antioxidant enzymes, such as superoxide dismutase, catalase and glutathione peroxidase (8
–10
). This imbalance can be further impaired by iron therapy (11
,12
).
Vitamin E is the most potent liposoluble antioxidant (13
) and has the potential to improve tolerance of iron supplementation and prevent further tissue damage. Vitamin E scavenges ROS, such as peroxyl radicals, and suppresses lipid peroxidation (14
). In addition, it has been reported to prevent the activation of NF-B (15
,16
). Because a large proportion of the oral vitamin E supplemented reaches the colon when given at a high dose, this can lead to both systemic and luminal antioxidant effects.
The purpose of this study was to investigate the effects of oral iron and vitamin E supplementation on intestinal inflammation and lipid peroxidation, using the rat model of dextran sulfate sodium (DSS)-induced colitis. We chose this model because it is a good model for human colitis (17
). DSS produces colonic epithelial injury followed by rapid influx of granulocytes and monocytes or macrophages, defining the classic features of acute intestinal inflammation. It is a reproducible model and has a clinical presentation similar to the human condition with bloody diarrhea, weight loss, mucosal inflammation and neutrophil infiltration (17
,18
)
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats (Charles River Labs, St-Constant, Quebec, Canada) weighing 100–120 g were housed individually under standard conditions (12-h light/dark cycles with room temperature of 21–25°C). All animals were handled according to the guidelines of the Canadian Council on Animal Care. The protocol was approved by the University of Toronto Animal Care Committee.
After 7 d of acclimation, acute colitis was induced in all rats by including 50 g/L of dextran sulfate sodium (DSS) (MW 8000; Sigma-Aldrich Canada Ltd, Oakville, ON, Canada) in drinking water for 7 d. In addition, rats were weighed and randomly assigned to one of the four experimental groups. The DSS group (n = 15) consumed the control nonpurified diet (#5001; Purina, Minneapolis, MN) containing 270 mg of iron and 49 mg of dl--tocopherol acetate per kg of diet. The DSS + iron group (n = 15) ate the same diet with an additional 3 g iron/kg (Purina Test Diet, Minneapolis, MN). The nonpurified diet was supplemented with pentacarbonyl iron, a 99 g/100 g pure form of elemental iron as microscopic spheres of 4.5–5.2 µm diameter, to increase bioavailability (Sigma-Aldrich Canada Ltd). The 10-fold iron supplementation used is comparable with that prescribed for moderate iron deficiency anemia. The DSS + vitamin E group (n = 23) consumed the nonpurified diet supplemented with vitamin E at 2 g/kg diet (dl--tocopherol acetate, Sigma-Aldrich Canada Ltd.). The DSS + iron + vitamin E (n = 14) group ate the regular diet supplemented with both iron and vitamin E, at the same doses as the DSS + Vitamin E and DSS + Iron groups.
During the induction of the colitis, fresh samples of feces were taken daily, homogenized with an equal weight of water and stored at -20°C until measurement of fecal heme.
On d 7 of the study, all rats were anesthetized by intraperitoneal administration of sodium pentobarbital (50 mg/kg body) and killed by cardiac puncture. Blood was collected into EDTA-containing and trace element-free vacutainers placed on ice, centrifuged at 3000 x g for 10 min at 4°C, and plasma was stored at -80°C for future analysis. Colon was removed from the colocecal junction to the anal verge. The colon was then opened, rinsed with ice-cold isotonic saline and cut longitudinally in two pieces for histological evaluation and tissue measurements, respectively. For histological examinations, the colon was fixed in 10% formalin, embedded in paraffin and stained with hematoxylin and eosin. The remaining colon was stored at -80°C.
Determination of disease activity.
Heme porphyrins in stool were measured by the Hemoquant assay (19
). Previous investigation has shown that iron does not interfere with this assay (20
). Briefly, an average of 20 mg of fecal homogenate was weighed accurately and added to 4 mL of a solution containing, 2.5 mol/L oxalic acid, 90 mmol FeSO4, 50 mmol uric acid and 50 mmol mannitol or 1.5 mol/L citric acid at 80°C and maintained at 80°C for 90 min. After centrifugation, the supernatant was mixed with 3 mL of ethyl acetate-acetic acid and 1 mL of potassium acetate (3 mol/L). The upper phase was then mixed with a mixture of 1-butanol and potassium acetate in a 1 mol/L solution of KOH. After centrifugation, the upper phase was added to 2 mol/L phosphoric acid: acetic acid mixture (9:1, by volume). After centrifugation, the coproporphyrin concentration in the lower phase was measured by fluorometry at an emission wavelength of 650 nm and an excitation wavelength of 400 nm. Standard solutions of 0–50 µg/L of coproporphyrin in 1.5 mol/l of HCl (Sigma Aldrich Canada) were used for this quantification. Heme from distal colonic bleeding was calculated as [heme in oxalic acid] –[heme in citric acid].
Crypt and inflammatory scores were determined by a pathologist who was unaware of the experimental protocol. The crypt injury was scored according to a validated scoring system (21
): grade 0, intact crypt; grade 1, loss of bottom third of the crypt; grade 2, loss of bottom two thirds of the crypt; grade 3, loss of entire crypt with the surface epithelium remaining intact; and grade 4, loss of the entire crypt and surface epithelium (erosion). The severity of inflammation was scored according to Onderdonk (22
): grade 0, normal; grade 1, focal inflammatory cells infiltration including polymorphonuclear leukocytes; grade 2, inflammatory cells infiltration, gland dropout and crypt abscess. Both scores also included a measure of the extent of involvement as follows: grade 1, 1–25%; grade 2, 26–50%; grade 3, 51–75%, and grade 4, 76–100% of the surface area examined. The final score is the product of either the inflammation or injury grade by the extent of involvement.
Determination of oxidative stress.
For colonic measurements, tissue samples were thawed, washed in isotonic saline, blotted dry, weighed and homogenized with 10-fold (v/w) ice-cooled HCl-Tris buffer at pH 7.4. Butylated hydroxytoluene 5 mmol/L was added to prevent ex vivo lipid peroxidation. The suspension was then centrifuged at 3000 x g for 10 min at 4°C before analysis of lipid peroxides (LPO) and glutathione peroxidase (GPx) activity.
Plasma and colonic LPO were measured using commercially available kits (Bioxytech LPO-586; OXIS International, Portland, OR) that measure free malondialdehyde and 4-hydroxyalkenals. Plasma levels of free and esterified 8-isoprostane were measured by immunoassays (Cayman Chemical Co, Ann Arbor, MI). Ex vivo generation of 8-isoprostane was prevented by adding 5 mol/L butylated hydroxytoluene during the extraction. Samples were purified by solid-phase extraction (Chromosep C18 SPE; Chromatographic Specialties, Brockville, ON, Canada) with tritium-labeled prostaglandin F2a (Amersham Biosciences, Piscataway, NJ) used as a tracer.
GPx activity of colonic homogenates was determined at 25°C with ter-butyl hydroperoxide (0.3 mmol/L) as the substrate using the Bioxytech GPx-340 kit from OXIS International. One unit of GPx is defined as 1 µmol of NADPH oxidized/min. Protein concentration in the colonic homogenate was determined by the Biuret method (23
). Plasma -tocopherol was determined by high-performance liquid chromatography (24
). This method uses an isocratic solvent (methanol/acetonitrile/tetrahydrofuran, 50:45:5, v/v/v), reverse phase C18 column and fluorescence spectrophotometry at 294 nm after a hexane extraction using 200 µL of plasma sample.
Statistics.
Data from this 2 x 2 factorial design study were analyzed by two-way analysis of variance. The two variables analyzed were iron and vitamin E. The effects of iron and vitamin E on disease activity variables were defined as primary outcomes. Secondary outcomes were lipid peroxidation and antioxidant defense system variables. Data were further analyzed by unpaired t test. The Fisher exact test was used to compare mortality rates among groups. Data processing and analysis were performed with SAS software (version 8.0; SAS Institute, Cary, NC). All tests of significance were two-sided, and the level of significant difference was determined at P < 0.05. Results are reported as means ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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At d 6 and 7 of the study, fecal heme concentration was greater in rats supplemented with iron and vitamin E supplementation was associated with less blood in the stools (Fig. 1)
.
|
. Oxidative stress also was greater in iron-supplemented rats. Colonic and plasma LPO (Fig. 3)
and plasma 8-isoprostane (Fig. 4)
were all elevated, whereas there was a decrease in colonic GPx (Fig. 5)
. However, despite its antioxidant activity and its elevated level in plasma of supplemented rats (see below), vitamin E did not effect any of these variables. However, for 8-isoprostane, there was an interaction between the effect of iron and vitamin E, suggesting that vitamin E was preventing the increase of 8-isoprostane due to iron supplementation (Fig. 4)
. Plasma -tocopherol concentrations were greater (P < 0.05) in vitamin E-supplemented rats (DSS: 15.05 ± 0.88 mmol/L, DSS + Iron: 12.28 ± 0.95 mmol/L, DSS + Vitamin E: 24.12 ± 1.42 mmol/L, DSS + Iron + Vitamin E: 25.08 ± 1.81 mmol/L).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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).
Normally, 5 to 10% of dietary iron is absorbed in the upper digestive tract. Even in severe iron-deficiency anemia, the maximal efficiency of iron absorption is 40% (26
). Therefore, with a daily ferrous sulfate supplement of 600 mg (120 mg of elemental iron), 
72–114 mg of elemental iron may reach the colonic lumen (27
). This amount is sufficient to drive the Fenton reaction maximally and produce excess hydroxyl radicals in feces, as demonstrated in vitro by Babbs (28
). Furthermore, one study investigated the effect of iron supplementation in healthy volunteers by giving them 120 mg of ferrous sulfate daily for 2 wk (29
). They found a significant increase in the fecal free radical production. Iron may also be found in the colonic mucosa and contribute to oxidative stress (30
). It was also recently reported that in rectal biopsies from patients with ulcerative colitis, exogenous iron chelators could reduce the production of ROS (31
). The effect of oral iron on intestinal inflammation was also reported in other animal models. In the iodoacetamine rat model of colitis, Reifen et al. (32
) found that oral iron supplementation enhanced mucosal damage. Another group assessed the effect of dietary and topical administered iron in a small number of interleukin-10–deficient mice with colitis (33
) and found no increase in colonic inflammation. However, oral and rectal administration of iron increased colonic proinflammatory cytokine production. In our study, we used the rat model with DSS-induced colitis because it is a good model for human colitis (17
). It is reproducible and has a clinical presentation similar to the disease in humans, with bloody diarrhea, weight loss, mucosal inflammation and neutrophil infiltration (17
,18
). This model is also frequently used to test the effects of various treatment regimens (17
,34
) and therefore was considered ideal for the present study.
Iron and ROS can enhance mucosal injury by several mechanisms. One is by initiating lipid peroxidation either by iron itself or by the ROS produced during the Fenton reaction. In sites of mucosal inflammation, the interaction of neutrophil-generated superoxide anion with the high concentration of chelate iron may produce more ROS, such as hydroxyl radicals (35
,36
). These, in addition to ferrous/ferric complexes of low molecular weight chelate iron, could also result in lipid peroxidation (37
). Lipid peroxidation of cell membranes, including mitochondrial membranes, can in turn compromise cell integrity and function and affect its energy status, thereby causing further tissue injury (38
,39
). Iron and ROS can also amplify intestinal inflammation by such mechanisms as increasing mucosal permeability (40
), recruiting and activating more neutrophils (41
) and activating NF-B, thereby up-regulating the production of proinflammatory cytokines (42
,43
). These other mechanisms were not investigated in the present study.
Sustained production of ROS during colonic inflammation can overwhelm the antioxidant defense system and there are reports of decreased antioxidant levels in patients with IBD and colitis (8
–10
). The antioxidant defense system can be further impaired by iron supplementation, as shown in our study, in which colonic GPx activity was reduced by iron intake. Rats supplemented with vitamin E had less disease activity as documented by a reduction in fecal heme and a decrease in histological scores for crypt damage and colonic inflammation. Another study performed in a different rat model of colitis also reported a significant reduction in colonic mucosal inflammation with vitamin E supplementation (44
). Vitamin E is a powerful lipid-soluble radical scavenger that suppresses lipid peroxidation. However, in our study, despite the beneficial effect of vitamin E on colonic inflammation, lipid peroxide variables were not reduced. The lack of effect on lipid peroxidation suggests the involvement of a different mechanism. Vitamin E was well absorbed as indicated by the increase in plasma -tocopherol levels. However, at this pharmacological dose, a large proportion of the vitamin E also reaches the colon (45
,46
). Therefore, vitamin E may have exerted its beneficial effect intraluminally, thereby reducing the free radical generating capacity of the feces. Vitamin E may also have reduced intestinal inflammation by preventing the activation of the transcription factor NF-B, which plays an important role in intestinal inflammation (47
,48
). This possibility is supported by several in vitro studies in which vitamin E inhibited tumor necrosis factor--induced NF-B activation in human Jurkat T-cells (15
) and inhibited the activation and translocation of NF-B to the nucleus and the binding of the activated proteins to the B DNA site (16
).
In conclusion, oral iron supplementation significantly enhanced disease activity in rats with DSS-induced colitis. This was associated with an increase in oxidative stress. Vitamin E, a potent antioxidant, did not reduce lipid peroxidation but significantly reduced intestinal inflammation and disease activity, even with concurrent iron supplementation. This suggests that adding vitamin E to oral iron therapy may improve gastrointestinal tolerance in patients with inflammatory bowel disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DSS, dextran sulfate sodium; GPx, glutathione peroxidase; IBD, inflammatory bowel disease; LPO, lipid peroxides; NF-B, nuclear factor B; ROS, reactive oxygen species.
Manuscript received 24 May 2002. Initial review completed 12 June 2002. Revision accepted 27 June 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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