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PubMed2001

Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis.

BACKGROUND & AIMS: Commonly accepted risk factors for colorectal carcinoma (CRC) in ulcerative colitis are duration and extent of disease. By identifying still unknown risk factors, surveillance strategies may be improved further. We investigated whether backwash ileitis is also a factor associated with CRC in ulcerative colitis. METHODS: Five hundred ninety consecutive patients with ulcerative colitis who received restorative proctocolectomy were classified into 3 groups: (1) pancolitis with backwash ileitis, (2) pancolitis without backwash ileitis, and (3) left-sided colitis. The association with CRC was analyzed in these 3 groups of patients. As further risk factors, we investigated disease duration, dysplasia, primary sclerosing cholangitis, age at diagnosis of disease, disease activity, and gender. Univariate and multivariate logistic regression were used for analysis. RESULTS: CRC was diagnosed in 11.2% of all patients. CRC was found in 29.0% of 107 patients in group 1, compared with 9.0% of 369 patients in group 2, and in 1.8% of 114 patients in group 3 (P < 0.001). Cancer patients in group 1 showed significantly more multiple tumor growth (45.2%) than patients in group 2 (24.2%) and group 3 (0%) (P = 0.041). Estimating the relative risk for CRC in the multivariate analysis, patients in group 1 showed a significantly higher odds ratio than patients in groups 2 and 3 (odds ratio: 19.36 vs. 9.58 vs. 1; P < 0.001). High-grade dysplasia, low-grade dysplasia, disease duration of more than 10 years, and disease duration of less than 10 years in patients older than 45 years were further factors with significantly increased risk (odds ratios: 21.69, 6.36, 3.63, 4.37), but primary sclerosing cholangitis was not (P = 0.080). However, primary sclerosing cholangitis was strongly associated with backwash ileitis. CONCLUSIONS: There is a strong association of backwash ileitis with CRC in patients with ulcerative colitis who undergo proctocolectomy. The predictive value of backwash ileitis for CRC and premalignant dysplasia in patients with ulcerative colitis should be investigated in future studies based on colonoscopic surveillance.

Adolescent↗
PubMed2002

Distinct inflammatory mechanisms mediate early versus late colitis in mice.

BACKGROUND & AIMS: Progression from the acute to chronic phase of inflammatory bowel disease cannot be easily evaluated in patients and has not been characterized in animal models. We report a longitudinal study investigating changes in the mucosal immune response in an experimental model of colitis. METHODS: Severity of colitis, body mass, stool consistency and blood content, serum amyloid A, and tissue histology were examined in interleukin (IL)-10-deficient mice over 35 weeks. The corresponding production of IL-12, IL-18, interferon gamma, tumor necrosis factor alpha, IL-4, and IL-13 by lamina propria mononuclear cells in the inflamed intestine was measured. Administration of neutralizing antibody to IL-12 at distinct times during disease progression permitted evaluation of its therapeutic potential. RESULTS: The clinical manifestations and intestinal inflammation delineated an early phase of colitis (10-24 weeks), characterized by a progressive increase in disease severity, followed by a late phase (>25 weeks), in which chronic inflammation persisted indefinitely. Lamina propria mononuclear cells from mice with early disease synthesized progressively greater quantities of IL-12 and interferon gamma, whereas production of both cytokines dramatically declined and returned to pre-disease levels in the late phase of colitis. Consistent with this pattern, neutralizing antibody to IL-12 reversed early, but not late, disease. In contrast, IL-4 and IL-13 production increased progressively from pre- to early to late disease. CONCLUSIONS: Colitis that develops in IL-10-deficient mice evolves into 2 distinct phases. IL-12 plays a pivotal role in early colitis, whereas its absence and the synthesis of IL-4 and IL-13 in late disease indicate that other immune mechanisms sustain chronic inflammation.

Acute Disease↗
PubMed2003

Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice.

BACKGROUND & AIMS: Indoleamine 2,3-dioxygenase (IDO), an interferon gamma-induced intracellular enzyme, inhibits lymphocyte proliferation through tryptophan degradation. IDO is highly expressed in the mammalian intestine. We sought to determine whether IDO played a regulatory role in the T-cell helper 1 (Th1)-mediated trinitrobenzene sulfonic acid (TNBS) model of colitis. METHODS: Intrarectal TNBS was given to SJL/J mice along with either placebo or a specific IDO inhibitor. IDO protein and mRNA expression were assessed by Western blotting and real-time PCR. Colonic lamina propria mononuclear cells (LPMNCs) were isolated, fractionated, and cultured, in the presence and absence of IFN-gamma, to determine the cell type(s) expressing IDO. RESULTS: IDO is expressed by professional antigen-presenting cells in the lamina propria. Induction of TNBS colitis resulted in a significant increase in IDO mRNA (P = 0.005) and protein expression. IDO inhibition during TNBS colitis resulted in an 80% mortality compared with 10% for placebo-treated animals (P = 0.0089). IDO inhibition resulted in a more severe colitis both histologically and morphologically (P < 0.05) and significantly increased colonic proinflammatory cytokine expression compared with placebo-treated animals. CONCLUSIONS: IDO is expressed in the normal colon and is up-regulated in the setting of TNBS colitis. Inhibition of IDO during TNBS colitis resulted in increased mortality and an augmentation of the normal inflammatory response. These findings suggest that IDO plays an important role in the down-regulation of Th1 responses within the gastrointestinal tract.

Animals↗
PubMed2004

Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis.

BACKGROUND & AIMS: We tested whether the attenuation of experimental colitis by live probiotic bacteria is due to their immunostimulatory DNA, whether toll-like receptor (TLR) signaling is required, and whether nonviable probiotics are effective. METHODS: Methylated and unmethylated genomic DNA isolated from probiotics (VSL-3), DNAse-treated probiotics and Escherichia coli (DH5 alpha) genomic DNA were administered intragastrically (i.g.) or subcutaneously (s.c.) to mice prior to the induction of colitis. Viable or gamma-irradiated probiotics were administered i.g. to wild-type mice and mice deficient in different TLR or in the adaptor protein MyD88, 10 days prior to administration of dextran sodium sulfate (DSS) to their drinking water and for 7 days thereafter. RESULTS: Intragastric and s.c. administration of probiotic and E. coli DNA ameliorated the severity of DSS-induced colitis, whereas methylated probiotic DNA, calf thymus DNA, and DNase-treated probiotics had no effect. The colitis severity was attenuated to the same extent by i.g. delivery of nonviable gamma-irradiated or viable probiotics. Mice deficient in MyD88 did not respond to gamma-irradiated probiotics. The severity of DSS-induced colitis in TLR2 and TLR4 deficient mice was significantly decreased by i.g. administration of gamma-irradiated probiotics, whereas, in TLR9-deficient mice, gamma-irradiated probiotics had no effect. CONCLUSIONS: The protective effects of probiotics are mediated by their own DNA rather than by their metabolites or ability to colonize the colon. TLR9 signaling is essential in mediating the anti-inflammatory effect of probiotics, and live microorganisms are not required to attenuate experimental colitis because nonviable probiotics are equally effective.

Absorption↗
PubMed2006

CD8+ cytotoxic T cells induce relapsing colitis in normal mice.

BACKGROUND & AIMS: Most mouse models of IBD have emphasized an effector role of type-1 CD4+ T cells in colitis. The aim of this study was to develop a model of antigen-specific relapsing colitis to investigate the relative contribution of CD4+ and CD8+ effectors. METHODS: Balb/C mice were sensitized and challenged with a suboptimal dose of 2.4 dinitrobenzene sulfonic acid to generate a colonic delayed-type hypersensitivity response. The respective role of CD4+ and CD8+ T cells in the initiation of colitis was analyzed by in vivo monoclonal antibody depletion and cell-transfer experiments. Dynamic and function of the colitogenic effectors were studied by immunohistochemistry, fluorescence-activated cell sorter analysis, enzyme-linked immunospot assay, quantitative polymerase chain reaction, and in vivo CTL assays. RESULTS: Relapsing colitis rapidly occurred only after challenge of previously sensitized mice. Interferon-gamma-producing cytotoxic CD8+ T cells (Tc1) specific for hapten-modified self-proteins were generated in colon-draining lymph nodes on day 5 after sensitization, before the onset of disease. These CD8+ T cells were rapidly recruited upon challenge into colon lamina propria as granzyme B-expressing effectors exerting ex vivo cytotoxicity against syngeneic hapten-modified colonic epithelial cells. Colitis was prevented by in vivo antibody depletion of CD8+, but not of CD4+, T cells and could be induced in naive recipients within 48 hours after transfer of CD8+, but not CD4+, T cells purified from sensitized mice. CONCLUSIONS: Our data show that antigen-specific CD8+ T cells can induce relapsing colitis in normal mice and suggest that the cytolytic function of CD8 Tc1 against epithelial cells may initiate the intestinal inflammatory process.

Animals↗
PubMed2006

Effect of adiponectin on murine colitis induced by dextran sulfate sodium.

BACKGROUND & AIMS: Adiponectin, an adipose tissue-derived hormone, exhibits anti-inflammatory properties and has various biological functions, such as increasing insulin sensitivity, reducing hypertension, and suppressing atherosclerosis, liver fibrosis, and tumor growth. The aim of the present study was to determine the effect of adiponectin on intestinal inflammation. METHODS: We investigated the effect of adiponectin on dextran sulfate sodium (DSS)-induced colitis by using adiponectin-knockout (APN-KO) mice and an adenovirus-mediated adiponectin expression system. We also examined the contribution of adiponectin deficiency to trinitrobenzene sulfonic acid (TNBS)-induced colitis. In vitro, we examined the effect of adiponectin on intestinal epithelial cells. RESULTS: After administration of 0.5% DSS for 15 days, APN-KO mice developed much more severe colitis compared with wild-type mice. The messenger RNA expression levels of chemokines were significantly higher in the colonic tissues of DSS-treated APN-KO mice compared with wild-type mice, accompanied by increased cellular infiltration, including macrophages. Adenovirus-mediated supplementation of adiponectin significantly attenuated the severity of colitis, but there were no differences in the severity of TNBS-induced colitis between the 2 groups. Adiponectin receptors were expressed in intestinal epithelial cells, and adiponectin inhibited lipopolysaccharide-induced interleukin-8 production in intestinal epithelial cells. CONCLUSIONS: Adiponectin is protective against DSS-induced murine colitis, probably due to the inhibition of chemokine production in intestinal epithelial cells and the following inflammatory responses, including infiltration of macrophages and release of proinflammatory cytokines.

Adiponectin↗
PubMed1995

[The computed tomographic morphology of Crohn's disease and ulcerative colitis].

PURPOSE: To assess the value of computed tomography for the diagnosis of Crohn's disease and ulcerative colitis. METHOD: We analysed the CT examinations of 109 patients with 197 involved bowel locations. 81 patients suffered from Crohn's disease, 28 from ulcerative colitis. Diagnosis was based on the combination of clinical, endoscopic and histopathologic findings. Three radiologists evaluated the CT series concerning the presence of morphologic changes analogous to conventional radiographic findings. RESULTS: In Crohn's disease, we found irregular outer contours in 26% of cases. The bowel wall was thickened in 82%. In acute phases, the bowel wall was thickened in 100%. Abscess and fistula as complications of inflammatory disease were present in 26 and 14% respectively. In ulcerative colitis, a target sign of the bowel wall was present in 40%, whereas in Crohn's disease a homogeneous wall density was present in all but two cases. Reduced attenuation due to submucosal fat deposits was found in 16% and mucosal tunneling in 27% of cases with ulcerative colitis. Even if severe mucosal destructions were found, the outer contour of the gut was smooth and regular in 95% of the ulcerative colitis cases. CONCLUSION: CT can provide additional information on acuity, extent and complications in inflammatory bowel disease. In combination with conventional radiographic findings a three-step classification for Crohn's disease and ulcerative colitis (early changes, acute and chronic phase) can be proposed.

Adolescent↗
PubMed1987

Risk of ulcerative colitis among former and current cigarette smokers.

We performed a case-control study of the effect of tobacco smoking on the risk of acquiring ulcerative colitis among the 304,000 members of a health maintenance organization. Smoking histories before the date of the onset of ulcerative colitis were compared in 212 cases and an equal number of controls matched for age and sex who were selected from the enrollment file of the health maintenance organization. The relative risk of ulcerative colitis among current cigarette smokers as compared with nonsmokers was 0.6 (95 percent confidence interval, 0.4 to 1.0); however, among former cigarette smokers it was 2.0 (95 percent confidence interval, 1.1 to 3.7). These values remained after adjustment for socioeconomic factors and for coffee and alcohol consumption. The higher risk among former smokers could not be explained by postulating that smokers gave up tobacco near the time of disease onset because of early symptoms of ulcerative colitis. The relative risk of ulcerative colitis among former smokers increased in proportion to the cumulative number of cigarettes smoked before the onset of disease, suggesting a causal relationship between this exposure and disease occurrence. No difference in risk was observed among current smokers according to cumulative amount smoked. We conclude that former and current tobacco use may have opposite effects on the risk of acquiring ulcerative colitis.

Adolescent↗
PubMed2002

What is diverticular colitis?

Diverticular colitis is the term used to describe a particular pattern of active chronic inflammation in the sigmoid colon affected by diverticular disease, namely the occurrence of luminal mucosal inflammation, whether or not there is evidence of inflammation within and/or around the diverticula themselves. The pathogenesis remains uncertain but is almost certainly multifactorial. In some cases mucosal prolapse, faecal stasis and relative mucosal ischaemia have been implicated as important pathogenetic factors, whilst other cases are clearly the result of a mass effect caused by subserosal peridiverticulitis and suppuration. Symptoms and endoscopic findings are diverse. Histologically, the disease may vary from modest inflammatory changes with vascular ectasia, through classical mucosal prolapse changes, to florid active chronic inflammation, closely mimicking chronic inflammatory bowel disease, especially ulcerative colitis. Thus, accurate clinical and endoscopic correlation is vital for the attainment of the correct diagnosis. Diverticular colitis may respond well to treatment similar to that used for chronic inflammatory bowel disease, adding to the similarities of this disease, notably localised to the sigmoid colon, and ulcerative colitis. Indeed, in a few cases described in the literature, diverticular colitis may 'progress' to otherwise classical ulcerative colitis, suggesting, in some cases at least, a similar pathogenesis.

Chronic Disease↗
PubMed2001

Mycophenolate mofetil reduces tissue damage and inflammation in an experimental model of colitis in rats.

BACKGROUND: Lymphocytes are widely believed to be responsible for persistent intestinal inflammation in inflammatory bowel diseases. Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits lymphocyte proliferation and has been shown to be effective in preventing allograft rejection after organ transplantation. The purpose of this study was to assess the modulating effects of MMF on intestinal inflammation in an experimental model of colitis in rats. METHODS: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in ethanol in male Sprague-Dawley rats. One group of rats (n = 10) was treated with MMF i.p. (25 mg/kg b.w.) daily for 1 week starting 24 h after induction of colitis. A second group of rats (n = 10) was treated with MMF at the same dose 2 days, I day and 1 h prior to induction of colitis. Control animals (n = 10) received vehicle only. After being killed, colonic tissue was macroscopically evaluated for necrosis and microscopically for ulcerations. Sections were stained and examined for the presence of granulocytes. RESULTS: Administration of MMF after induction of TNBS colitis reduced macroscopic injury by 62% compared to control animals (P = 0.01). Microscopic ulcerations were reduced by 64% compared to controls (P = 0.009). In addition, posttreatment significantly reduced the number of granulocytes. MMF pretreatment did not significantly prevent macroscopic or microscopic tissue damage, or change the number of granulocytes. CONCLUSION: Systemic administration of MMF significantly ameliorates tissue damage in a model of experimental colitis in rats suggesting that this compound may play an important role as an immunosuppressant in the therapy of inflammatory bowel diseases.

Animals↗
PubMed2001

Low molecular weight heparin treatment in steroid refractory ulcerative colitis: clinical outcome and influence on mucosal capillary thrombi.

BACKGROUND: In ulcerative colitis, a state of hypercoagulation has frequently been observed. Unfractionated heparin has shown beneficial effects as an adjuvant treatment of steroid refractory ulcerative colitis in open trials and in one placebo-controlled trial. Low molecular weight heparin (LMWH) offers advantages in the method of administration, but it has not been evaluated in severe ulcerative colitis. We therefore assessed the tolerability, safety and potential therapeutical effects of LMWH in hospitalized patients with steroid refractory ulcerative colitis. METHODS: Twenty-five patients with severely active ulcerative colitis were included in an open-labelled trial. All patients had a flare-up of disease under glucocorticosteroid treatment. Nadroparine calcium 5.700 IE anti-Xa/0.6 mL s.c. was self-administered twice daily for 8 weeks. Patients were monitored for possible adverse events, and changes in clinical symptoms and in laboratory, endoscopical and histological results were analysed. RESULTS: Tolerability and compliance were excellent and no serious adverse events occurred. In 20 of 25 patients, a good clinical and laboratory response was observed. Also, the endoscopic and histological signs of inflammation were found to be significantly improved. However, this was not accompanied by a significant reduction in the number of mucosal microvascular thrombi after 8 weeks of LMWH treatment. CONCLUSION: LMWH may be a safe adjuvant therapy for patients with active, glucocorticosteroid refractory ulcerative colitis.

Anticoagulants↗
PubMed2002

Effects of topical ropivacaine on eicosanoids and neurotransmitters in the rectum of patients with distal ulcerative colitis.

BACKGROUND: Topical administration of lidocaine has been suggested to have beneficial clinical effects in patients with active ulcerative colitis, but the mechanism of action, if any, remains obscure. As local anaesthetics may exert anti-inflammatory actions through their inhibition of nervous reflexes, we have studied the local effects of a single rectal dose of ropivacaine gel on rectal concentrations of eicosanoids and neurotransmittors in patients with relapsing ulcerative colitis. METHODS: In a randomized, double-blind, placebo-controlled study, concentrations of leukotriene B4, thromboxane B2 and prostaglandin E2 in rectal dialysates and concentrations of substance P, neurokinin A, somatostatin, vasoactive intestinal polypeptide and calcitonin gene-related peptide in rectal biopsies from 19 patients with active, distally located, ulcerative colitis were measured before and after rectal administration of a 200-mg dose of ropivacaine- or placebo-gel by use of radioimmunoassays. For comparison with normal conditions, concentrations of neuropeptides were measured in another 19 patients with relapsing ulcerative colitis and 14 controls with non-inflamed colon. RESULTS: No significant changes in concentrations of eicosanoids or neuropeptides were observed after ropivacaine or placebo administration. Baseline concentrations of all neuropeptides, except somatostatin, were significantly lower in active ulcerative colitis than in controls with non-inflamed colon. CONCLUSIONS: These findings reveal no evidence of anti-inflammatory actions by ropivacaine in active ulcerative colitis and thus provide no rationale for topical treatment with local anaesthetics.

Administration, Rectal↗
PubMed2002

Galacto-oligosaccharides stimulate the growth of bifidobacteria but fail to attenuate inflammation in experimental colitis in rats.

BACKGROUND: Galacto-oligosaccharides potentially attenuate colonic inflammation by two mechanisms: through beneficial effects on intestinal microflora and by increasing the colonic short-chain fatty acid concentration. The purpose of this study was to investigate the effects of galacto-oligosaccharides on the development of inflammation and on the growth of bifidobacteria in trinitrobenzene sulphonic acid (TNBS)-induced colitis, a model that has been shown to benefit from short-chain fatty acid administration and to be associated with alterations in the colonic microflora. METHODS: Rats were given daily either whey-derived or lactose-derived galacto-oligosaccharides (4 g kg(-1) day(-1), p.o.); starting 10 days before colitis induction, or dexamethasone (2 mg kg(-1) day(-1), s.c., a positive control), starting at colitis induction. Colon wet weight, macroscopic damage and myeloperoxidase activity were assessed 72 h after the induction of colitis. Faecal bifidobacteria were counted at the beginning of the study, and immediately before and 72 h after colitis induction. RESULTS: Galacto-oligosaccharides increased the colonic levels of bifidobacteria but also the levels of other bacterial species. Neither whey-derived nor lactose-derived galacto-oligosaccharides reduced the severity of inflammation. CONCLUSIONS: Galacto-oligosaccharides are able to modify gut microflora in severe TNBS-induced colitis, but unable to attenuate the inflammation.

Animals↗
PubMed2002

Cyclooxygenase-2 inhibition and experimental colitis: beneficial effects of phosphorothioated antisense oligonucleotide and meloxicam.

BACKGROUND: The effects of cyclooxygenase-2 (cox-2) inhibition by a cox-2 selective antisense phosphorothioated oligonucleotide (AS) and meloxicam were examined in experimental colitis. METHODS: Colitis was induced by trinitrobenzenesulphonic acid (TNBS) and acetic acid (Hac) separately in male Sprague-Dawley rats. Both groups of animals were treated daily intraperitoneally with AS and a mismatched control oligo (CO) (3 mg/kg), and orally with meloxicam (7.5 mg/kg) 1 h before induction of colitis. The animals were killed on day 4 (Hac) and on day 5 (TNBS). Tissue samples from colon, ileum, liver, kidney and spleen were collected for mRNA, myeloperoxidase activity (MPO), prostaglandin E2 (PGE2) estimation and for histology, and blood samples for PGE2, thromboxane B2 (TxB2) and TNF-alpha. RESULTS: Both TNBS and Hac increased colonic MPO activity, PGE2 concentrations and infiltration of colonic wall by inflammatory cells. Serum levels of TNF-alpha were increased in both models, whereas PGE2 was increased only in TNBS colitis. Only meloxicam suppressed the level of PGE2 significantly below the basal level. The animals in both models also showed splenomegaly. The colitis-induced changes were significantly suppressed by the treatment of the test compounds but not by the CO. Cox-2 mRNA but not cox-1 was decreased by the AS, but not by meloxicam or in CO-treated colitic animals. CONCLUSION: The findings demonstrate comparable beneficial effects of the cox-2 selective antisense oligonucleotide and meloxicam, which seem to be mediated by a combined inhibition of both PGE2 and TNF-alpha in the present models of colitis.

Animals↗
PubMed2000

Effects of trimetazidine on oxidant/antioxidant status in trinitrobenzenesulfonic acid-induced chronic colitis.

Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male Swiss Albino rats with ethanol (50%) and trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) produced colitis as evidenced by histopathologic damage and inflammatory alterations, lipid peroxidation [increased malondialdehyde (MDA) levels], and enhanced neutrophil infiltration [increased myeloperoxidase (MPO) activity] without marked change in glutathione status. Administration of TMZ (5 mg/kg) to TNBS-treated rats failed to affect the TNBS-induced changes in histopathology and MPO activities. Unexpectedly, intrarectal (i.r.) administration of TMZ significantly elevated colonic MDA levels to a greater extent than TNBS alone. Intraperitoneal (i.p.) TMZ treatment seemed to increase total glutathione (tGSH), GSH, and GSH/GSSG values. In conclusion, our results demonstrated that (a) i.r. administration of ethanol and TNBS is an effective way of inducing a chronic colitis model, (b) inflammation and lipid peroxidation augment tissue damage in the chronic colitis model, (c) i.p. TMZ treatment significantly inhibits MDA production in the chronic colitis model, (d) TMZ treatment is more effective via the i.p. compared to i.r. route, and (e) TMZ seems to show its antioxidant effect via preserving the tissue's GSH/GSSG ratios.

Administration, Rectal↗
PubMed2003

Effects of trimetazidine on acetic acid-induced colitis in female Swiss rats.

Induction of colitis by acetic acid (AA) in the rat is widely used experimental model of inflammatory bowel disease (IBD) and ulcerations. AA as an irritant induces colitis involving infiltration of colonic mucosa with neutrophils and increased production of inflammatory mediators, such as hydrogen peroxide (H2O2), nitric oxide (NO), myeloperoxidase activity (MPO), and tumor necrosis factor (TNF-alpha). Trimetazidine (TMZ), an antianginal compound, was administered to investigate if its cytoprotective features in cardiac tissue are also effective in AA colitis where ischemic injury contributes to colitis. Administration of TMZ intraperitoneally improved the macroscopic and microscopic score alterations produced by AA. AA administration significantly elevated colonic MPO activity; however, treatment with TMZ significantly lowered this enzyme activity compared to AA. AA administration significantly enhanced superoxide dismutase (SOD) activities, except for AA + TMZ given rectally. TMZ treatment significantly lowered nitrate levels, but AA increased these levels. AA administration markedly lowered TNF-alpha levels, but TMZ treatment elevated these levels to control. These findings indicate that overproduction of NO may be involved in the immunosuppression observed during acute AA-induced rat colitis. In conclusion, TMZ treatment was more effective via the intraperitoneal than rectal route, and may be beneficial in therapy of colitis.

Acetic Acid↗
PubMed1996

Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance.

In previous studies we showed that a chronic colitis associated with a Th1 T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation of mucosal T cells producing TGF-beta and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-beta and secreted increased amounts of IL-4 and IL-10 but lower levels of IFN-gamma in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-beta but decreased IL-12 expression by immunohistochemical studies and isolated mononuclear cells from HCP-fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration of anti-TGF-beta or rIL-12 suggesting a reciprocal relationship between IL-12 and TGF-beta on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-beta production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-beta levels may have relevance to the treatment of human inflammatory bowel disease.

Animals↗
PubMed1996

T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice.

Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10-/- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG-2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon-gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule.

Animals↗