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PubMed2001

In vivo detection of experimental ulcerative colitis in rats using fiberoptic confocal imaging (FOCI).

Fiberoptic confocal imaging (FOCI) is a noninvasive microscopic technique that enables subsurface imaging of living tissue in vivo. The aim of the present study was to assess the suitability of FOCI for the in vivo detection of early subsurface changes in the mucosal architecture of the colon in a rat model of ulcerative colitis. Mild colitis was induced in Sprague-Dawley rats (180-250 g) by the oral ingestion of 5% (w/v) dextran sulfate sodium (DSS; Mr 40,000 Da) in drinking water. Control animals were provided with water ad libitum. After three, five or seven days of oral consumption of DSS, the mucosal surface of the colon of anesthetised rats was surgically exposed. Morphological changes in the mucosa were examined (Optiscan F900e personal confocal system with rigid endomicroscope attachment; excitation 488 nm argon ion laser, detection above 515 nm) following the topical application of a fluorescent dye (fluorescein, eosin, or acridine orange). Confocal images were correlated with conventional histology and clinical parameters including occult blood and stool consistency. Histological evaluation of colon sections demonstrated that DSS-induced colitis was characterized by focal loss of mucous crypts, loss of epithelial cells, and neutrophilic infiltration into the mucosa. The extent of mucosal damage was positively correlated with the time of ingestion of DSS. Morphological changes associated with disease activity could be detected microscopically in vivo using FOCI but were not evident by visual inspection of the colon surface. Acridine orange enabled imaging of the colonic crypts at the surface of the mucosa. Morphological changes associated with colitis, including inflammatory cell infiltrate, crypt loss, and crypt distortion, could be detected using this fluorophore. Application of fluorescein and eosin enabled subsurface imaging of the lamina propria surrounding the crypts; however, no change in structure was detected in association with colitic disease activity. This study has shown that the topical application of acridine orange enables in vivo imaging of early colitis in a rat model. FOCI may be suitable for the diagnosis and monitoring of human inflammatory bowel disease.

Animals↗
PubMed2002

Effect of cyclosporine in a murine model of experimental colitis.

The use of immunosuppressive therapy may be associated with significant toxicity. The aim of this study was to investigate the effect of cyclosporine A (CsA) in murine model of experimental colitis. Experimental colitis was induced in NMRI mice using an enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. After inducing colitis, experimental groups of animals were treated with CsA (1, 3, 5, 10, 25, 50 mg/kg/day) intraperitoneally (i.p.) or intracolonically (i.c.), and control groups were treated with phosphate-buffered saline intraperitoneally or intracolonically, respectively. Colonic inflammatory changes were assessed using a histopathologic score of 0-30, and pooled whole blood samples were processed with monoclonal antibodies for cyclosporine concentration. In addition, two groups of animals with experimental colitis were treated intraperitoneally or intracolonically with 3 mg/kg/day of CsA, and the colons were also taken for immunohistochemistry for CD25. CsA diminished the extent of colitis in groups treated with 3, 5, 10, or 25 mg/kg intraperitoneally or intracolonically, and in groups treated with 1 and 50 mg/kg intracolonically (P < 0.05). The effect of intracolonic application of CsA was not related to whole blood cyclosporine concentrations. In addition, the effect of CsA at 3 mg/kg, applied intraperitoneally or intracolonically was, in part, expressed in decreasing the numbers of CD25+ cells within colonic mucosa/submucosa (P < 0.05). In conclusions, the results of this study indicate the possibility of intracolonic application of cyclosporine in order to widen the therapeutic window for effective, but possibly toxic drug, such as cyclosporine.

Animals↗
PubMed1998

Collagenous colitis and Yersinia enterocolitica infection.

Collagenous colitis is a rare clinical and pathological entity characterized by watery diarrhea and deposition of collagen beneath the surface epithelium of the colon. Its etiology is unknown. We present a careful retrospective clinicopathological analysis of six patients with collagenous colitis diagnosed at our hospital during a three-year period. Three of the patients had had a Yersinia enterocolitica infection, detected by stool culture and elevated serum antibody titers, preceding the diagnosis of collagenous colitis. Four patients had duodenal villous atrophy, which in two patients was refractory to a gluten-free diet. We propose that Yersinia enterocolitica infection may be a triggering factor for the development of collagenous colitis in some cases. Duodenal villous atrophy not responding to gluten withdrawal is common in association with collagenous colitis.

Adult↗
PubMed1997

Immunoglobulin G subclass distribution of anti-endothelial cell antibodies (AECA) in patients with ulcerative colitis or Crohn's disease.

Anti-endothelial cell antibodies have been described in sera from patients with inflammatory bowel disease. The aim of this study was to determine, by ELISA, the IgG subclass distribution of anti-endothelial cell antibodies, in patients with ulcerative colitis (N = 28) or Crohn's disease (N = 82) as compared with blood donors (N = 95). Thirty-six percent of ulcerative colitis and 23% of Crohn's disease patients were positive for at least one of the IgG anti-endothelial cell subclasses. Interestingly, the pattern of IgG anti-endothelial cell subclass observed in the two inflammatory bowel diseases differs. In Crohn's disease, the IgG1 anti-endothelial cell antibody level was significantly increased (P < 0.05) while IgG2 and IgG4 anti-endothelial cell antibody levels were decreased (P < 0.0001 and P < 0.01, respectively) as compared to ulcerative colitis patients. The immunoglobulin G3 anti-endothelial cell antibody level was decreased in both ulcerative colitis and Crohn's disease patients as compared to healthy blood donors. No relationship was detected between disease activity of ulcerative colitis or Crohn's disease patients and anti-endothelial cell IgG subclasses. Finally, the disparity of IgG anti-endothelial cell subclass distribution in these two inflammatory bowel diseases suggests that the ability to activate effector mechanisms is not identical, and hence, deals with the concept of distinctive pathogenetic mechanisms in these two diseases.

Adolescent↗
PubMed1997

Effects of colectomy on gallbladder motility in patients with ulcerative colitis.

In order to gain insight into the possible mechanisms involved in gallstone formation in colectomized ulcerative colitis patients, we studied gallbladder motility by means of ultrasonography in three groups of subjects: controls (N = 40) and ulcerative colitis patients without (N = 30) and with (N = 20) colectomy. Impaired gallbladder emptying after a liquid fatty meal stimulus was observed in ulcerative colitis patients with colectomy compared with those obtained in ulcerative colitis patients without colectomy and controls (P = 0.001). The maximum percentage of gallbladder emptying also, was significantly lower (59.8%) than those seen in ulcerative colitis patients without colectomy (74.5%) and controls (77.8%) (P = 0.001). Diminished gallbladder emptying with ensuing stasis might be a contributory factor to the increased prevalence of gallstones in colectomized patients.

Adult↗
PubMed1997

Intracolonic release of nitric oxide during trinitrobenzene sulfonic acid rat colitis.

Nitric oxide is thought to play an important role in modulating the inflammatory process. Recently an increase in the inducible form of nitric oxide synthase (iNOS) has been found in the rat trinitrobenzene sulfonic acid model of experimental colitis, and inhibition of nitric oxide synthase activity resulted in an amelioration of tissue injury. The aim of our study was to evaluate in vivo intracolonic release of nitric oxide in this model of colitis. Experimental colitis was induced in male Sprague-Dawley rats by a single intracolonic administration of trinitrobenzene sulfonic acid. Nitrite levels were determined in rectal dialysates by HPLC. The tissue myeloperoxidase and iNOS and the luminal leukotriene B4 were also measured. Nitrite levels were significantly increased in rectal dialysates during colitis and correlated significantly with tissue myeloperoxidase and iNOS activity. The correlation between nitrite dialysate levels and wall iNOS activity confirms that nitrite in dialysates is produced by inflammatory cells and not by colonic bacterial flora. Determination of nitrite levels in rectal dialysates seems a valuable method to monitor colonic inflammation in rat trinitrobenzene sulfonic acid colitis.

Animals↗
PubMed1999

Amino acid polymorphism at residue 71 in HLA-DR beta chain plays a critical role in susceptibility to ulcerative colitis.

The association of ulcerative colitis with distinct HLA-DRB1 alleles has not been easy to ascertain. Recent studies show that among HLA-DR2 alleles, DRB1*15 but not DRB1*16, is associated with the disease. Similarly, in the HLA-DR1 group, only DRB1*0103 is increased in ulcerative colitis patients. The aim of our study was to identify critical DRB1 residues that might account for these differences. We typed 121 patients with ulcerative colitis and 275 controls using gene amplification and sequence-specific oligonucleotide probing for HLA-DRB1 and DRB3. We observed a strong negative association between HLA-DRB1 alleles that encode lysine at position 71 in their beta-chain and susceptibility to ulcerative colitis. Differences in the prevalence among other alleles differing only in the third hypervariable region suggested a hierarchy of susceptible and protective class II alleles related to the presence of an acidic, neutral, or basic amino acid residue at position 71. These data implicate most strongly the amino acid residues in the third hypervariable region of the DRbeta chain, especially DRbeta71, in the association between ulcerative colitis and HLA. However, this does not exclude the contribution of other parts of the molecule and other immunoregulatory genes.

Adult↗
PubMed1999

Temporal patterns of colonic blood flow and tissue damage in an animal model of colitis.

This study tested the hypothesis that altered colonic blood flow may contribute to tissue damage during the development of colitis in the rabbit. This was achieved by using radioactive microspheres to measure colonic blood flow at various times after colitis induction with trinitrobenzene sulfonic acid. Significant colonic damage occurred 6 hours post colitis induction and persisted throughout the 5 day study. Blood flow to the muscularis propria and mucosa/muscularis mucosae compartments increased significantly from 5 minutes until one hour post induction. At 6 and 12 hours post induction colonic blood flow returned to control levels before increasing again from 24 to 96 hours. This second increase in flow was, however, predominantly in the mucosa/muscularis mucosae compartment. Blood flow in the stomach and non-gastrointestinal tissues did not change significantly at any time. These data demonstrate that increased colonic blood flow may be disrupted in the early stages of colitis and that this coincides with the onset of significant damage. It is concluded that maintenance of elevated colonic blood flow throughout the development of colitis may help to ameliorate subsequent tissue injury.

Animals↗
PubMed1999

Molecular basis of altered contractility in experimental colitis: expression of L-type calcium channel.

Colitis in experimental animals or idiopathic inflammatory bowel disease, such as ulcerative colitis or Crohn's disease in humans, is associated with reduced muscle contraction. This is predicted to be due to disturbance of Ca2+ homeostasis in the inflamed muscle cell. However, the underlying molecular mechanism remains to be elucidated. Since the catalytic alpha-1 subunit of the L-type Ca2+ channel regulates Ca2+ influx, levels of the alpha-1 mRNA and protein were examined. Colitis induced by intrarectal administration of trinitrobenzenesulfonic acid was monitored by measuring the myeloperoxidase activity and histology. The levels of mRNA and protein were estimated using RT-PCR and immunoblotting. Myeloperoxidase activity increased in the inflamed colon, and the lamina propria and muscle layers showed infiltration of inflammatory cells and loss of crypts. Two alternatively spliced alpha-1 mRNA isoforms were detected in the colonic muscle. The ratio of unspliced to spliced mRNA isoforms remained unaltered in inflamed muscle. In contrast, the level of corresponding protein isozymes decreased in the colitic animals. Thus colitis-induced reduction in the alpha-1 protein may account for the reduced colonic contractility seen in colitis.

Animals↗
PubMed1999

Ulcerative colitis associated with primary biliary cirrhosis.

Primary biliary cirrhosis and ulcerative colitis are two diseases with many features of autoimmunity. Thirteen cases of coexistence of the two diseases have been reported in the literature so far. Patients are usually younger and more often males than the ordinary primary biliary cirrhosis patient, while the colitis is mild and easily controllable. In a homogeneous population of 550,000 inhabitants of the island of Crete, 412 cases of ulcerative colitis and 82 individuals with primary biliary cirrhosis or autoimmune cholangitis have been identified. In two cases, coexistence of the two diseases was found. Immunological screening for AMA positivity in 150 ulcerative colitis sera disclosed no further cases. Prevalence of primary biliary cirrhosis in ulcerative colitis patients seems at least 30 times higher than in the general population in our area. A possible immunological link between the two diseases is discussed.

Aged↗
PubMed2000

VCAM-1, but not ICAM-1 or MAdCAM-1, immunoblockade ameliorates DSS-induced colitis in mice.

Adhesion molecule immunoneutralization is envisioned as a promising therapy for inflammatory bowel disease, but the relative value of selective blockade of different adhesion molecules has not been established. The aims of this study were to measure expression and functional relevance of endothelial intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in leukocyte recruitment in experimental colitis and to compare the therapeutic effectiveness of their selective blockade. For this purpose, cell adhesion molecule expression was measured by the dual radiolabeled antibody technique in mice with dextran sulfate sodium-induced colitis and controls. Leukocyte-endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. Therapeutic effects of chronic treatment with anti-ICAM-1, anti-VCAM-1, or anti-MAdCAM-1 antibodies were also assessed. Whereas colonic endothelial ICAM-1 was constitutively expressed and had a mild up-regulation in colitic animals, constitutive expression of VCAM-1 and MAdCAM-1 was low, but markedly increased after induction of colitis. Leukocyte adhesion was abrogated by immunoneutralization of VCAM-1 or MAdCAM-1 but not by treatment with an anti-ICAM-1 antibody. Chronic administration of anti-VCAM-1 antibody, but not anti-ICAM-1 or anti-MAdCAM-1, resulted in significant attenuation of colitis in terms of disease activity index, colon length, ratio of colon weight to length, and myeloperoxidase activity. In conclusion, VCAM-1 plays a central role in leukocyte recruitment in colitis and blockade of this adhesion molecule has higher therapeutic effect than immunoneutralization of ICAM-1 or MAdCAM-1 in this experimental model.

Animals↗
PubMed2002

Nitric oxide supplementation ameliorates dextran sulfate sodium-induced colitis in mice.

Nitric oxide (NO) synthesis is up-regulated in inflammatory bowel disease. However, its role in the pathophysiology of this condition is controversial. The aims of this study were to assess whether nitric oxide administration ameliorates experimental colitis and to determine the possible mechanisms underlying its effects on intestinal inflammation. For this purpose, the NO donor diethylamine NONOate (DETA/NO; 0.01, 0.1, 1, 5, or 10 mg/kg/day), or the DETA moiety, was administered daily to mice with dextran sulfate sodium-induced colitis. Daily body weight and colonic pathologic alterations at Day 10 were determined. Leukocyte endothelial cell interactions in colonic venules were assessed with intravital microscopy, and expression of endothelial cell adhesion molecules was determined using radiolabeled antibodies. IL-12 and IFN-gamma production were measured in intestinal tissue. Colitis induced a significant loss of body weight, reduction of colon length, and increase in colon weight and myeloperoxidase activity. Administration of 1 mg/kg/day DETA/NO significantly attenuated these pathologic changes. The marked increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of 1 mg/kg/day DETA/NO. Development of colitis was associated with a marked increase in endothelial expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Supplementation with NO significantly attenuated the up-regulation of endothelial intercellular adhesion molecule-1 and P-selectin, but not vascular cell adhesion molecule-1, in colonic tissue. NO abrogated the increase in IL-12 and IFN-gamma mRNA expression in the colon of colitic mice. The DETA moiety alone did not have any effect on any of the parameters studied. In conclusion, exogenous NO supplementation significantly ameliorates dextran sulfate sodium-induced colitis. This effect is related to a reduction in leukocyte recruitment and proinflammatory cytokine production.

Animals↗
PubMed2001

Development of chronic colitis is dependent on the cytokine MIF.

The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohn's disease, these data suggested that MIF is a new target for intervention in Crohn's disease.

Adoptive Transfer↗
PubMed2003

Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by alpha2-adrenoceptors in the presence of experimental colitis.

1 This study investigates the influence of intestinal inflammation on: (1) the control of intestinal neurotransmission and motility by prejunctional alpha(2)-adrenoceptors and (2) the expression of intestinal alpha(2)-adrenoceptors. Experimental colitis was induced by intrarectal administration of 2,4-dinitrobenzenesulphonic acid (DNBS) to rats. 2 UK-14,304 inhibited atropine-sensitive electrically evoked contractions of ileal and colonic longitudinal muscle preparations. UK-14,304 acted with similar potency, but higher efficacy, on tissues from DNBS-treated animals; its effects were antagonized with greater potency by phentolamine than rauwolscine. 3 Electrically induced [(3)H]noradrenaline release from ileal preparations was reduced in the presence of colitis. Tritium outflow was decreased by UK-14,304 and stimulated by rauwolscine or phentolamine: these effects were enhanced in preparations from animals with colitis. 4 Reverse transcription-polymerase chain reaction and Western blot assay demonstrated the protein expression of alpha(2A)-adrenoceptors in mucosal and muscular tissues isolated from ileum and colon. The induction of colitis increased alpha(2A)-adrenoceptor expression in both ileal and colonic muscular layers, without concomitant changes in mucosal tissues. 5 Induction of colitis reduced gastrointestinal propulsion of a charcoal suspension in vivo. In this setting, the gastrointestinal transit was inhibited by intraperitoneal (i.p.) UK-14,304 and stimulated by i.p. rauwolscine. After pretreatment with guanethidine, the stimulant action of rauwolscine no longer occurred, and UK-14,304 exerted a more prominent inhibitory effect that was antagonized by rauwolscine. 6 The present results indicate that, in the presence of intestinal inflammation, prejunctional alpha(2)-adrenoceptors contribute to an enhanced inhibitory control of cholinergic and noradrenergic transmission both at inflamed and noninflamed distant sites. Evidence was obtained that such modulatory actions depend on an increased expression of alpha(2A)-adrenoceptors within the enteric nervous system.

Acetylcholine↗
PubMed2002

IL-10 gene therapy prevents TNBS-induced colitis.

The transfer of genes encoding immunomodulatory proteins to the intestinal mucosa is a promising new approach to the treatment of Crohn's disease (CD). This study investigates the therapeutic efficacy of an adenoviral vector encoding IL-10 (AdvmuIL-10) in experimental colitis. BALB/c mice were treated with a single intravenous injection of AdvmuIL-10, empty cassette virus (Adv0) or PBS prior to the induction of trinitrobenzene sulphonic acid (TNBS) colitis. AdvmuIL-10 treatment prevented the severe loss of body weight associated with TNBS administration. In addition, AdvmuIL-10 therapy led to a significant reduction in both stool markers of inflammation (IL-1beta and TNFR-II) and acute phase response (serum amyloid protein). Finally, the histological scores of mice with TNBS colitis treated with AdvmuIL-10 were significantly lower than Adv0- or PBS-treated controls. The therapeutic efficacy of AdvmuIL-10 was associated with a decrease in the IFN-gamma and IL-6 levels detected in colonic homogenates from mice with TNBS colitis, whereas no effect was observed on cytokine release from stimulated systemic lymphocytes. Thus, AdvmuIL-10 is an effective therapy in the TNBS model of colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammatory conditions such as CD.

Adenoviridae↗
PubMed1992

Sulphation of colonic and rectal mucin in inflammatory bowel disease: reduced sulphation of rectal mucus in ulcerative colitis.

1. Normal colonic mucin is heavily sulphated and this increases its resistance to degradation by bacterial enzymes. Any defect in mucus sulphation could therefore be important in the pathogenesis of ulcerative colitis. 2. Rectal biopsies taken at colonoscopy from patients with ulcerative colitis (n = 9), patients with Crohn's disease (n = 6) and control subjects (n = 16) were cultured for 24 h in the presence of N-[3H]acetylglucosamine and [35S]sulphate. Mucin was then extracted and purified, and the ratio of [35S]sulphate to N-[3H]acetylglucosamine incorporated into pure mucin was assessed. 3. The ratio of [35S]sulphate to N-[3H]acetylglucosamine incorporated into mucin was significantly reduced in rectal biopsies taken from patients with ulcerative colitis (0.463, 0.305-0.703, geometric mean and 95% confidence intervals) compared with control subjects (0.857, 0.959-1.111, P < 0.01). In patients with Crohn's disease the reduction in this ratio (0.559, 0.378-0.829) did not quite reach statistical significance (P = 0.06). There was no difference between the ratio of [35S]sulphate to N-[3H]acetylglucosamine incorporated into mucin in Crohn's disease and that in ulcerative colitis (P = 0.26). 4. In control subjects the ratio of [35S]sulphate to N-[3H]acetylglucosamine incorporated into mucin was higher in the rectal biopsies (0.882, 0.618-1.022) than in their paired proximal colonic biopsies (0.602, 0.421-0.861; P < 0.01), but this regional variation was not observed in either ulcerative colitis (rectum: 0.450, 0.262-0.773; right colon: 0.470, 0.321-0.690, P = 0.3) or Crohn's disease (rectum: 0.459, 0.260-0.815; right colon: 0.492, 0.260-0.929, P = 0.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Review article: medical treatment of severe ulcerative colitis.

Approximately 15% of patients with ulcerative colitis have a severe attack requiring hospitalization at some time during their illness. This treatment leads to a remission in 60-80% of patients and non-responders may require a total colectomy. Mortality in severe episodes of ulcerative colitis decreased from 31-61% in the 1950s to 5-9% in the 1960s thanks to the introduction of steroids and to a policy of early colectomy. Recently, some new drugs have been shown to be effective in the treatment of severe steroid-refractory ulcerative colitis. This review concentrates on the clinical evaluation, prognostic factors and new developments in medical therapy in severe ulcerative colitis. A retrospective evaluation of a consecutive series of patients with severe ulcerative colitis admitted to a Gastroenterology Department in Torino, Italy, is also reported.

Anti-Bacterial Agents↗
PubMed1996

Xanthine oxidase activity is not increased in the colonic mucosa of ulcerative colitis.

AIM: To measure urate and xanthine by high-performance liquid chromatography in mucosal biopsies from patients with ulcerative colitis and controls. RESULTS: Reactive oxygen metabolite activity was demonstrated by a cystine to cysteine ratio of 0.24 +/- 0.08 in the control biopsies compared with 1.79 +/- 0.25 in ulcerative colitis. The product to substrate ratio (urate to xanthine) for xanthine oxidase and mucosal urate concentrations were not different between ulcerative colitis patients and controls. Xanthine oxidase activity after incubation of homogenized biopsies was 0.451 (+/- 0.175) nmol.min/mg protein in ulcerative colitis patients compared with 2.585 (+/- 0.823) nmol.min/mg protein in controls (P < 0.01). CONCLUSION: These results suggest that xanthine oxidase may not be the major source of superoxide formation in ulcerative colitis.

Biopsy↗