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PubMed1997

Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis.

BACKGROUND: Aminosalicylates are used as standard treatment for maintaining remission in ulcerative colitis. As yet, there is no other existing alternative with proven efficacy. In light of the hypothesis that the intestinal environment may contribute to the pathophysiology of ulcerative colitis, a trial was conducted to test the effects of probiotic treatment with an oral preparation of non-pathogenic E. coli. METHODS: A total of 120 patients with inactive ulcerative colitis were included in a double-blind, double-dummy study comparing mesalazine 500 mg t.d.s. to an oral preparation of viable E. coli strain Nissle (Serotype 06: K5: H1) for 12 weeks with regard to their efficacy in preventing a relapse of the disease. Study objectives were to assess the equivalence of the clinical activity index (CAI) under the two treatment modalities and to compare relapse rates, relapse-free times and global assessment. RESULTS: The start and end scores of the CAI demonstrated no significant difference (P = 0.12) between the two treatment groups. Relapse rates were 11.3% under mesalazine and 16.0% under E. coli Nissle 1917 (N.S.). Life table analysis showed a relapse-free time of 103 +/- 4 days for mesalazine and 106 +/- 5 days for E. coli Nissle 1917 (N.S.). Global assessment was similar for both groups. Tolerability to the treatment was excellent and did not differ. No serious adverse events were reported. CONCLUSIONS: From the results of this preliminary study, probiotic treatment appears to offer another option for maintenance therapy of ulcerative colitis. Additional support is provided for the hypothesis of a pathophysiological role for the intestinal environment in ulcerative colitis.

Adult↗
PubMed1997

Treatment of corticosteroid-resistant ulcerative colitis with heparin--a report of 16 cases.

BACKGROUND: Heparin, a group of sulphated glycosaminoglycans, in addition to its anticoagulant activity, has a wide range of potentially anti-inflammatory effects. These include inhibition of neutrophil elastase and inactivation of chemokines. Previous reports of fortuitous improvement in ulcerative colitis patients treated with heparin for prophylaxis of venous thrombosis, prompted us to perform a pilot study in patients with corticosteroid-resistant ulcerative colitis. METHODS: Sixteen hospitalized patients in relapse from ulcerative colitis and unresponsive to high-dose corticosteroid therapy were treated with intravenous standard heparin (subcutaneous in two patients), the dose was adjusted to provide standard anticoagulant activity. Five patients continued with subcutaneous injections on discharge, with a gradual reduction in the frequency of doses. RESULTS: Within 1 week of starting heparin, 12/16 patients had shown a considerable reduction in stool frequency. After 2 weeks of heparin therapy median stool frequency had improved from 8.0/day (range 6.3-10.0) pre-treatment to 3.5/day (2.5-5.25) (P = 0.008), and by 4 weeks 12/16 achieved clinical remission, Four patients required elective colectomy. Three patients were treated with heparin on a second occasion during a relapse, two failed to respond and required subsequent colectomy. Nine remain well. No serious complications were seen due to the anticoagulant activity, apart from bruising at subcutaneous injection sites. CONCLUSION: The response to heparin in patients with ulcerative colitis resistant to standard therapy is encouraging and supports the previous uncontrolled evidence for a therapeutic effect. A controlled trial of heparin in ulcerative colitis is clearly indicated.

Adrenal Cortex Hormones↗
PubMed1997

Anti-thyroid drugs decrease mucosal damage in a rat model of experimental colitis.

BACKGROUND: Methimazole, an anti-thyroid drug, was recently found to be useful in the treatment of systemic lupus erythematosus and other autoimmune diseases. Moreover, decreased thyroid hormone production is associated with a variety of immunological manifestations, such as reduced activation of CD4+ cells, increased CD8+ cell activity and reduced soluble IL-2 receptors. In the present study we examined the effects of methimazole and propylthiouracil on a rat model of experimental colitis. METHODS: Colitis was induced by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB). Two weeks prior to induction of colitis, rats were treated by either methimaziole (0.04%) or propylthiouracil (0.01%) in drinking water after a week of free access to water. Rats were sacrificed 48 h or 7 days after induction of colitis. The colon was isolated, rinsed with ice-cold water and weighed. Damage was assessed both macroscopically and microscopically and myeloperoxidase (MPO) activity determined. RESULTS: All treated rats were hypothyroid as manifested by a significant elevation of thyroid stimulating hormone (TSH), by comparison with the control groups (mean -1.82 +/- 0.40 versus 0.11 +/- 0.02 mmol/L, respectively). The inflammatory response elicited by TNB resulted in severe mucosal damage 48 h after damage induction, which persisted for 7 days. Pre-treatment with either methimazole 0.04% or propylthiouracil 0.01% significantly decreased mucosal damage macroscopically (lesion area, lesion score and segmental weight) microscopically and also significantly decreased MPO level at both time points (P < 0.01). CONCLUSIONS: Methimazole and propylthiouracil significantly reduce mucosal damage and colonic weight in a rat model of colitis. The mode by which they do so remains to be studied.

Animals↗
PubMed1999

Immunosuppressive therapy for ulcerative colitis: results of a nation-wide survey among consultant physician members of the British Society of Gastroenterology.

BACKGROUND: The role of immunosuppressive therapy in ulcerative colitis remains controversial. There is little information available on how frequently immunosuppressives are used, the circumstances, dose and duration of use and perceived benefit. METHODS: A postal survey was sent to consultant gastroenterologist members of the British Society of Gastroenterology. RESULTS: Questionnaires were returned by 81% of the 496 UK consultants approached. Azathioprine use was frequent, with 93% reporting previous use and 86% use within the past year. Although 95% usually prescribed a < or =2 mg/kg dose, only 39% were prepared to prescribe higher doses. There was marked variation in duration of use, with 46% using azathioprine for <2 years and 17% continuing it for 4 years or longer. Consultants with more experience of azathioprine in ulcerative colitis used it at higher maintenance doses for longer periods, and in patients with less extensive disease. Cyclosporin use was reported by 47% of those caring for ulcerative colitis patients, with 36% having used it at least once in the past year. However, 65% of users estimated that fewer than 50% of patients subsequently avoided colectomy. On stopping cyclosporin only 21% always introduced an alternative immunosuppressive, while 23% never did so. Potentially serious side-effects attributable to azathioprine and cyclosporin were reported by 36% and 45% of users of each drug, respectively. CONCLUSIONS: This survey reveals considerable variation in the amount and pattern of immunosuppressive use in ulcerative colitis, with serious side-effects commonly seen. There is a pressing need for further randomized controlled trials to provide reliable evidence as to how immunosuppressive therapy should be used in ulcerative colitis.

Azathioprine↗
PubMed2000

Role of inducible nitric oxide synthase in dextran sulphate sodium-induced colitis.

BACKGROUND: Different authors have postulated both toxic and protective effects for nitric oxide (NO) in the pathophysiology of active inflammation. AIM: To examine the role of NO, especially that produced by the inducible form of nitric oxide synthase (iNOS), by investigating the effects of NOS inhibitors and NO donors on inflammation in experimental acute colitis. METHODS: Acute colitis was induced in rats by dextran sulphate sodium (DSS). White blood cell counts and levels of thiobarbituric acid reactants in the portal blood were determined, as were histological changes in the colonic mucosa. We then evaluated the effects of N(G)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and an NO donor on DSS-induced changes in these inflammatory parameters. RESULTS AND CONCLUSIONS: Inhibition of NO production by either L-NAME or AG worsened DSS-induced inflammation, suggesting a protective role for NO in acute colitis. On the other hand, a NO donor also exaggerated DSS-induced inflammatory parameters, suggesting that acute colitis may be aggravated by either too much or too little NO. These results suggest that medical treatment of ulcerative colitis must aim for maintenance of appropriate NO levels in the intestinal mucosa.

Animals↗
PubMed1998

Paracetamol metabolism in patients with ulcerative colitis.

AIMS: The capacity for sulphation of phenols appears to be impaired in the colonic mucosa of patients with ulcerative colitis. The aim of the present study was to investigate the systemic capacity for sulphation of phenols in patients with ulcerative colitis assessed by the metabolic clearances of paracetamol to the sulphate, glucuronide and glutathione derived metabolites. METHODS: Ten patients with ulcerative colitis and 10 control subjects received a single oral dose of paracetamol (1 g). Venous blood samples were collected frequently for pharmacokinetic determinations (one compartment model). Urine was collected for 24 h. Plasma samples were analysed for parent drug and urine samples for parent drug and metabolites by h.p.l.c. Partial metabolic clearances were calculated as the fractional urinary recovery of each conjugate multiplied by the apparent oral clearance of paracetamol. RESULTS: The apparent oral clearance of paracetamol and the partial clearances of its metabolites were not significantly different between the two study groups. Median value and the corresponding 25th and 75th percentiles for the clearance of the sulphate metabolites were 93.6 (82.5-138.8) ml kg(-1)h(-1) and 77.4 (75.5-99.1), patients with ulcerative colitis and control subjects, respectively. CONCLUSIONS: These results do not indicate a general impairment of the systemic capacity for sulphation of paracetamol in patients with ulcerative colitis.

Acetaminophen↗
PubMed1999

DNA aneuploidy as a marker of premalignancy in surveillance of patients with ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis have an increased risk of developing colorectal cancer. Specific and sensitive markers for premalignancy are needed. The present study evaluates the status of DNA aneuploidy (abnormal stemlines) as such a marker. METHODS: A prospective surveillance programme was conducted for all patients with ulcerative colitis from a defined area. Regular colonoscopy with mucosal sampling for histological evaluation and flow cytometric DNA analysis was performed. Some 147 patients were studied from 1984 to 1997. RESULTS: DNA aneuploidy was found in 20 patients. All but one had total colitis. The time from onset of disease to aneuploidy ranged from 5 to 31 years. Fourteen of the patients developed morphological alterations. In the same interval 127 patients, of whom 75 had total colitis, did not develop aneuploidy. Among patients with morphological alterations and aneuploidy, aneuploidy preceded these alterations in four patients and was present at the same examination in three; in seven patients the morphological alterations preceded the aneuploidy. Aneuploidy was diagnosed before the appearance of a dysplasia- associated lesion or mass in four of five cases. CONCLUSION: Flow cytometric DNA analysis has definite value as a complement to histological examinations in cancer surveillance of patients with ulcerative colitis. Aneuploidy indicates a high risk for developing severe premalignant changes. However, there is no evidence to support the use of DNA aneuploidy as a sole indication for prophylactic surgery against cancer.

Aneuploidy↗
PubMed2001

Tumour necrosis factor inhibitors reduce the acute-phase response in hapten-induced colitis.

BACKGROUND: Tumour necrosis factor (TNF) alpha has been implicated in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess the contribution of TNF to the pathogenesis of hapten-induced colitis. METHODS: Colitis was induced in Wistar rats using intracolonic instillation of the hapten trinitrobenzenesulphonic acid (TNBS) in ethanol. Animals were treated with monoclonal anti-TNF antibody (cTN3), an idiotype control antibody (CB0006) or pentoxifylline. Colonic and systemic inflammation was assessed quantitatively. RESULTS: The use of either TNF inhibitor attenuated the acute-phase response in the early stages of colitis. Median (interquartile range (i.q.r.)) alpha 2-macroglobulin levels were reduced in animals pretreated with cTN3 (421 (279-915) micromol/ml) or pentoxifylline (567 (253-1454) micromol/ml) compared with levels in untreated colitic animals (1552 (1406-1998) micromol/ml) (P < 0.001 and P = 0.006, respectively). In established colitis, administration of anti-TNF antibodies resulted in an increase in median (i.q.r.) weight gain (percentage change in body-weight): colitic animals -2.3 (- 5.5 to 9.2) per cent versus cTN3-treated rats 15 (7.5-16.7) per cent; P < 0.05. CONCLUSION: The systemic response to TNBS-induced colitis appears to be at least partially dependent on TNF. This study did not provide evidence to support a role for TNF in the pathogenesis of colonic inflammation in this model. Presented in part to the 86th meeting of the Surgical Research Society in Nottingham, UK, 9-11 July 1997, and published in abstract form as Br J Surg 1997; 84: 1613

Acute-Phase Reaction↗
PubMed1998

Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines.

Oral administration of DSS has been reported to induce an acute and chronic colitis in mice. The aim of our study was to evaluate if the chronic phase of DSS-induced colitis was characterized by a Th1/Th2 response and how this would relate to mucosal regeneration. Swiss Webster mice were fed 5% DSS in their drinking water for 7 days, followed by 2-5 weeks consumption of water. Control mice received only water. The animals were killed at 3 and 6 weeks after induction. Their colons were isolated for histology and immunohistochemistry, using specific MoAbs for T and B cells, macrophages, interferon-gamma (IFN-gamma), IL-4 and IL-5. Colons were scored for inflammation, damage and regeneration. Two weeks after stopping DSS the colonic epithelium had only partially healed. Total colitis scores were still increased, especially in the distal colon, which was due to more inflammation, damage and less regeneration. In areas of incomplete colonic healing the basal parts of the lamina propria contained macrophages and CD4+ T cells. These CD4+ T cells showed a focal increase of IFN-gamma and IL-4 staining compared with control animals. These findings were still observed 5 weeks after stopping DSS in some mice, albeit less extensive. Chronic DSS-induced colitis is characterized by focal epithelial regeneration and a Th1 as well as Th2 cytokine profile. We postulate that chronic immune activation mediated by both populations of Th cells can interfere with colonic healing and can play a role in the pathogenesis of chronic colitis.

Animals↗
PubMed2003

Contrasting activity of cytosin-guanosin dinucleotide oligonucleotides in mice with experimental colitis.

Intestinal inflammation in inflammatory bowel disease (IBD) and experimental models of colitis is characterized by a dysregulated intestinal immune response with elevated levels of Th1 cytokines. The luminal flora has been implicated as a major factor contributing to the initiation and perpetuation of inflammation in experimental colitis by mechanisms not known. Bacterial DNA contains unmethylated cytosin-guanosin dinucleotides (CpG) which strongly activate Th1-mediated immune responses. To test whether these CpG-motifs modulate intestinal inflammation we treated mice with dextran sulphate sodium (DSS)-induced colitis with CpG-containing oligodeoxynucleotides (CpG-ODN). CpG-ODN given after the onset of DSS colitis aggravated the disease, as indicated by a significantly increased loss of body weight and a 30% increase of the histological score. Further, we found a severe increase of proinflammatory cytokines (interleukin (IL)-6: 40-fold; interferon (IFN)-gamma: 11-fold). In a pretreatment setting CpG-ODN reduced weight loss significantly and reduced intestinal inflammation by 45%. Colonic IFN-gamma and IL-6 mRNA levels were reduced by 75%, and IL-10 was elevated by 400% compared to controls. The prophylactic CpG-effect was not imitated by IL-12 because IL-12 pretreatment was not protective. In time-course experiments, CpG-ODN pretreatment over 5 days resulted in a tolerance effect concerning its IFN-gamma-inducing quality, and during the following days of colitis induction IL-10 secretion from mesenterial lymph node cells was elevated compared to controls. Therefore, the prophylactic effect of CpG-ODN might be explained by its tolerizing effect and/or the increased ability for IL-10 production during the consecutive intestinal inflammation.

Acute Disease↗
PubMed1998

Distribution of calcitonin gene-related peptide, somatostatin, substance P and vasoactive intestinal polypeptide in experimental colitis in rats.

Immunohistochemistry was used to examine the distribution of calcitonin gene-related peptide (CGRP), substance P, somatostatin and vasoactive intestinal polypeptide (VIP) in experimental colitis induced with trinitrobenzene sulphonic acid (TNBS) in rats. CGRP immunoreactivity was observed throughout the colonic wall. A significant reduction of CGRP-immunoreactive (IR) nerve fibres was observed in the mucosa after the induction of colitis. After TNBS treatment substance P immunoreactivity was reduced throughout the colon; however, after 7 days there was a marked re-innervation of the circular muscle. Somatostatin immunoreactivity was distributed sparsely within the colonic wall, and was comparatively less affected by colitis. VIP immunoreactivity was abundantly distributed in the colonic wall and underwent an immediate reduction in the mucosa after TNBS treatment. After 2 days, there was a consistent and progressive increase in the number and density of VIP-IR nerve fibres in the inflamed colon, particularly the circular muscle. This change was associated with a proliferation of nerve fibres within the muscle layers. It was concluded that the early decrease in these neuropeptides was consistent with release from peripheral nerve terminals or the loss of nerves during the initial stages of colonic inflammation, which may be an essential condition for the development of colitis in this model. The observation that the intensity and density of substance P and VIP-IR nerve fibres increased in the circular muscle 7 days after the induction of colitis suggests their possible involvement in tissue repair.

Animals↗
PubMed1999

Altered myoelectrical activity in noninflamed ileum of rats with colitis induced by trinitrobenzene sulphonic acid.

Changes in gastric emptying and orocaecal transit time in patients with ulcerative colitis suggest that disturbances in gut motility may not be restricted to inflamed sites. This study sought to characterize changes in the motility of noninflamed ileum in a rat colitis model and to explore the mechanism(s) potentially involved. The myoelectrical activity of the ileum was recorded in rats with trinitrobenzene sulphonic acid (TNBS)-induced colitis. The degree of ileal and colonic inflammation was assessed by quantification of macroscopic damage and myeloperoxidase activity (MPO). The effect on ileal motility of pretreatment with atropine, indomethacin and NG-nitro-L-arginine-methyl ester (L-NAME) was investigated. TNBS-induced inflammation was restricted to the distal colon, as evidenced by morphological scores and MPO. Colitis was associated with increased frequency of ileal migrating motor complexes, characterized mainly by a decrease in the duration of phases I and III. The occurrence of ileal giant migrating complexes remained unchanged. The myoelectrical changes observed in the ileum persisted after treatment with atropine, indomethacin and L-NAME. Distal colitis is associated with abnormal myoelectrical activity in the noninflamed ileum of rats. Neither acetylcholine nor prostaglandins and nitric oxide seem to be involved.

Animals↗
PubMed2003

Phlebosclerotic colitis coincident with carcinoma in adenoma.

Phlebosclerosis of the colon is a rare disease characterized by a thickening of the wall of the colon with fibrosis, hyalinization and calcification to the affected veins. These symptoms result in a type of ischemic colitis known as phlebosclerotic colitis. A case of phlebosclerotic colitis coincident with carcinoma in adenoma is reported. A 74-year-old Japanese woman was admitted to hospital because of a mass in her right lower abdomen. Abdominal computed tomography examination revealed linear calcifications in the wall of the cecum and the ascending colon. Colonoscopy revealed dark purple mucosa with multiple ulcers in the cecum and the ascending colon. Biopsy specimens showed a marked hyalinous thickening of the wall of small blood vessels in the mucosa. Phlebosclerotic colitis was suspected because of negative results with amyloid stain. Alternative ileocolic angiography showed the serpentine of the peripheral nature blood vessels and pooling at the late venous phase. Microscopic examination of the surgically resected colon revealed mucosal and submucosal fibrosis, and a thickening of the venous wall with fibrosis, hyalinization and calcification from the mucosa to the serosa, which caused a marked luminal narrowing. A small polypoid lesion was also found in the affected region and was diagnosed histologically as carcinoma in adenoma. To our knowledge, this is the first reported case of phlebosclerotic colitis complicated by carcinoma.

Adenoma↗
PubMed2003

Successful treatment of ulcerative colitis with leukocytapheresis using non-woven polyester filter.

Ulcerative colitis is a chronic inflammatory disease of the rectum and colon. Although the pathogenesis of ulcerative colitis is not fully elucidated, cell-mediated immunity plays an important role in disease pathogenesis. Leukocytapheresis is a newly emerging therapy to eliminate activated leukocyte from systemic circulation. We have studied the effects of leukocytapheresis on patients with ulcerative colitis who had failed to respond to conventional therapy. A total of 51 patients with ulcerative colitis were treated with apheresis using a non-woven polyester fiber filter (Finecell, Asahi Medical Co.,Tokyo, Japan) originally developed as a microcoagulation elimination filter for massive transfusion. Of the 51 patients, 33 (64.7%) achieved clinical remission manifested by clinical activity and colonoscopic findings without any adverse effects. This result suggested that leukocytapheresis using Finecell might serve as an alternative therapy for ulcerative colitis as other leukocytapheresis using centrifugation or column.

Adolescent↗
PubMed1996

Colitis causes bone loss in rats through suppression of bone formation.

BACKGROUND & AIMS: Idiopathic inflammatory bowel disease (IBD) is associated with bone loss in more than 30% of cases. Nevertheless, the pathogenesis of the bone loss is uncertain. The aim of this study was to investigate the bone loss and underlying mechanisms using an animal model of IBD. METHODS: Severe colitis was induced by intrarectal administration of a hapten, 2,4,6-trinitrobenzenesulfonic acid (TNBS). Severity of IBD was graded macroscopically and histologically. Bone histomorphometry was performed on cancellous bone of the tibiae. RESULTS: A florid transmural colitis was observed 3 weeks after administration of TNBS. In these animals, there was considerable cancellous bone loss of 33% compared with age-matched, pair-fed control animals. This was associated with a marked suppression of the cancellous bone formation rate to < 30% of that in control animals. Thereafter, bone formation rate increased in parallel with healing of colitis. Twelve weeks after TNBS administration, the persistent increase in bone formation rate was associated with return of bone volume to control levels. CONCLUSIONS: The data suggest that bone loss can occur rapidly in colitis and is associated with suppression of bone formation. This study also shows that the bone loss that occurs during TNBS-induced colitis is reversible.

Animals↗
PubMed2000

Adrenal cortical activation in murine colitis.

BACKGROUND & AIMS: Proper adrenal glucocorticoid secretion is crucial in the course of inflammatory diseases. However, the function and structure of the adrenal glands have not been examined in inflammatory bowel diseases. METHODS: After induction of trinitrobenzene sulfonic acid (TNBS) colitis in SJL/J mice, plasma hormone and cytokine levels were measured, adrenal structure was analyzed by immunohistochemistry and electron microscopy, and adrenal cytokine/cytokine receptor expression were studied by RNase protection. RESULTS: Adrenals of colitic animals were enlarged and hypervascularized. These animals had a marked increase in plasma corticosterone levels during the course of colitis (270 +/- 34 vs. 16 +/- 11 ng/mL; P < 0.0001) but only a modest elevation of their concurrent adrenocorticotropin levels (57 +/- 13 vs. 29 +/- 9 pmol/L; NS). On electron microscopy, adrenocortical cells showed ultrastructural signs of marked stimulation, and intra-adrenal lymphocytes were frequently found in direct contact with these cells. Concurrent plasma levels of interleukin (IL)-6, the major cytokine activating the hypothalamic-pituitary-adrenal axis, were markedly increased (495 +/- 131 vs. 20 +/- 1.5 pg/mL; P < 0.0001), and this cytokine directly stimulated corticosterone secretion by adrenocortical cells in vitro. Intra-adrenal expression of IL-6 in animals with colitis was increased 80-fold, and the IL-6 receptor subunits IL-6R alpha and gp130 were present in the adrenal cells. Treatment of animals with neutralizing anti-IL-6 antibody reduced the TNBS-induced growth and activation of the adrenal cortices. CONCLUSIONS: Colitis is associated with a profound stimulation of adrenocortical cell function and glucocorticoid release. Direct immune-adrenal interactions seem to contribute to this activation of the adrenal glands during colitis.

Adrenal Cortex↗
PubMed2001

The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis.

BACKGROUND & AIMS: Differences in genetic background may play a role in the development of ulcerative colitis (UC)-related neoplasia. Loss of heterozygosity (LOH) of APC has been reported in human UC-associated neoplasia. To investigate the role of genetic differences in UC-associated neoplasia, we compared differences in dextran sodium sulfate (DSS) colitis-associated neoplasia between wild-type C57BL/6J mice (WT-DSS) and C57BL/6J mice with a germline mutation in Apc (Min-DSS). METHODS: DSS colitis was induced in female wild-type and Min mice. Age- and sex-matched non-DSS-treated Mins were also studied. Animals were sacrificed after 1 and 2 cycles of DSS. The cecums and large intestines were studied for numbers of dysplasias/cancers. Dysplasias were studied for LOH of Apc. RESULTS: No WT-DSS, 100% of Min-DSS, and 50% of non-DSS-treated Mins had dysplasia. The mean numbers of lesions per mouse were 0 (WT-DSS), 15.6 and 29.3 (1 and 2 cycles Min-DSS, respectively), 1.2 and 1.9 (age-matched control Min, 1 and 2 cycle equivalents, respectively; P < 0.0002, Min-DSS vs. WT-DSS and non-DSS-treated Min; P = 0.03, Min-DSS 2 cycle vs. Min-DSS 1 cycle). Cancers were seen in 0%, 22%, and 40% of non-DSS Min, Min-DSS-1 cycle, and Min-DSS-2 cycle animals, respectively. LOH of Apc was observed in 90.6% of dysplasias and 6% of nondysplastic mucosa. CONCLUSIONS: A germline mutation in Apc contributes significantly to the development of colitis-associated neoplasia. Colitis markedly accelerates the development of dysplasia and cancer in the Min mouse. Dysplasia in Min-DSS occurs through LOH of Apc.

Adenoma↗
PubMed2002

Rapid development of colitis in NSAID-treated IL-10-deficient mice.

BACKGROUND & AIMS: Interleukin (IL)-10 is an anti-inflammatory and immune regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central regulator of the mucosal immune response. Prostaglandins are lipid mediators that may be important mediators of intestinal inflammation. In this study we assessed the role of prostaglandins in the regulation of mucosal inflammation in the IL-10(-/-) mouse model of IBD. METHODS: Prostaglandin (PG) synthesis was inhibited with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity of inflammation was assessed histologically. Cytokine production was assessed by ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2) levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was assessed by Western blot analysis. RESULTS: Nonsteroidal anti-inflammatory drug (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast, NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of colitis characterized by infiltration of the lamina propria with macrophages and interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice. However, the combination of COX-1- and COX-2-selective inhibitors did induce colitis. CONCLUSIONS: NSAID treatment of IL-10(-/-) mice results in the rapid development of severe, chronic IBD. Endogenous PGs are important inhibitors of the development of intestinal inflammation in IL-10(-/-) mice.

Animals↗