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B and Collagen Formation
School of Nutritional Sciences, The Hebrew University of Jerusalem, Rehovot, Israel;
*
The Institute of Brain Chemistry and Human Nutrition, The University of North London, London, UK; and
The Volcani Center, Agricultural Research Organization, Bet Dagan, Israel
1To whom correspondence should be addressed. E-mail: reifen{at}agri.huji.ac.il.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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B (NF-B) and oxidative stress were determined by electrophoretic mobility shift and plasma malondialdehyde (MDA) and RBC Cu/Zn-superoxide dismutase activity, respectively. Vitamin A deficiency in the noncolitic rats impaired food consumption and weight gain (P < 0.05) and increased plasma MDA, (P = 0.01) activity of NF-B (P < 0.05) and deposition of collagen in the colon. Our data suggest that vitamin A deficiency induces colonic inflammation. Colitis is amplified by deficiency and ameliorated by supplementation of the vitamin. These findings have implications for the management of inflammatory bowel disease.
KEY WORDS: • vitamin A • colitis • nuclear factor-B • fibrosis • oxidative stress
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). In active IBD, there is increased local production of proinflammatory cytokines [interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF)-
], synthesis of eicosanoids and recruitment of both immunologically specific and nonspecific inflammatory cells from the circulation (2
,3
).
Nuclear factor-B (NF-B) is a transcription factor that regulates a variety of key cellular genes involved in immune responses, inflammation and cell proliferation (4
,5
). There is evidence that NF-B is activated by oxidative stress and that its activation could be modulated by antioxidant compounds (6
). It has been indicated that the blocking of NF-B activation by antioxidants in disorders with underlying oxidative stress and accompanying inflammatory component such as diabetes, chronic lung disease, Alzheimer’s disease and atherosclerosis, may have a therapeutic value for preventing or ameliorating inflammatory conditions (7
–10
).
Growing evidence demonstrates that free radicals play an important role in the pathogenesis of IBD in humans (11
,12
) and experimental animals (13
) and that NF-B is involved in the initiation of the relapsing inflammatory process of the disease (14
–16
). Indeed, sulfasalazine, one of the most effective agents for treating IBD is a potent and specific inhibitor of NF-B activation (17
). Oral administration of vitamins with antioxidant properties reduced damage and promotes healing of the colon in a rat model of induced colitis (18
).
Vitamin A and its analogs are potent regulators of epithelial proliferation and differentiation; they are important for the proper functioning of the immune system (19
) and have antioxidant properties (20
). Vitamin A deficiency (VAD) heightens inflammatory responses, as manifested by an increase in the number of circulating leukocytes, enhanced T-cell proliferative response and release of nitric oxide from peritoneal phagocytes (21
). In previous animal studies, we demonstrated that VAD is associated with functional and morphological changes of the gastrointestinal tract (22
,23
).
There are no comprehensive published studies that have investigated the role of vitamin A and its analogs in IBD. In the present study, we tested the possibilities that inflammation and its sequelae are enhanced by VAD and ameliorated by supplementation with the vitamin, in a rat model of induced colitis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male weanling Wistar rats, specific pathogen–free, were obtained from the Harlan Laboratory, The Weizmann Institute of Science, Rehovot, Israel. They were housed in metal cages in a room with controlled temperature (25 ± 2°C), relative humidity (65 ± 5%) and light (0800–2000 h). Ethical approval was obtained for the study and all the procedures were conducted in a full compliance with the strict guidelines of the Hebrew University Policy on Animal Care and Use.
Experimental design and diets.
Male weanling rats (40–45 g) were distributed randomly into three groups. Group 1, VAD (n = 31), was fed a pelleted version of the vitamin A–deficient diet (cat. no. 960220, ICN Nutritional Biochemicals, Costa Mesa, CA; Table 1
). Group 2, vitamin A sufficient (VAS; n = 31), was fed the custom control diet for vitamin A deficiency, containing retinyl palmitate (1200 µg/kg diet) (ICN Nutritional Biochemicals, Costa Mesa, CA). Group 3, Vitamin A supplemented (VASUP; n = 31), was fed the same custom control diet; however, during the last 4 wk of the experiment, rats in this group were intubated daily with 300 µg retinyl palmitate in 0.25 mL of 1% glycerol. Rats in group 4 (n = 15) were pair-fed (PF) the VAS diet such that each rat in this group received the amount consumed by a VAD rat the previous day. All other groups consumed food ad libitum. Food intake was monitored daily and the rats were weighed every other day.
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After 7 wk of feeding, colitis was induced in 16 rats from the VAD, VAS and VASUP groups by administration of 0.5 mL of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 100 g/L dissolved in 50% ethanol) through the anal canal for a distance of 8 cm into the colon, just proximal to the splenic flexure (24
). Before the induction of colitis in the deficient group, two rats were killed to confirm that liver vitamin A was sufficiently depleted. Colitis was induced when the level of the vitamin approached the analytical detection limit. After 24 and 72 h of induction, time frames that mirror acute and chronic phases of the disease, an equal number of rats were killed and colon, liver and blood (from portal vein) collected for various analyses. Samples that were not immediately processed were frozen in liquid nitrogen and kept at -80°C.
Histological examination.
Fresh colonic specimens were placed in PBS and fixed overnight in 4% paraformaldehyde in PBS at 4°C. Serial 5-µm sections were prepared after the samples had been dehydrated in graded ethanol solutions, cleared in chloroform and embedded in paraplast. For morphometric analysis, sections were stained with hematoxylin and eosin and were evaluated by light microscopy by a pathologist unaware of the experiment being performed. Colonic inflammation and fibrosis were evaluated by differential staining of collagenous and noncollagenous protein using saturated picric acid with 0.1% Sirius red and 0.1% Fast green as a counterstain, a histological technique developed by Gascon-Barre et al. (25
). Acute inflammatory changes were determined based on infiltrate of neutrophils, macrophages and lymphocytes involving the mucosa. Wide mucosal ulceration was indicative of severe inflammatory cell infiltrate involving all layers of the intestinal wall.
Electrophoretic mobility shift assay (EMSA).
The DNA-binding activity of NF-B in the colonic tissue was assayed by EMSA as described by Helenius et al. (26
). Nuclear extracts from colonic tissue were prepared. A consensus DNA-binding oligonucleotide of NF-B target genes (5'-AGT TGA GGG GAC TTT CCC AGG-3') was used as a probe and labeled using a random priming kit (Promega, Madison, WI) in the presence of (-32P)-deoxycytidine triphosphate (1.1 x 1011 Bq/mmol; Amersham Pharmacia Biotech, London, UK). Nuclear extracts (1 µg protein) were incubated with radiolabeled DNA probes (
10 ng, 4.5 x 105 dpm) in 20 µL of binding buffer (Promega) for 20 min at room temperature. Samples were run in 0.25 x TBE buffer [10x; (mmol/L): Tris, 890; boric acid, 890; EDTA, 20; pH 8.0] with loading dye on nondenaturing 6% polyacrylamide gel at 100 V for 2 h. Gels were wrapped with saran wrap and analyzed by autoradiography.
Liver and plasma vitamin A (retinol).
Liver and plasma vitamin A were extracted from plasma and liver samples with petroleum ether after saponification with 50% ethanolic potassium hydroxide (KOH). The concentration was determined by HPLC equipped with a fluorescence detector (MD-910, JASCO, Tokyo, Japan) (26
). A 5-µm C18 reversible column, ethyl acetate eluting solvent (20% in methanol) and retinyl acetate internal standard were used for the analysis (27
).
Plasma malondialdehyde (MDA).
MDA concentration in plasma was determined colorimetrically from the intensity of the chromogen (color complex) formed when lipid peroxides resulting from oxidative stress reacted with thiobarbituric acid (TBA) (28
). Plasma sample, 1 mL was mixed with 2 mL trichloroacetic acid (TCA)/TBA/HCl reagent (50 g/L TCA, 375 g/L TBA and 0.25 mol/L HCl). The mixture was heated in boiling water for 15 min, centrifuged at 2000 x g for 10 min and the absorbance of the resulting supernatant color complex measured at 535 nm.
Red blood cell Cu/Zn-superoxide dismutase.
The activity of the antioxidant enzyme Cu/Zn-superoxide dismutase (SOD) in RBC was measured on the basis of the kinetic reaction (xanthine/xanthine oxidase, ferricytochrome C) (29
).
Statistical analysis.
The results are express as means ± SD. A modified one-way ANOVA and Tukey’s post-hoc test were used to investigate the effects of vitamin A status on the markers of inflammation and oxidative stress in the noncolitic and colitic rats. Changes due to colitis within diet groups were not tested. A statistical package, SAS (SAS Institute, Cary, NC), was used to analyze the data. Differences were considered significant if P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The VAD rats consumed less food than the other two groups (VAS and VASUP) starting at wk 3 (P < 0.05). Weight gain did not differ between the VAS and VASUP groups (270 ± 14 g), or between the VAD and PF groups (189 ± 11 g) at wk 7. However, the weight gains of the former and latter pairs differed (P < 0.05).
Liver, serum and colon vitamin A.
At wk 7, in the noncolitic rats, the liver vitamin A concentration of the VAD rats was lower (P < 0.001) and that of the VASUP rats higher (P < 0.001) than in the VAS groups (Table 2
). These levels were maintained 24 and 72 h after the induction of colitis. The liver vitamin A levels of the PF group (55.3 ± 8.1 nmol/g) did not differ from the VAS liver level. Both serum and colon vitamin A concentrations of the VAD group were lower (P < 0.001) and that of the VASUP group higher P < 0.01 than the VAS group (Table 2)
. The serum vitamin A level of the PF control group (7.1 ± 1.39 µmol/L) did not differ from the VAS group.
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The concentration of plasma MDA of the VAD group was higher than that of the VAS and VASUP noncolitic groups (P < 0.05; Table 3
). In contrast, the activity of the antioxidant enzyme Cu/Zn SOD in RBC was not different among the control VAD, VAS and VASUP rats (Table 4
). There were no differences in plasma MDA concentration among the VAD, VAS and VASUP rats 24 h after induction of colitis. However, at 72 h after induction, the MDA concentration in VAD rats was higher than in VAS (P < 0.05) and VASUP (P < 0.01) rats (Table 3)
. There were no differences in the activity of SOD among the VAD, VAS and VASUP groups at either 24 or 72 h after induction of colitis (Table 4)
.
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B.
Figure 1
shows a representative gel shift experiment (Fig. 1
A) and the corresponding densitometry (Fig. 1
B), demonstrating increased amounts of DNA binding NF-B in nuclear extracts of colons of VAD and colitic rats compared with colons of noncolitic VAS rats. There was a significant increase in NF-B activity in the colonic mucosa of the noncolitic VAD group compared with the control (noncolitic VAS group) which was further enhanced by colitis induced for 24 h in the VAD group. NF-B activity in the colonic mucosa of VAS colitic rats (24 h after induction) was also more pronounced than in the corresponding noncolitic VAS rats. No differences were observed in NF-B activity between 24 and 72 h of colitis in the different groups (data not shown). Furthermore, vitamin A supplementation did not seem to modulate the binding capacity of NF-B in the colitic group compared with the colitic VAS group (data not shown).
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Microscopic examination of colon sections revealed a normal structure in the noncolitic VAS, PF and VASUP groups. In contrast, the noncolitic VAD rats had a shortening of the villi, mucosal infiltration by inflammatory cells (Fig. 2A
), enhanced collagen content and fibrosis (Fig. 2
B). Similarly, the colons of all colitic groups showed extensive crypt distortion, infiltration of inflammatory cells, transmural necrosis (Fig. 2
A) and fibrosis of connective tissue (Fig. 2
B) during the acute phase, 24 h after induction of colitis. There was a marked destruction of the tissue architecture in the VAD rats (Fig. 2
A) but no further changes in the VAS and VASUP groups during the chronic phase, 72 h after induction.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Consistent with our previous findings in rats (22
) and chicks (30
), VAD was associated with a reduction of food consumption and weight gain. The mechanism for this adverse effect is not well understood. Nevertheless, we found that taste preference is impaired in VAD (31
) and this may have an adverse effect on food consumption.
The most important finding of the investigation was the morphological and inflammatory changes in the colon of the VAD noncolitic rats. This phenomenon, characterized by shortened villi, infiltration of inflammatory cells and hyperplasia, fibrosis and activation of NF-B, was not manifested in the pair-fed group, which were vitamin A sufficient. Hence, it could not be attributed to an insufficiency of vital nutrients other than vitamin A or low energy intake resulting from the reduced food consumption.
Although not as severe, the colon pathology of the VAD noncolitic rats was akin to that of the VAD and VAS colitic groups. The infiltration of inflammatory cells in the colon was markedly ameliorated in the supplemented rats. In an earlier study (30
), we found a reduction of mucosal protein, villous height, crypt depth and in the activities of disaccharidases, transpeptidase and alkaline phosphatase in VAD chickens. Similarly, Al-Awadi et al. (32
) reported histological alterations in colonic mucosa and infiltration of lymphocytes and neutrophils around the crypts in the lamina propria in VAD mice.
Consistent with our present findings, others have reported an inverse relationship between vitamin A status and the inflammatory response (33
,34
). However, the mechanism involved is not well understood. The plasma MDA concentration of the VAD noncolitic rats, which was higher than that of the corresponding VAS and VASUP noncolitic groups by 45 and 78%, respectively, indicates that the deficient rats were under oxidative stress. It seems that this oxidative load in the noncolitic deficient group may have resulted in lipid peroxidation, activation of NF-B and the subsequent inflammatory cascade, i.e., chemotaxis and infiltration of inflammatory cells and collagen deposition in the colon. There is evidence that the antioxidant vitamin A exerts its influence in part by inhibiting translocation of the transcription factor NF-B and interrupting the secretion of inflammatory cytokines (9
).
Liver vitamin A in the colitis VAS group was lower than in the VAS control group. Similar decreases in acute infection, inflammation and trauma were reported in plasma (35
) and in tissues (36
,37
). This could be because of increased mobilization from the liver in response to enhanced demand and utilization by the affected tissue. It has been proposed that the diversion of vitamin A into either storage pools or target tissues is regulated by the expression of lecithin:retinol acyltransferase (38
).
The study demonstrates that vitamin A deficiency induces inflammation, fibrosis and morphological and histological changes in the colon. Colitis is amplified by VAD and ameliorated by supplementation of the vitamin. This could be because of oxidative stress–induced activation of NF-B. Conversely, vitamin A may have a direct influence on the expression of NF-B and its sequelae. Our findings may have practical relevance for the management of various inflammatory and infectious disorders of the gastrointestinal mucosa.
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FOOTNOTES |
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B, nuclear factor-B; PF, pair fed; SOD superoxide dismutase; TBA, thiobarbituric acid; TNBS, trinitrobenzene sulfonic acid; TNF, tumor necrosis factor; VAS, vitamin A sufficient; VAD, vitamin A deficient; VASUP, vitamin A supplemented. 
Manuscript received 8 February 2002. Initial review completed 3 April 2002. Revision accepted 31 May 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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