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PubMed2005

Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis.

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid) is an antiinflammatory lipid mediator derived from omega-3 fatty acid eicosapentaenoic acid (EPA). At the local site of inflammation, aspirin treatment enhances EPA conversion to 18R-oxygenated products, including RvE1, which carry potent antiinflammatory signals. Here, we obtained evidence for reduced leukocyte infiltration in a mouse peritonitis model, where the administration of EPA and aspirin initiated the generation of RvE1 in the exudates. Similar results were obtained with the administration of synthetic RvE1, which blocked leukocyte infiltration. RvE1 also protected against the development of 2,4,6-trinitrobenzene sulfonic acid-induced colitis. The beneficial effect was reflected by increased survival rates, sustained body weight, improvement of histologic scores, reduced serum anti-2,4,6-trinitrobenzene sulfonic acid IgG, decreased leukocyte infiltration, and proinflammatory gene expression, including IL-12 p40, TNF-alpha, and inducible nitric oxide synthase. Thus, the endogenous lipid mediator RvE1 counter-regulates leukocyte-mediated tissue injury and proinflammatory gene expression. These findings show an endogenous mechanism that may underlie the beneficial actions of omega-3 EPA and provide targeted approaches for the treatment of intestinal inflammation.

Animals↗
PubMed2004

[Modulation of intestinal mucosal inflammatory factors by curcumin in rats with colitis].

OBJECTIVE: To explore the mechanism of modulation of intestinal mucosal inflammatory factors by curcumin, the inhibitor of the transcriptional factor nuclear factor -kappaB (NF-kappaB), in rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis, and screen for a targeted therapeutic agent for treatment of inflammatory bowel disease (IBD). METHODS: Rats with TNBS-induced colitis were fed with diet containing 2.0% curcumin (treatment group), 0.5% sulfasalazine (SASP, positive control group), and normal diet (model group and negative control group). Changes in colonic mucosal histological scores were evaluated and the cytokine mRNA expressions in the colonic tissue assessed by semiquantitative reverse transcriptional PCR (RT-PCR). RESULTS: Treatment with curcumin ameliorated the histopathologic signs in rats with TNBS-induced intestinal inflammation. Curcumin and sulfasalazine obviously suppressed the high expression of proinflammatory cytokine interleukin (IL)-1beta mRNA and increased the low expression of IL-10 mRNA in the colonic mucosa. Expression of the anti-inflammatory cytokine IL-4 mRNA was detected in none of the groups. CONCLUSIONS: Curcumin could modulate the expressions of IL-1beta and IL-10 mRNA in murine model of IBD, which suggests the potential of curcumin as a targeted therapeutic agent for IBD.

Animals↗
PubMed2004

Colonic expression of MUC2, MUC5AC, and TFF1 in inflammatory bowel disease in children.

BACKGROUND: The quantity and quality of mucins are affected in inflammatory bowel disease (IBD) both because of a reduction in the number of goblet cells and a decrease in the number of sugar residues per oligosaccharide side chain. Alteration in the types of mucins and aberrant location may contribute to the underlying pathology by affecting the mucus barrier function or may instead be a response to inflammation. The authors used the periodic acid-Schiff/Alcian blue stain to distinguish neutral and acidic mucins, and used specific antibodies to the mature goblet cell mucin MUC2, MUC2 core antigen, foveolar cell mucin MUC5AC, and gastric trefoil factor (TFF1), to characterize their presence and distribution in colonic tissue sections from patients with IBD. RESULTS: Both core and mature MUC2 were expressed in all colonic goblet cells from patients with ulcerative colitis (UC) and Crohn disease and from healthy controls. MUC5AC and TFF1, which are not normally expressed by colonic tissue, also were expressed in scattered goblet cells, coexpressing with MUC2. In areas of goblet cell depletion, MUC2 was present in cytoplasmic granules of flattened, cuboidal, nongoblet-cell-like surface cells. The staining was more intense and homogenous with the MUC2 core antibody, suggesting expression of relatively immature mucin. Some of these cells also coexpressed MUC5AC but to a lesser extent. These findings are not unique to IBD but were also found in other types of intestinal inflammation. CONCLUSION: The study confirms earlier observations that MUC2 is the major colonic mucin in IBD. It appears in two forms: mature MUC2 in goblet cells and immature MUC2 especially in secretory granules of cells that are not phenotypically goblet cells. MUC5AC and TFF1 expression in goblet cells is common in IBD and other inflammatory conditions of the colon. These changes may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.

Adolescent↗
PubMed2006

Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis.

CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell transfer model of colitis. Using Foxp3 as a marker of regulatory T cell activity, we now provide a comprehensive analysis of the in vivo distribution of Foxp3+CD4+CD25+ cells in wild-type mice, and during cure of experimental colitis. In both cases, Foxp3+CD4+CD25+ cells were found to accumulate in the colon and secondary lymphoid organs. Importantly, Foxp3+ cells were present at increased density in colon samples from patients with ulcerative colitis or Crohn's disease, suggesting similarities in the behavior of murine and human regulatory cells under inflammatory conditions. Cure of murine colitis was dependent on the presence of IL-10, and IL-10-producing CD4+CD25+ T cells were enriched within the colon during cure of colitis and also under steady state conditions. Our data indicate that although CD4+CD25+ T cells expressing Foxp3 are present within both lymphoid organs and the colon, subsets of IL-10-producing CD4+CD25+ T cells are present mainly within the intestinal lamina propria suggesting compartmentalization of the regulatory T cell response at effector sites.

Animals↗
PubMed2005

Tumor necrosis factor-alpha and interferon-gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine.

A major mechanism for apical peptide absorption by small intestine is via the proton-coupled transporter PepT1. PepT1 is expressed at a high level in proximal small intestine, but it is not expressed in the healthy colon. However, in chronic states of intestinal inflammation, such as in Crohn's disease and ulcerative colitis, PepT1 expression in colonic epithelia is increased, serving as a pathway for entry of bacteria-derived molecules such as muramyl dipeptide (MDP) and fMet-Leu-Phe (fMLP). As little is known of how inflammation induces PepT1, we investigated whether or not inflammatory cytokines and mediators such as interleukins (IL)-1beta, IL-2, IL-8, IL-10, tumor necrosis factor-alpha, (TNF-alpha) and interferon-gamma (IFN-gamma ) up-regulate PepT1 activity and expression. Uptake of the PepT1 substrate glycylsarcosine [(3)H]-Gly-Sar was studied in vitro in the human colon carcinoma cell line Caco2/bbe monolayers as well as in vivo in mice injected with cytokines. TNF-alpha and IFN-gamma increased the activity, and total and apical membrane protein expression of PepT1 protein in a concentration- and time-dependent fashion. No changes in PepT1 mRNA were observed, suggesting post-transcriptional regulation. All three cytokines increased PepT1 protein expression in mouse proximal and distal colon but not in jejunum or ileum. TNF-alpha and IFN-gamma, but not IL-1beta, increased Gly-Sar uptake in mouse proximal and distal colon; however, no changes were observed in the small intestine with any cytokine treatment. Whereas neither TNF-alpha nor IFN-gamma increased PepT1 mRNA expression in any segment of the intestine, treatment with IL-1beta increased PepT1 mRNA expression in mouse proximal and distal colon and decreased PepT1 mRNA expression in jejunum and ileum. Since PepT1 transports bacteria-derived peptides, the up-regulation of protein expression and activity observed after treatment with TNF-alpha or IFN-gamma may play a role in activating host responses in involved colon.

Animals↗
PubMed2004

Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe?

Crohn's disease and ulcerative colitis are examples of inflammatory bowel disease (IBD), and are multifaceted chronic autoimmune disorders with unknown etiology; to date, there is no known cure. IBD is thought to occur as a result of an inappropriate immune response to environmental factors in a genetically predisposed host, and it has become increasingly clear that cytokines play an important role in this process. In recent years, several groups have provided evidence that IL-18 is significantly up-regulated during the course of chronic intestinal inflammation and appears to play a pivotal role in the pathogenesis of human IBD, particularly in Crohn's disease. IL-18 is a pleiotropic cytokine with several biological functions, but is most commonly associated with its ability to synergistically induce the expression of IFN-gamma. However, although IL-18 has been extensively studied in both human IBD as well as in murine models of colitis, no definitive function of IL-18 during the initiation and perpetuation of chronic gut inflammation has been firmly established, and its precise role in the pathogenesis of IBD has yet to be determined. In light of the recent observation that the transcription factor interferon regulatory factor-1 has the ability to regulate the functional activity of IL-18, and concomitantly disease severity, in a murine model of colitis through altered expression of its endogenous inhibitor, IL-18-binding protein, this commentary will review what is currently known regarding the role of IL-18 in normal mucosal immunity and during the pathogenesis of IBD.

Animals↗
PubMed1996

Persistent clonal expansions of peripheral blood CD4+ lymphocytes in chronic inflammatory bowel disease.

It is increasingly recognized that chronic Ag exposure may lead to clonal expansions of T cells, including those within the peripheral blood. Inflammatory bowel disease is a chronic, multisystemic disease of unknown origin that predominantly affects the intestine. We sought to determine whether clonal expansions of T cells are present in the peripheral blood of patients with inflammatory bowel disease by an examination of TCR usage. Positively selected CD4+ and CD8+ peripheral blood T cells were isolated from subjects with active ulcerative colitis, Crohn's disease, and diverticulitis and from normal controls. Analysis of complementarity determining region 3 lengths of 24 TCR-beta chain V region families from CD4+ and CD8+ peripheral blood T cells showed a skewed distribution in the three inflammatory groups, consistent with expansion of T cell clones, in comparison to the normally distributed pattern observed among the control donors. Random sequencing of the PCR amplification products of CD4+ peripheral blood T cells from the subjects with ulcerative colitis, Crohn's disease, and diverticulitis revealed reiterative TCR-beta chain sequences that were not found in the normal donors. In subjects with Crohn's disease, the reiterative TCR-beta chain sequences from the CD4+ peripheral blood T cells were persistent over at least a 1-yr period. The persistently expanded TCR-beta chain sequences of CD4+ peripheral blood T cells were identifiable in genomic DNA isolated from archival tissue of intestine from subjects with Crohn's disease and ulcerative colitis by Southern blotting and direct DNA sequencing. An identical twin pair, concordant for Crohn's disease, shared the same reiterative TCR-beta chain sequences in their CD4+ peripheral blood T cells. These studies show that chronic intestinal inflammation is associated with expansions of CD4+ peripheral blood T cells. Furthermore, in inflammatory bowel disease these T cell clonal expansions are persistent and shared among HLA-identical individuals, implicating a response to specific, persistent, and stimulating Ags in these diseases.

Amino Acid Sequence↗
PubMed2003

Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease.

BACKGROUND & AIMS: The chronic, small intestinal inflammation that defines celiac disease is initiated by a HLA-DQ2 restricted T-cell response to ingested gluten peptides after their in vivo deamidation by tissue transglutaminase (TG2). To date, celiac disease can only be treated by a lifelong abstinence from foods that contain wheat, rye, or barley; better therapeutic options are hence needed. An attractive target would be to identify nontoxic wheat cultivars or components thereof with intact baking qualities. Because these qualities are mainly determined by the high molecular weight (HMW) glutenin proteins of gluten, it is critical to know if these proteins are toxic or, more specifically, if they will trigger the activation of T cells in the celiac lesion. METHODS: Different, highly purified HMW glutenins were isolated from wheat cultivars or expressed as recombinant proteins. The proteins were first tested for recognition by a large panel of gluten-specific T-cell lines established from celiac lesions and then applied during ex vivo challenges of celiac biopsies to allow for a direct identification of HMW specific T cells. RESULTS: Intestinal T-cell responses to TG2-deamidated HMW glutenins but not the corresponding native proteins were detectable in 9 of the 22 adult and childhood celiac disease patients tested. CONCLUSIONS: T cells within celiac lesions frequently recognize deamidated HMW glutenin proteins. This finding questions the possibility of implementing these proteins in novel food items destined to be nontoxic for celiac disease patients.

Adult↗
PubMed1990

Changes in distribution of Ia antigen on epithelium of the jejunum and ileum in rats infected with Nippostrongylus brasiliensis.

This study compared the tissue distribution and cellular expression of Ia antigen in jejunal and ileal epithelium at various stages of intestinal inflammation produced by infecting rats with the nematode parasite Nippostrongylus brasiliensis. Tissues were examined at Day 0 (control), Day 4 (early), Day 10 (acute), and Day 16 (recovering). Frozen sections were stained with the MRC OX-4 anti-Ia monoclonal antibody using an immunoperoxidase technique. Control jejunal sections demonstrated positive epithelial Ia expression mainly in the mid-regions of the villi. The stain appeared to be mostly intracellular in the supranuclear area; the basolateral membrane stained faintly. At Day 4, a greater percentage of the epithelial cells expressed Ia, including those at the tips of the villi. The Day 10 sections demonstrated no staining at all of villus enterocytes, but the crypt epithelium was Ia positive. At Day 16, the pattern of Ia expression was similar to that seen in the early infection. In the ileum, stain was present in enterocytes over most of the villus and crypt regions except in the villus-crypt junction and did not change significantly during infection. We conclude that the changes in the expression of Ia antigen by intestinal epithelium are local to the site of infection and probably occur as a consequence of the host's inflammatory response.

Animals↗
PubMed2002

Selective reduction of intestinal trefoil factor in untreated coeliac disease.

The trefoil factor family (TFF) encompasses small peptides of which intestinal trefoil factor (ITF) is expressed specifically in goblet cells of the small and large intestine. Previous studies have shown that ITF plays an important role in mucosal protection and repair. Coeliac disease represents a model of immune-mediated small intestinal inflammation and damage, with recovery on gluten-free diet. The aim of this study was to investigate the expression of ITF in the distal duodenal mucosa of subjects with coeliac disease, before and after treatment with a gluten-free diet. Expression of ITF and mucin in the distal duodenal biopsies from treated (n = 11) and untreated (n = 9) coeliac subjects and controls (n = 8) was investigated by immunohistochemistry and semiquantitative PCR. In untreated coeliac disease, there was reduction of ITF immunoreactivity in goblet cells but mucin expression was preserved. Mucosal recovery on gluten-free diet was associated with increased ITF immunoreactivity in goblet cells. There was also reduction in the expression of ITF transcripts, relative to MUC2 mRNA, in untreated coeliac duodenal samples, with recovery on gluten-free diet. Our study suggests that there is a selective reduction in the expression of the ITF gene in untreated coeliac disease. Recovery of ITF expression on a gluten-free diet suggests that the mucosal immune system regulates goblet cell differentiation and ITF expression in the human intestinal mucosa.

Adult↗
PubMed1994

Aetiology and pathogenesis of chronic inflammatory bowel disease.

While Crohn's disease and ulcerative colitis are both conditions characterized by intestinal inflammation, with some overlap in their clinical and histological features, they are essentially different in pathogenesis. Crohn's disease appears to be primarily a condition of chronic T-lymphocyte activation, with tissue damage induced by secondary macrophage activation. What activates the T-cells is unknown. In this chapter we look at the evidence for and against cell-wall deficient mycobacteria species, viral infection of vascular endothelium and luminal contents as potential mechanisms of chronic activation. In ulcerative colitis, by contrast, there is no strong evidence for T-cell activation, and humoral mechanisms predominate. While the finding of atypical anti-neutrophil cytoplasmic antibodies (P-ANCAs) may be useful in screening, the only novel pathogenetic discovery is the co-localization of a 40 kD colonic autoantibody with immunoglobulins and complement on the apical enterocyte surface. Despite the fundamental differences in initiating mechanisms, the two conditions have many 'downstream' inflammatory processes in common. We discuss the evidence for local production of cytokines, arachidonic acid metabolites and reactive oxygen and nitrogen radicals, highlighting the potential adverse consequences for intestinal vascular integrity.

Colitis, Ulcerative↗
PubMed1996

A receptor decoy inhibits the enterotoxic effects of Clostridium difficile toxin A in rat ileum.

BACKGROUND & AIMS: Clostridium difficile toxin A causes secretion and intestinal inflammation in rodents by binding to a specific trisaccharide Gal alpha 1-3Gal beta 1-4 GlcNAc on enterocyte receptors. The purpose of this study was to explore the ability of Synsorb 90 (Synsorb Biotech Inc., Calgary, Alberta, Canada), and inert support carrying this trisaccharide, to bind toxin A in vitro and to inhibit its enterotoxic effects in vivo. METHODS: Binding of [3H]toxin A to Synsorb 90, Synsorb 83 (beta-mannose attached), and Chromosorb P (inert support with no sugar attached) (Synsorb Biotech Inc.) was measured. The inhibitory effects of these compounds on toxin A-mediated fluid secretion, mannitol permeability, and histological damage were measured in ileal loops in vivo. RESULTS: Toxin A showed specific binding to Synsorb 90, bearing the specific trisaccharide that binds toxin A, but not to Synsorb 83 or to Chromosorb P. Pretreatment of rats with Synsorb 90 by gavage (200 mg/kg body wt), but no Synsorb 83 or Chromosorb P at the same doses, dramatically reduced toxin A-associated fluid secretion and permeability. CONCLUSIONS: An immobilized toxin A receptor sequesters toxin A in the intestinal lumen and inhibits its effects of ileal mucosa. These results suggest a potential use for this agent in treating patients with C. difficile colitis.

Animals↗
PubMed2006

Immunogenetic phenotypes in inflammatory bowel disease.

The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease (IBD) are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/or barrier function, with onset triggered by environmental stimuli. These factors and their interactions may also be important determinants of disease phenotype and disease progression. The emergence of immunogenetic phenotypes lends support to the proposed hypothesis that susceptibility genes regulate distinct immune processes, driven by luminal antigens, expressed as specific immune phenotypes which in turn influence clinical phenotypes in IBD patient.

Antibodies, Bacterial↗
PubMed2005

Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid.

AIM: To ascertain the molecule mechanism of nuclear factor-kappaB (NF-kappaB) inhibitor curcumin preventive and therapeutic effects in rats' colitis induced by trinitrobenzene sulfonic acid (TNBS). METHODS: Sixty rats with TNBS-induced colitis were treated with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine (SASP). Thirty negative control rats and thirty model rats were treated with general diet. Changes of body weight together with histological scores were evaluated. Survival rates were also evaluated. Cell nuclear NF-kappaB activity in colonic mucosa was evaluated by using electrophoretic mobility shift assay. Cytoplasmic IkappaB protein in colonic mucosa was detected by using Western Blot analysis. Cytokine messenger expression in colonic tissue was assessed by using semiquantitative reverse-transcription polymerase chain reaction. RESULTS: Treatment with curcumin could prevent and treat both wasting and histopathologic signs of rats with TNBS-induced intestinal inflammation. In accordance with these findings, NF-kappaB activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of cytoplasmic IkappaB protein in colonic mucosa were blocked by curcumin treatment. Proinflammatory cytokine messenger RNA expression in colonic mucosa was also suppressed. CONCLUSION: This study shows that NF-kappaB inhibitor curcumin could prevent and improve experimental colitis in murine model with inflammatory bowel disease (IBD). The findings suggest that NF-kappaB inhibitor curcumin could be a potential target for the patients with IBD.

Animals↗
PubMed1998

Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA.

Inflammation is characterized by increased nitric oxide production. Nitrotyrosine has recently been suggested to be useful as a marker for NO-mediated tissue damage. In context of the development of an ELISA for detection of nitrotyrosine in plasma, monoclonal anti-nitrotyrosine antibodies were developed by injecting mice with nitrated keyhole limpet hemocyanin. The specificity of the antibodies was determined by binding to nitrated BSA, lack of binding to unmodified BSA, tyrosine, 3-chlorotyrosine or phenylalanine and inhibition of binding by nitrotyrosine. The antibodies developed are useful for Western blot analysis and immunohistochemical staining. Using these antibodies a nitrotyrosine sandwich ELISA was developed with a lower detection limit of approximately 0.2 nM. The intra- and interassay variance were 2.4% and 11.9%, respectively. Using this newly developed ELISA, 1.27 +/- 1.03 microM nitrotyrosine was detected in plasma samples of celiac disease patients whereas nitrotyrosine was undetectable in control samples. Elevated nitrotyrosine levels were paralleled by an increase in plasma concentrations of NO-oxidation products (NOx), nitrite and nitrate from 15.1 +/- 6.1 microM in controls to 61.0 +/- 28.2 microM in celiac disease patients. Both nitrotyrosine and NOx levels declined when the patients were on a gluten-free diet, suggesting a relation between intestinal inflammation and plasma nitrotyrosine and NOx levels.

Animals↗
PubMed1983

A fifty year experience with Meckel's diverticulum.

Four hundred and two patients with Meckel's diverticulum are reviewed. Symptoms referable to the diverticulum occurred in 68 patients or 16.9 per cent of the group. Obstruction of the small intestine, inflammation and lower gastrointestinal tract bleeding accounted for 90 per cent of the presenting symptoms. A 10.3 per cent mortality and a 17.6 per cent morbidity rate were noted for symptomatic diverticuli. Patients most likely to have symptoms develop were 40 years of age, or younger; those whose diverticuli were 2 centimeters or more in length; those whose diverticuli contained heterotopic mucosa, and, probably, those who were males. Patients more than 40 years of age with diverticuli less than 2 centimeters in length with no heterotopic mucosa and who were females constitute a lower risk group. The decision to perform an incidental Meckel's diverticulectomy should be based upon the risk of the individual patient having symptoms develop from the diverticulum.

Adolescent↗
PubMed2004

Regulation of T-lymphocyte trafficking by ICAM-1, MAdCAM-1, and CCR7 in microcirculation of appendicular and intestinal lymphoid tissues.

OBJECTIVE: Although the appendix is recognized as an inductive site of intestinal inflammation, lymphocyte migration to lymphoid tissues of the appendix has not been characterized. The authors investigated if there are specific features in T-lymphocyte adhesion to microvessels of the appendix compared to mouse Peyer's patches (PPs). METHODS: T-lymphocyte interaction with postcapillary venules (PCVs) of lymph follicles of the appendix and PPs was observed using an intravital microscope. Antibodies against ICAM-1, MAdCAM-1, or anti-L-selectin were administered prior to lymphocyte administration, and in some experiments CCR7 on T-lymphocytes was desensitized by excess CCL21. RESULTS: The number of adhered T-lymphocytes reached the maximum value earlier in PCVs of PPs than in those of the appendix. T-lymphocyte adherence was significantly inhibited by anti-MAdCAM-1 at either the appendix or PPs, but adherence in the appendix was also significantly inhibited by anti-ICAM-1, suggesting a dependency on ICAM-1 in the appendix. Histologically, there was a significant ICAM-1 expression in the appendix. Desensitization of CCR7 suppressed T-cell adhesion in PCVs of the appendix and PPs to the same extent. CONCLUSION: ICAM-1 appeared to be more important in T-lymphocyte sticking in PCVs of the appendix compared with intestinal PPs, while MAdCAM-1 and CCR7 were shown to play important roles in T-lymphocyte adherence in all sites.

Animals↗
PubMed2004

Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine.

Oxidant stress has been implicated in the pathogenesis of inflammatory bowel disease. Antioxidant enzymes, such as superoxide dismutase (SOD), are candidate drugs for modulating this pathogenic factor. This study was designed to determine the therapeutic value of SOD in an experimental model of colitis and to study the mechanisms underlying its effects on intestinal inflammation. For that purpose, colitic (trinitrobenzene sulfonic acid-induced) and control rats were studied. Groups of colitic animals were treated with different doses of SOD (1, 4, or 13 mg/kg/day) or vehicle, starting after induction of colitis and during 7 days. Clinical and pathological markers of colitis severity and lipid peroxidation in colonic tissue were measured. Leukocyte-endothelial cell interactions in colonic venules and expression of vascular cell adhesion molecule 1 (VCAM-1) were determined. Development of colitis was associated with a significant loss in body weight, an increase in macroscopic and microscopic damage scores, and colonic myeloperoxidase activity. Administration of SOD significantly attenuated these changes in a dose-dependent manner and reduced lipid peroxidation in colonic tissue. The increase in leukocyte rolling and adhesion in colonic venules of colitic rats were significantly reduced by administration of SOD, 13 mg/kg/day. Development of colitis was associated with a marked increase in endothelial VCAM-1 expression, which was significantly reduced by treatment with SOD. In conclusion, treatment with SOD significantly reduces peroxidation reactions in the inflamed colon and affords significant amelioration of colonic inflammatory changes in experimental colitis. This effect is related to a reduction in VCAM-1 expression and leukocyte recruitment into the inflamed intestine.

Animals↗