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PubMed2006

The new low calcemic vitamin D analog 22-ene-25-oxa-vitamin D prominently ameliorates T helper cell type 1-mediated colitis in mice.

In addition to its well defined role as a key regulator of calcium and bone metabolism, 1,25-dihydroxyvitamin D(3) (calcitriol) has been established as a potent modulator of immune cell function. Still, because of the hypercalcemic toxicity occurring after systemic application of the parent compound, its clinical application as an immunosuppressant has been hampered. Recently, we described 22-ene-25-oxa-vitamin D (ZK156979) as a representative of a novel class of low calcemic vitamin D analogs with well preserved immunosuppressive activity in vitro. Here, in vivo colitis was induced by applying a rectal enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to male BALB/c mice, and calcitriol (0.2 microg/kg) or ZK156979 (0.1-2.0 microg/kg) was given i.p. from days 0 to 3 or 3 to 5. Body mass and clinical activity score of colitis were recorded daily. Colon tissue was analyzed macroscopically and microscopically, myeloperoxidase activity and cytokine levels [tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-10, and IL-4] were determined by enzyme-linked immunosorbent assay, and T-box transcription factor (T-bet) expression was determined by immunoblot analysis. We found that treatment with ZK156979 clearly reduced the severity of TNBS-induced colitis without exhibiting calcemic effects. Both early and late treatment abrogated body weight loss, diarrhea, and macroscopic intestinal inflammation with a potency comparable with that of calcitriol. The therapeutic effect of ZK156979 was accompanied by a down-regulation of myeloperoxidase activity, TNF-alpha, IFN-gamma, and T-bet expression decreased, whereas local tissue IL-10 and IL-4 protein levels increased. To conclude, our data provide the first clear evidence that ZK156979 exhibits a beneficial prophylactic as well as therapeutic profile in T helper cell type 1-like experimental colitis, offering new therapeutic options for the treatment of human inflammatory bowel diseases.

Animals↗
PubMed2002

Temporal changes in colonic vascular architecture and inflammatory mediator levels in animal models of colitis.

This study investigated the temporal relationship between inflammatory mediator production and colonic vascular architecture in rabbit and rat trinitrobenzene sulfonic acid (TNBS) models of colitis. In both species significant colonic damage and loss of mucosal integrity occurred over time. In the rabbit there was a significant increase in TxB2 levels in the muscularis propria and mucosa at 1, 6, and 48 hr after TNBS, with a significant elevation in PGE2 production in the muscularis propria at 48 hr. However, elevated mediator levels were not associated with measurable changes in vascular architecture. In contrast, significant changes in the numbers and diameters of colonic blood vessels were observed in the rat, in the absence of significant elevations in TxB2 or PGE2 levels. These data suggest that the role of lipid mediators in acute colitis is species-dependent and, although there are corresponding gross and microscopic changes in both models, these occur through disparate mechanisms.

Animals↗
PubMed1994

Pathological features of inflammatory bowel disease in childhood.

Inflammatory bowel disease (IBD) in childhood is realistically interpreted to mean ulcerative colitis (UC) and Crohn's disease of the colon. Their gross and microscopic features are discussed along with the differential diagnosis from other childhood conditions associated with bloody diarrhea.

Child↗
PubMed1982

[Collagenous colitis (author's transl)].

Collagenous colitis, reported four times until now, is characterised histologically by subepithelial tape-like collagen deposits in the rectum and colon. On endoscopy the mucosa appears normal or slightly oedematous. The main symptom is chronic watery diarrhoea without admixture of blood. The cause of diarrhoea is thought to be defective absorption of electrolytes in the colon as a consequence of the pathological collagen deposition. Using endoscopic, histological and electron microscopic findings two further cases of so-called collagenous colitis could be detected. In one of the two female patients chronic watery diarrhoea occurred connected time-wise with the administration of an H2 receptor antagonist. In addition, a clearly increased pancreatic polypeptide (PP) in serum was demonstrated without proof of an endocrinologically active (pancreatic) tumour.

Colitis↗
PubMed1997

[Chronic diarrhea: a difficult diagnosis. A rare cause: lymphocytic colitis].

Lymphocytic colitis is a clinicopathological entity, characterized by chronic watery diarrhea, not bloody. Previously termed microscopic, it is now named lymphocytic for histological features, the most important seems to be the diffuse infiltration of intraepithelial lymphocytes, that must be investigated in multiple biopsies during colonoscopy. This review evidences that during endoscopy the mucosa is normal, but this does not exclude a biopsy, only way for take a diagnosis. Ethiologies are unknown too although a correlation with autoimmune diseases as possible. Lymphocytic colitis is a definition histological entity, while the term ''microscopic'' includes different histological entities under the same ''umbrella'', in relation to the concept of no macroscopic changes and multiple different histological specimens. The treatment is based for the first time on mesalazine or sulphasalazine and then in case of non responders, on corticosteroids.

Editorial↗
PubMed2005

Ileitis in ulcerative colitis: is it a backwash?

PURPOSE: This study aims to determine the incidence, demography, pathologic nature, and clinical significance of ileitis in ulcerative colitis patients who underwent restorative proctocolectomy. METHODS: A prospectively collected pouch database and the case notes of 100 consecutive patients who underwent restorative proctocolectomy for ulcerative colitis, under the care of a single surgeon, between 1988 and 2003 were reviewed. The original proctocolectomy specimens and pouch biopsies were reexamined and regraded blind, using the current diagnostic criteria. Patients were divided into two groups, those who had ileitis and those who had not. The demographic, clinical, and pathologic characteristics and the incidence of pouchitis of both groups were compared. RESULTS: Twenty-two patients had ileitis (22 percent). Compared with those with noninflamed ileum, patients with ileitis had a significantly shorter disease duration (P < 0.005), many of them presented or progressed to a fulminant state requiring acute surgical intervention (P < 0.01), had strong association with pancolitis and primary sclerosing cholangitis (P < 0.001), and had a higher incidence of subsequent development of pouchitis (P < 0.001). There was no correlation between the presence of ileitis and colitis severity. CONCLUSIONS: Ileitis in ulcerative colitis is not rare and does influence the prognosis, and the term "backw ash" is a misnomer. Ulcerative colitis with ileitis represents a distinct disease-specific subset of patients. Its true incidence and clinical significance can be determined only if detailed microscopic characterization of the terminal ileum is performed routinely in every patient with ulcerative colitis and the clinical outcome of these patients is audited prospectively.

Adolescent↗
PubMed1975

The pseudomembranous colitis associated with clindamycin therapy--a viral colitis.

Four patients are described who developed pseudomembranous colitis in association with clindamycin therapy. Rectal biopsies from two patients were studied with the electron microscope and compared with the ultrastructural appearance of the rectal mucosa from seven normal people. Ultrastructural evidence for a viral colitis was obtained. The significance of the clindamycin therapy to the viral colitis and the contribution of the viral colitis to the clinical state are discussed.

Adult↗
PubMed1997

Collagenous colitis: histopathology and clinical course.

OBJECTIVES: Collagenous colitis is a chronic diarrheal disease characterized by a normal or near-normal mucosa endoscopically and microscopic inflammation in the lamina propria, surface epithelial injury and a thick subepithelial collagen layer. The symptoms of collagenous colitis vary in duration and intensity, and long periods of remission have been described, but long-term follow-up data are limited. Our goal was to determine the natural clinical history of collagenous colitis and to determine whether there was a relationship between histopathologic changes and course of disease. METHODS: Cases were identified at the University of Michigan Hospitals using surgical pathology records before 1992. All charts, including medical records from other hospitals, were reviewed, and a telephone interview was conducted with each locatable patient (pt). Biopsy specimens were reviewed by two pathologists for degree of collagen layer thickness, epithelial damage, and inflammation. RESULTS: There were 31 patients (26 F, 5 M) with a mean age of 66 yr (range 33-83) and a mean duration of symptoms of 5.4 yr at the time of diagnosis. Of the 31 patients, 18 (56%) had some form of arthritis, and 22 (71%) were using NSAIDS regularly at the time of diagnosis. Follow-up interviews were conducted at least 2 yr after diagnosis (mean 3.5 yr, range 2-5 yr) with 27 of 31 patients (3 could not be located, 1 died). Two definable groups of patients were identified: (1) those with either spontaneous or treatment-related symptom resolution (63%), and (2) those with ongoing or intermittent symptoms requiring at least intermittent therapy (37%). There was no significant difference between the two groups with regard to sex, age, associated diseases, and use of medications. Patients with symptom resolution (mean duration 3.1 yr) had been treated with antidiarrheals (6), sulfasalazine (3), discontinuation of NSAIDS (3), reversal of jejunoilial bypass (1), or nothing (4). Those with ongoing symptoms experienced a wide range of symptom severity. Two required only antidiarrheals, but five required or failed steroids, azathioprine, or sandostatin. There was no significant difference in collagen thickness, epithelial damage, and inflammation between the two groups, but Paneth cell metaplasia was seen more often in those with ongoing symptoms. In 24 of 27 patients, diagnostic changes were present in left-sided biopsies. CONCLUSIONS: In our cohort of patients, 63% had lasting resolution of symptoms after a mean 3.5 yr follow-up. There was a high incidence of arthritis and NSAID use in our population, but there was no relationship between these entities and clinical course or histology. Initial histology, except possibly for Paneth cell metaplasia, did not reliably predict severity or course of disease. Finally, although variable in clinical presentation, treatment-free remissions are common in collagenous colitis.

Adult↗
PubMed1978

Enteritis cystica profunda.

In addition to hamartomatous polyps of the small intestine, a patient with Peutz-Jeghers disease had gross and microscopic lesions of the ileum that were analogous to colitis cystica profunda in the large intestine and rectum. To the authors' knowledge, this is the first such case in an adult to be reported. They suggest the designation, "enteritis cystica profunda." The histology of the lesions and their association with a disease known to produce hamartomatous lesions lend support to the proposition that some cases of colitis cystica are also hamartamatous. It is also believed that some reported cases of small-intestinal adenocarcinoma in patients with Peutz-Jeghers syndrome are in reality examples of the benign process of enteritis cystica profunda.

Adenocarcinoma↗
PubMed2006

Colon lesions: pathology specific to women.

Lymphocytic colitis and collagenous colitis represent two conditions that fall under the category of microscopic abnormalities within the lamina propria of the colon. Patients are predominantly women in the sixth decade of life who present with non-bloody watery diarrhea. Few other symptoms exist. Diagnosis is based upon finding characteristic abnormalities in the colonic mucosa, more likely to be found on the right side of the colon than the left. Treatment is symptomatic, although some newer therapies suggest regression of the lesion. Other autoimmune associations have been described, including celiac disease, and appropriate work-up for this condition should be considered for the patient who has seemingly refractory colitis. The natural history is benign, and most patients experience resolution of their symptoms.

Colitis, Collagenous↗
PubMed1992

Diversion colitis--20 years a-growing.

During the last decade, clinical and pathologic studies of diversion colitis have led to a better understanding of its nature. The clinical features are well described, and the endoscopic appearances, and gross and microscopic pathology are now defined. Thus, firm diagnosis and distinction from other colitides, notably ulcerative colitis and Crohn's disease, are possible in most cases. Restoration of the fecal stream cures diversion colitis, which in some cases may be successfully treated with short-chain fatty acid enemas, although the efficacy of this method remains to be substantiated. An understanding of the pathogenesis of diversion colitis (currently unknown) may lead to better methods of prevention and treatment.

Colitis↗
PubMed1999

Effect of DA-6034, a derivative of flavonoid, on experimental animal models of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a multifactorial disorder with unknown etiology and pathogenesis. DA-6034, 7-carboxymethyloxy-3', 4', 5-trimethoxy flavone, is a synthetic flavonoid known to possess anti-inflammatory activity. This study was performed to evaluate the oral therapeutic effect of DA-6034 in three experimental animal models of IBD: two chemical-induced IBD models of rats and the human leukocyte antigen (HLA)-B27 transgenic rat model known to develop spontaneous colitis without the use of exogenous agents. Acute chemical colitis was induced by intracolonic instillation of 1.2 ml of 4% acetic acid solution. Prednisolone (1 mg/kg), sulfasalazine (100 mg/kg) and DA-6034 (0.3 to approximately 3 mg/kg) were orally administered twice daily for 6 days in these rats. In addition, chronic chemical colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS) 30 mg in 50% ethanol and agents were orally administered for 6 or 20 days. In chemical-induced IBD models, all of these agents reduced the severity of colitis and specially, DA-6034 (3 mg/kg) showed more potent effect than other drugs in macroscopic lesion score. In HLA-B27 transgenic rats, DA-6034 (3 mg/kg) and prednisolone (0.5 mg/kg) were treated orally twice daily for 6 weeks. The HLA-B27 transgenic rats showed only mild colitis, compared with the chemical-induced colitis models. DA-6034 ameliorated the loose stool and decreased microscopic damage, which is the important indicator of this model. In conclusion, oral therapy of DA-6034 attenuated the macroscopic and histologic damages of the colon in all three experimental models of IBD, which suggest that DA-6034 could be a promising drug in the treatment of IBD.

Acetic Acid↗
PubMed2000

Increased presence of eosinophilic granulocytes expressing transforming growth factor-beta1 in collagenous colitis.

BACKGROUND: Collagenous colitis is a disease characterized by chronic watery diarrhea, and on microscopic examination of colonic tissue, a typical thickening of the subepithelial collagen layer is seen. The etiology and pathophysiology behind this disease state are largely unknown. METHODS: We have used in situ hybridization and immunohistochemistry to study the expression of transforming growth factor (TGF) -beta1, a growth factor with the capacity to cause accumulation of collagen in tissues, in collagenous colitis. Colonic pinch biopsy specimens from a total of 34 patients were investigated: 17 patients with collagenous colitis and 17 controls. RESULTS: In patients with collagenous colitis there was increased expression of the TGF-beta1 gene compared with controls, as visualized by in situ hybridization. The vast majority of the TGF-beta1-expressing cells were eosinophils, both in collagenous colitis and controls, but there were also scattered fibroblastic and histiocytic stromal cells. Immunohistochemistry showed the presence of TGF-beta1, mainly in eosinophils, in the colonic mucosa. Morphometric quantification showed 603 +/- 192 eosinophils/mm2, (mean +/- standard error of the mean) in the colonic mucosa of patients with collagenous colitis compared with 30 +/- 7 eosinophils/mm2 in the controls. CONCLUSIONS: The present results suggest that eosinophils expressing TGF-beta1 may be of pathophysiologic importance in the connective tissue remodeling seen in collagenous colitis.

Adult↗
PubMed2006

Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection.

BACKGROUND & AIMS: Expression of mucin MUC2, the structural component of the colonic mucus layer, is lowered in inflammatory bowel disease. Our aim was to obtain insight in the role of Muc2 in epithelial protection. METHODS: Muc2 knockout (Muc2(-/-)) and Muc2 heterozygous (Muc2(+/-)) mice were characterized and challenged by a colitis-inducing agent, dextran sulfate sodium (DSS). We monitored clinical symptoms, intestinal morphology, and differences in intestine-specific protein and messenger RNA levels. RESULTS: The Muc2(-/-) mice showed clinical signs of colitis (as of 5 weeks), aggravating as the mice aged. Microscopic analysis of the colon of Muc2(-/-) mice showed mucosal thickening, increased proliferation, and superficial erosions. Colonic goblet cells in the Muc2(-/-) mice were negative for Muc2, but trefoil factor 3 was still detectable. In Muc2(-/-) mice, transient de novo expression of Muc6 messenger RNA was observed in the distal colon. On day 2 of DSS treatment, the histologic damage was more severe in Muc2(+/-) versus wild-type (Muc2(+/+)) mice, but the disease activity index was not yet different. By day 7, the disease activity index and histologic score were significantly elevated in Muc2(+/-) versus Muc2(+/+) mice. The disease activity index of the Muc2(-/-) mice was higher (versus both Muc2(+/+) and Muc2(+/-) mice) throughout DSS treatment. The histologic damage in the DSS-treated Muc2(-/-) mice was different compared with Muc2(+/+) and Muc2(+/-) mice, with many crypt abscesses instead of mucosal ulcerations. CONCLUSIONS: This study shows that Muc2 deficiency leads to inflammation of the colon and contributes to the onset and perpetuation of experimental colitis.

Animals↗
PubMed1999

Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis.

BACKGROUND: The trefoil peptides are major secretory products of mucus cells of the gastrointestinal tract and show increased expression after inflammatory or ulcerative damage. Recombinant human TFF2 (spasmolytic polypeptide) has been shown to be cytoprotective, and enhances repair in models of gastric injury. AIMS: To test the healing effects of recombinant human (h)TFF2 in a rat model of chronic colitis. METHODS: Colitis was induced by intracolonic administration of dinitrobenzene sulphonic acid in ethanol. Mucosal repair was quantified macroscopically, microscopically by image analysis of tissue histology, and by measuring myeloperoxidase activity. RESULTS: Initial validation studies showed that maximal injury and inflammation occurred at the end of the first week after colitis induction (active phase), and that spontaneous healing was complete by eight weeks. Once daily intrarectal application of hTFF2 (2.5 mg/kg; approximately 0.5 mg/rat) for five days after maximal damage had been sustained, reduced both microscopic and macroscopic injury by 80% and inflammatory index by 50% compared with vehicle controls. In addition, endogenous concentrations of rat TFF2 and TFF3 (intestinal trefoil factor) were increased in the active phase of colitis and were reduced to basal levels by hTFF2 treatment. CONCLUSIONS: This study has shown that hTFF2 enhances the rate of colonic epithelial repair, and reduces local inflammation in a rat model of colitis, and suggests that luminal application of trefoil peptides may have therapeutic potential in the treatment of inflammatory bowel disease.

Administration, Rectal↗
PubMed2005

Immunohistochemical assessment of mucosal cytokine profile in acetic acid experimental colitis.

UNLABELLED: Experimental colitis induced by acetic acid has been used extensively as a model for intestinal inflammatory disease. Colonic tissue lesions of intestinal inflammatory disease patients seem to be related to the increased local production of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha, and IFN-gamma). PURPOSE: To assess the cytokine expression pattern identified through immunohistochemistry in colonic mucosa after experimental colitis induced by acetic acid and establish the relationship between this pattern and the presence of macroscopic lesions. MATERIALS AND METHODS: Adult male Wistar rats (n = 39) were divided at random into 4 groups: NC45 and NC24 (control without colitis; sacrificed at 45 minutes and 24 hours, respectively); and WC45 and WC24 (with experimental colitis induced by acetic acid; sacrificed at 45 minutes and 24 hours, respectively). Macroscopic and microscopic alterations in colonic tissue were evaluated, and cytokine expression was assessed through immunohistochemistry. RESULTS: After 24 hours, IL-1 expression was greater in the groups with colitis when compared to the groups without colitis. IL-4 expression was higher in the WC45 group. There was an increase in both INF-gamma and IL-6 related to the presence of necrosis of the colonic mucosa in the groups with colitis for both periods evaluated. CONCLUSION: The immunohistochemical technique was efficient for the analysis of various cytokine expressions in the colonic tissue. There was an increase in the IL-1 pro-inflammatory cytokines as well as in IL-6 and IFN-gamma associated with the presence of colonic necrosis. Experimental colitis induced by acetic acid is a useful model for the development of studies assessing the role of cytokines in the inflammation of mucosa as well as anti-cytokine therapies.

Acetic Acid↗
PubMed2003

The effects of sodium phosphate and polyethylene glycol-electrolyte bowel preparation solutions on 2,4,6-trinitrobenzenesulfonic acid-induced colitis in the rat.

The aim of the present study is to evaluate the effects of sodium phosphate (NaP) and polyethylene glycol-electrolyte (PEG-EL) colon cleansing solutions on histopathology of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and ethanol (E)-induced colitis in the rat and normal rat colon. The presence of hyperemia, inflammation and ulcer was evaluated to score of macroscopic morphologic damage. The microscopic criteria including ulceration, mucus cell depletion, crypt abscesses, inflammatory cysts, mucosal atrophy, edema, inflammatory cell infiltration, and vascular dilatation were evaluated to determine the extent of inflammatory reaction. Colitis findings were determined on the rats which were administered TNBS-E. Aphthoid lesions were seen 30% and 20 % of rats, respectively, by NaP and PEG-EL solutions in healthy group. Microscopic examination of aphthoid lesions revealed edema within the lamina propria and lymphoid hyperplasia in the mucosa and submucosa without erosion, ulceration and inflammatory cell infiltration. No significant difference was statistically found either macroscopically or microscopically in terms of the effects of saline, NaP and PEG-EL solutions in healthy rats and rats with colitis (p > .05). Under the present conditions, we concluded administration of NaP and PEG-EL solutions did not cause evident morphological changes on the rectal mucosa macroscopically and microscopically, although in a proportion of rats aphthoid lesions seem as a marker of mucosal damage macroscopically.

Animals↗
PubMed1998

Lymphocytic colitis: clinical presentation and long term course.

BACKGROUND: Lymphocytic colitis is characterised by chronic watery diarrhoea with normal endoscopic or radiological findings and microscopic evidence of pronounced infiltration of the colonic mucosa with lymphocytes. AIM: To investigate the long term clinical and histological evolution of the disease in a large group of patients with well characterised lymphocytic colitis. METHODS: Between 1986 and 1995 the histological diagnosis of lymphocytic colitis was obtained in 35 patients; 27 of these agreed to a follow up examination. All clinical, endoscopic, and histopathological records were reviewed at that time and the patients had a second endoscopic examination with follow up biopsies. RESULTS: The patients initially presented with the typical findings of lymphocytic colitis. After a mean (SD) follow up of 37.8 (27.5) months, diarrhoea subsided in 25 (93%) and histological normalisation was observed in 22 (82%) of the 27 patients. Progression from lymphocytic colitis to collagenous colitis was not observed. CONCLUSIONS: Lymphocytic colitis is characterised by a benign course with resolution of diarrhoea and normalisation of histology in over 80% of patients within 38 months. Considering the benign course of the disease, the potential benefit of any drug treatment should be carefully weighed against its potential side effects.

Adult↗