Dataset Information

Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.

ABSTRACT: Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, are chronic inflammatory disorders that increase the risk for colorectal cancer. The mitochondrial translocator protein (TSPO) is a high-affinity drug- and cholesterol-binding protein expressed in the colon and its expression is increased in colon cancers. The aim of this study was to investigate TSPO expression in IBD biopsies and to establish an animal model of IBD to examine the role of TSPO. In addition, we evaluated the potential use of TSPO drug ligands in diagnosing and treating IBD.TSPO expression in IBD biopsies was evaluated using immunohistochemistry. IBD was induced in a rat experimental model via treatment with dextran sodium sulfate (DSS). Colon morphology, TSPO expression, and proinflammatory cytokine production were evaluated in addition to the effect of TSPO drug ligands on disease pathology.TSPO protein levels were elevated in the enterocytes of IBD biopsies. TSPO expression was localized to the enterocyte mitochondria. DSS treatment induced a time-dependent phenotype mimicking IBD with tissue injury and subsequent tissue regeneration. Coadministration of DSS and the TSPO drug ligands PK 11195 or Ro5-4864 increased both the rate of colon ulceration and regeneration, whereas administration of the TSPO drug ligand flunitrazepam partially prevented this pathology. These data correlated with changes in proinflammatory cytokine plasma levels, as well as increased cytokine production and secretion from the colon.TSPO may serve as a marker of the IBD repair process, and TSPO drug ligands should be further evaluated for IBD treatment.

SUBMITTER: Ostuni MA

PROVIDER: S-EPMC2930116 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.

Ostuni Mariano A MA Issop Leeyah L Péranzi Gabriel G Walker Francine F Fasseu Magali M Elbim Carole C Papadopoulos Vassilios V Lacapere Jean-Jacques JJ

Inflammatory bowel diseases 20100901 9

<h4>Background</h4>Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, are chronic inflammatory disorders that increase the risk for colorectal cancer. The mitochondrial translocator protein (TSPO) is a high-affinity drug- and cholesterol-binding protein expressed in the colon and its expression is increased in colon cancers. The aim of this study was to investigate TSPO expression in IBD biopsies and to establish an animal model of IBD to examine the role of TSPO ...[more]

PMID: 20222126

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Project description:Inflammatory Bowel Disease (IBD), mainly comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic condition that primarily affects the intestine and is characterized by leukocytic infiltration. Blocking the migration of leukocytes from the circulation is therefore a reasonable therapeutic goal. Recent clinical trials using this approach have shown promise, with the monoclonal antibody to ?4?7 integrin, vedolizumab, and previously with the monoclonal antibody to the ?4 subunit, natalizumab. Directly targeting the subset of ?4?7 expressing cells that co-express CC chemokine receptor 9 (CCR9), using the orally administered antagonist, CCX282-B, also known as vercirnon, has also been evaluated in Phase II and III trials that have produced mixed results. Although CCX282-B showed efficacy in inducing response in active CD in early studies, this was not confirmed in a Phase III study. CCX282-B was also more effective than placebo in maintaining remission, and this result has yet to be confirmed in Phase III. The efficacy of blocking CCR9 in UC, where vedolizumab was effective, has not been tested. The prospect of targeting CCR9 in IBD remains attractive. Much of the local accumulation of inflammatory cells in the intestine arises from migration rather than local proliferation and genetic and pharmacological targeting of CCR9 or its ligand in preclinical models that mimic UC and CD ameliorate inflammation in some cases. Furthermore, binding of chemokine ligands to receptor is a critical step in activating integrin binding, so there is a potential for synergistic action between integrin and chemokine antagonists. CCR9 is expressed on a smaller proportion of circulating cells than ?4?7 integrin, which may offer greater specificity of effect, particularly in long term use. Furthermore, while ?4?7 is widely expressed on T and B cell subsets, CCR9 is mainly expressed on effector memory Th1 cells. Indications for the use of intestine-specific integrin and chemokine receptor targeting may also extend beyond IBD, to include, for example, postoperative ileus, and primary sclerosing cholangitis.

Project description:Diagnosing IBD in horses is challenging and requires a multimodal approach, since no conclusive diagnostic test is available. The objectives of this study were to provide an overview of population characteristics, results of applied diagnostic tests, treatment modalities and outcome in a large group of horses thought to have IBD and that were presented to four large equine referral hospitals, and to provide an exploratory investigation of possible associations between results of applied diagnostic tests, applied treatment modalities and outcome. A retrospective case series was performed across four large equine referral hospitals. Seventy-eight horses, thought to have IBD were included. Case history, clinical findings, diagnostic test results including oral glucose tolerance test (OGTT) and enteral biopsies (both duodenal and rectal), applied therapy and outcome were studied. A Chi-Square test was used to identify associations between results of diagnostic tests, treatment and outcome. P-values <?0.05 were considered significant.Lethargy, diarrhoea, recurrent colic and weight loss were recorded in respectively 21,8%; 14,1%; 28,2% and 78,2% of cases. Over 70% of horses thought to have IBD had an abnormal OGTT. Only weight loss was significantly associated with aberrant enteral biopsy results, but not with abnormal OGTT results or low blood total protein. There was no association between an aberrant biopsy result and a disturbed OGTT. There was no association between either OGTT results or enteral biopsy results and a low blood total protein content, presence of gastric ulcer disease or an aberrant endoscopic aspect of the duodenal entrance.Weight loss is a highly prevalent symptom in IBD suspected horses. Enteral biopsies may be a useful diagnostic aid in the work-up of horses thought to suffer from IBD, however further research is required to demonstrate their true diagnostic value. Until more standardized scientific research is available, one should be careful with the interpretation of enteral biopsy results There is a need for better standardization of enteral biopsy procedures and the histopathological scoring of biopsies.

Dataset Information

Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.

Publications

Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.

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