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PubMed2003

Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis.

BACKGROUND: Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin-2 renders lymphocytes steroid resistant. AIM: To explore the therapeutic potential of interleukin-2 receptor blockade in steroid-resistant ulcerative colitis with both in vitro measures and a pilot in vivo study. METHODS: Ten patients with steroid-resistant ulcerative colitis received a single bolus of 40 mg of intravenous basiliximab plus steroid treatment in an open-label, uncontrolled, 24-week study. The outcome was assessed using the Ulcerative Colitis Symptom Score, rectal biopsy and Inflammatory Bowel Disease Questionnaire. Lymphocyte steroid sensitivity was measured in vitro in 39 subjects in the presence or absence of basiliximab. RESULTS: Nine of the 10 patients achieved clinical remission within 8 weeks. At 24 weeks, seven patients were in clinical remission. Marked improvement in the Ulcerative Colitis Symptom Score was seen by 1 week (P = 0.004) and on rectal biopsy and Inflammatory Bowel Disease Questionnaire by 2 weeks (both P < 0.05). Improvements persisted to 24 weeks (Ulcerative Colitis Symptom Score, Inflammatory Bowel Disease Questionnaire, both P < 0.005). Eight of the nine responders relapsed (median, 9 weeks), but remission was re-achieved with further corticosteroids and the addition of azathioprine. At 24 weeks, seven patients were in full clinical remission, five off all steroid therapy. In vitro measurement of lymphocyte steroid sensitivity demonstrated steroid resistance in 22% of subjects. All were rendered steroid sensitive in the presence of basiliximab. CONCLUSIONS: Basiliximab appears to be effective at inducing remission in steroid-resistant ulcerative colitis. In vitro, basiliximab also produced a dramatic increase in lymphocyte steroid sensitivity in healthy subjects. Confirmation in randomized controlled studies is required.

Adult↗
PubMed2002

beta7 Integrin expression is not required for the localization of T cells to the intestine and colitis pathogenesis.

beta7 Integrins have been shown to have an important role in the localization of T cells to the intestine. Utilizing two different experimental mouse models of inflammatory bowel disease (IBD), this study was undertaken to determine if beta7 integrin expression is critical for T cell localization to the intestine and colitis pathogenesis. Transfer of CD4+ CD45RBhigh cells into immunodeficient mice results in colitis. To examine the role of beta7 integrins, donor cells were obtained from beta7 integrin gene-deficient animals and disease induction was examined following transfer into severe combined immunodeficiency (SCID) mice. Additionally, beta7 integrin gene-deficient animals were crossed to IL-2-deficient mice and the onset of spontaneous colitis that normally occurs in IL-2-deficient animals was examined. No differences in the onset or severity of spontaneous colitis was noted in animals that were deficient in both beta7 integrin and IL-2. In contrast, the onset of colitis in recipients of T cells from beta7 integrin-deficient donors was delayed significantly. In mice receiving beta7 integrin negative cells, the initial lack of colitis appeared to correlate with fewer numbers of CD3+beta7 integrin -/- donor lymphocytes present in the host colon. The eventual development of disease, however, was associated with increased numbers of donor beta7 integrin -/- lymphocytes. These results show that beta7 integrin expression is not absolutely required for T cell localization to the intestine and colitis pathogenesis.

Adoptive Transfer↗
PubMed1999

Tenascin labelling in colorectal biopsies: a useful marker in the diagnosis of collagenous colitis.

AIMS: This study was undertaken to clarify whether immunohistological detection of tenascin (TN), an extracellular matrix glycoprotein that is expressed during stromal remodelling, may allow a more precise diagnosis of collagenous colitis. METHODS AND RESULTS: We studied multiple colorectal biopsies specimens from 15 patients with clinically suspected collagenous colitis for TN expression by using a monoclonal antibody. Biopsies from further 15 patients without symptoms and signs of collagenous colitis served as controls. In seven of the 15 cases with clinically suspected collagenous colitis a prominent and selective subepithelial tenascin expression was identified. The TN expression pattern closely correlated with the conventional detection of a subepithelial collagen band diagnostic of collagenous colitis. The immunohistological labelling for TN allowed a quicker and more precise measurement of the thickness of the diagnostic collagen deposits than conventional staining. By this approach one further case could be reclassified as collagenous colitis. CONCLUSIONS: Our data show that immunohistological detection of TN allows a more correct and easy diagnosis of collagenous colitis.

Adult↗
PubMed1999

Temporal distribution of neuronal and inducible nitric oxide synthase and nitrotyrosine during colitis in rats.

Nitric oxide (NO) has been implicated in the pathogenesis of inflammatory bowel disease since increased NO production is observed in this disease. NO can react with superoxide to generate peroxynitrite which causes and/or exacerbates colitis. Peroxynitrite, in turn, nitrates tyrosine residues to form nitrotyrosine which can be identified immunohistochemically. We investigated the distribution of neuronal and inducible nitric oxide synthase (iNOS) and nitrotyrosine over time in experimental colitis. Colitis was induced by intracolonic administration of trinitrobenzene sulphonic acid (TNBS) in rats. Animals were killed 1, 2, 7 and 14 days after treatment. Myeloperoxidase activity was used as an index of inflammation, and tissues were examined using immunohistochemistry. Neuronal NOS immunoreactivity was present throughout the colon, and was only slightly reduced 1 day after the induction of colitis. Conversely, iNOS immunoreactivity almost absent in controls dramatically increased in the mucosa and submucosa at the early stages of inflammation. iNOS was present in monocytes and macrophages and also another unidentified cell type. Seven and 14 days after the induction of colitis, iNOS was also found in nerves in the circular muscle and in the myenteric plexus. Nitrotyrosine immunoreactivity present in a few cells in the normal mucosa also increased 1 day after the induction of colitis and decreased thereafter. The pattern of distribution of nitrotyrosine immunoreactivity was distinct from that of iNOS. The increase of iNOS expression at the early stage of inflammation may play a role in causing tissue injury via peroxynitrite formation. The expression of iNOS seen in the enteric nerves in the later stage of inflammation correlates temporally with the beginning of tissue repair and with the re-innervation and compensatory growth of nerves. NO may potentially play a physiological as well as pathological role in experimental colitis.

Animals↗
PubMed2003

Evidence for the critical role of interleukin-12 but not interferon-gamma in the pathogenesis of experimental colitis in mice.

BACKGROUND AND AIMS: The imbalance between helper T (Th)1/Th2 cytokines has been observed in human inflammatory bowel disease and various animal models. Because interleukin (IL)-12 and interferon-gamma (IFN-gamma) productions are known to be a hallmark of Th1-dominant intestinal inflammation such as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we strictly addressed the roles of IFN-gamma and IL-12 in the development of colitis, employing knockout mice with IFN-gamma receptor (IFN-gammaR) or IL-12 p40 gene disruptions and mice administered with neutralizing monoclonal antibodies (mAbs) against IFN-gamma or IL-12. METHODS: To induce colitis, 2.5 mg of the hapten reagent TNBS in 50% ethanol was administered into the colon. Two milligrams of rat anti-mouse IFN-gamma mAb, rat anti-mouse IL-12 mAb, or control rat IgG were administered intraperitoneally into mice before TNBS administration. Change in the body weight of mice was evaluated and the degree of inflammation of the colon of these mice was investigated histologically. Immunohistochemical and immunofluorescence analyses were performed to detect CD4+ T cells, macrophages and IL-12 in TNBS-induced colitis lesions. The profile of Th1 and Th2 cytokine expressions in colonic tissues was examined by cytokine-specific semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Single rectal administration of TNBS developed significant colitis in IFN-R-/- mice and anti-IFN-gamma mAb-pretreated mice, as well as control wild-type mice. Conversely, administration of TNBS produced no signs of colitis in IL-12 p40-/- and anti-IL-12 mAb-pretreated mice. CONCLUSIONS: IL-12, but not IFN-gamma, plays a pivotal role in the pathogenesis of TNBS-induced colitis.

Animals↗
PubMed1996

A prospective study of the epidemiology of colitis and colon cancer in cotton-top tamarins (Saguinus oedipus).

BACKGROUND & AIMS: Spontaneous colitis and colon cancer in the cotton-top tamarin have been shown to resemble human ulcerative colitis and its associated cancer. The effect of environment and diet on the evolution of the disease was studied in animals from birth to 5 years of age. METHODS: Newborn tamarins were assigned to three groups reared in (1) a colony in which colitis was highly prevalent and fed a standard diet; (2) an isolation unit and fed a standard diet or one of two semipurified diets; and (3) a multispecies nursery, returned to the colony, and fed the same semipurified diets. Mucosal biopsy specimens from the descending colon were taken at 4-month intervals. RESULTS: Acute colitis and chronic mucosal changes were significantly higher in the colony than in the isolation unit. Diet had no effect on acute colitis, but chronic mucosal changes were significantly higher in animals fed a standard diet than semipurified diets. CONCLUSIONS: Data suggest that acute colitis was associated with environment. Factors in the environment, including a transmissible agent, are discussed. Chronic mucosal changes were modified by diet. Cancer was associated with acute colitis and chronic changes and seems to be associated with diet.

Adenocarcinoma↗
PubMed2000

Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration.

BACKGROUND & AIMS: Experimental colitis in most animal models is caused by dysregulation of T lymphocytes that display a T helper 1 (Th1) phenotype. CD154 (CD40L/gp39), a member of the tumor necrosis factor (TNF) family, is up-regulated on T cells on activation and has been shown to play a key role in the induction of a Th1 response. We investigated whether chronic experimental colitis is dependent on the CD154/CD40 pathway and whether disease can be prevented by anti-CD154 antibody treatment. METHODS: Two models of chronic colitis were used: CD45Rb(hi) cell transfer into recombination activation gene-deficient (Rag(-/-)) mice and bone marrow transplant of tgepsilon26 animals. In both models, mice were reconstituted with cells from CD154-deficient animals. In another series of experiments, wild-type CD45Rb(hi) T cell-reconstituted recipients were treated with anti-CD154, either from the start of the experiment or after onset of disease. RESULTS: T cells deficient in CD154 induced a milder clinical disease, less weight loss, and fewer histologic signs of colitis than wild-type cells. The level of interleukin 12 in the serum of CD154-deficient T-cell recipients was 5-fold less than that of wild-type cell recipients. Nevertheless, no signs of deviation from a Th1 phenotype were observed. Treatment with anti-CD154 antibodies substantially impaired disease development, even when started after the onset of colitis. CONCLUSIONS: The CD154/CD40 pathway plays a critical role in Th1-induced chronic experimental colitis. Blocking CD154, even after the onset of disease, ameliorates colitis but does not induce a T helper 2 (Th2) phenotype.

Animals↗
PubMed2001

Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg(epsilon26) mice.

BACKGROUND & AIMS: Normal resident bacteria are required for development of colitis in several rodent models. We determined whether bacterial stimulation is necessary for both induction and perpetuation of mucosal inflammation and T-cell activation in Tg(epsilon26) mice, in which transplantation of wild-type bone marrow (BM-->Tg(epsilon26)) causes colitis under specific pathogen-free (SPF) conditions. METHODS: BM from (C57BL/6 X CBA/J) F1 mice was transplanted into germfree (GF) or SPF Tg(epsilon26) mice. Mesenteric lymph node (MLN) cells from these mice were then transferred into SPF or GF recipients. Colitis and activation of MLN cells were measured by histologic scores, membrane marker analysis, and intracellular cytokine staining. Cytokine secretion by MLN cells stimulated by anti-CD3 or by luminal or epithelial antigens was measured by ELISA. RESULTS: Colitis did not develop when BM was transferred into GF recipient mice (BM-->GF Tg(epsilon26)). T lymphocytes that secreted interferon gamma upon activation were present in the MLN of BM-->GF Tg(epsilon26) mice, albeit in lower frequency than in control BM-->SPF Tg(epsilon26) mice. Furthermore, transfer of MLN cells from BM-->SPF Tg(epsilon26) mice into SPF Tg(epsilon26) recipients induced active colitis, but not if the same cells were transferred into GF Tg(epsilon26) recipients. Although CD4 T cells were detected in the colonic mucosa of GF recipients, no inflammation was observed for at least 31 weeks. In a reciprocal experiment, MLN cells from BM-->GF Tg(epsilon26) mice without colitis transferred disease to SPF Tg(epsilon26) recipients within 2-4 weeks. CONCLUSIONS: Activated T cells are present in the mucosa of BM-->GF Tg(epsilon26) mice but are incapable of inducing disease unless colonic bacteria are present. Moreover, pathogenic T cells require the continuous presence of colonic bacteria to sustain colitis.

Animals↗
PubMed2002

Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis.

BACKGROUND & AIMS: Impaired mucosal barrier, cytokine imbalance, and dysregulated CD4(+) T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA, are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation. METHODS: The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate-induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. Similarly, these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice. RESULTS: In all models of experimental and spontaneous colitis examined, ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metalloproteinases in both dextran sodium sulfate- and hapten-induced colitis. CONCLUSIONS: As the colon is continuously exposed to bacterial DNA, these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease.

Adjuvants, Immunologic↗
PubMed2002

Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model.

BACKGROUND & AIMS: Regulatory CD4(+) cells secreting the anti-inflammatory cytokine interleukin (IL)-10 play a key role in maintaining the immune balance in the intestinal mucosa. In this study we engineered primary CD4(+) cells to express IL-10 and investigated the efficacy of this approach in offering protection against experimental colitis. METHODS: Spleen-derived CD4(+) cells were transduced by using a retroviral vector to simultaneously express IL-10 and green fluorescent protein (GFP). The therapeutic benefit of CD4(+) cells transduced with IL-10 GFP was studied in experimental colitis, induced by transfer of CD45RB(high) CD4(+) cells to severe combined immunodeficient mice, and in acute trinitrobenzene sulfonic acid (TNBS)-induced colitis. RESULTS: Transferred engineered GFP fluorescent cells were detected for at least 15 weeks in peripheral blood, spleens, colon, and lymph nodes draining the intestine of recipient SCID mice. IL-10-GFP CD4(+) cells prevented CD45RB(high)-induced transfer colitis effectively, whereas no effect was observed after transfer of nontransduced CD4(+) cells. IL-10-GFP CD45RB(high) CD4(+) cells lost the capacity to induce colitis. By contrast, no therapeutic benefit was observed in TNBS-induced colitis. CONCLUSIONS: Primary murine CD4(+) cells that were engineered to express IL-10 by retroviral transduction act as regulatory cells in CD45RB(high)-induced transfer colitis. This approach may induce long-term maintenance of mucosal immune homeostasis in Crohn's disease.

Animals↗
PubMed2003

Ameliorating effect of anti-inducible costimulator monoclonal antibody in a murine model of chronic colitis.

BACKGROUND & AIMS: Inducible costimulator (ICOS)/B7RP-1 represents a newly described receptor/ligand pair involved in costimulation of T cells by antigen-presenting cells. We investigated the involvement of the ICOS/B7RP-1 interaction in the pathogenesis of colitis and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in experimental colitis METHODS: We administered anti-ICOS or anti-B7RP-1 mAb to mice with experimental colitis induced by transfer of CD4(+)CD45RB(high) T cells from normal mice into SCID mice. The ability of CD4(+)CD45RB(high) cells derived from ICOS-/- mice to induce colitis was assessed. Th2 cytokine production and apoptosis in infiltrating T cells was examined after administration of anti-ICOS mAb. RESULTS: ICOS was strongly induced on CD4(+) T cells, and B7RP-1 was expressed by macrophages in the inflamed mucosa of colitic mice. Anti-ICOS mAb, but not anti-B7RP-1, ameliorated chronic colitis when administered in prevention or therapeutic protocols. Transfer of CD4(+)CD45RB(high) T cells from ICOS-/- mice induced colitis. Treatment with anti-ICOS mAb did not enhance the production of Th2 cytokines, but a single dose of anti-ICOS mAb induced massive apoptosis of infiltrating ICOS-expressing T cells. CONCLUSIONS: ICOS/B7RP-1 interactions are not required for the development of colitis. However, treatment with anti-ICOS mAb can prevent and reverse intestinal inflammation by inducing apoptosis of ICOS-expressing T lymphocytes.

Adoptive Transfer↗
PubMed2003

Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County.

BACKGROUND & AIMS: A population-based cohort from Copenhagen County comprising 1160 patients diagnosed with ulcerative colitis between 1962 and 1987 was followed-up until 1997 to describe survival and cause-specific mortality. METHODS: Observed vs. expected deaths were presented as standardized mortality ratio (SMR) with exact 95% confidence intervals (CI) calculated by using individually registered person-years at risk and Danish 1995 mortality rates. Cumulative survival curves were calculated. RESULTS: A total of 261 deaths occurred, not significantly different from the expected number of 249 (SMR, 1.05; 95% CI, 0.92-1.19). The median age at death among men was 70 years (range, 6-96 years) and among women 74 years (range, 25-96 years). Twenty-five deaths (9.6%) were caused by complications to ulcerative colitis, mostly infectious and cardiovascular postoperative complications. Patients older than 50 years of age at diagnosis and with extensive colitis showed an increased mortality within the first 2 years because of ulcerative colitis-associated causes. The mortality from colorectal cancer was not increased and that of cancer in general was significantly lower than expected: 50 vs. 71 (SMR, 0.70; 95% CI, 0.52-0.93). A significantly increased mortality from pulmonary embolism and pneumonia was found. Among women only, death from genitourinary tract diseases and suicide was significantly increased. CONCLUSIONS: Despite an overall normal life expectancy for patients with ulcerative colitis, patients >50 years of age and with extensive colitis at diagnosis had increased mortality within the first 2 years after diagnosis, owing to colitis-associated postoperative complications and comorbidity.

Adolescent↗
PubMed2005

Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial.

BACKGROUND & AIMS: Ulcerative colitis is most common in Western industrialized countries. Inflammatory bowel disease is uncommon in developing countries where helminths are frequent. People with helminths have an altered immunological response to antigens. In animal models, helminths prevent or improve colitis by the induction of regulatory T cells and modulatory cytokines. This study determined the efficacy and safety of the helminth Trichuris suis in therapy of ulcerative colitis. METHODS: This was a randomized, double blind, placebo-controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of > or =4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks. RESULTS: The primary efficacy variable was improvement of the Disease Activity Index to > or =4. After 12 weeks of therapy, improvement according to the intent-to-treat principle occurred in 13 of 30 patients (43.3%) with ova treatment compared with 4 of 24 patients (16.7%) given placebo (P = .04). Improvement was also found with the Simple Index that was significant by week 6. The difference in the proportion of patients who achieved an Ulcerative Colitis Disease Activity Index of 0-1 was not significant. Treatment induced no side effects. CONCLUSIONS: Ova therapy seems safe and effective in patients with active colitis.

Administration, Oral↗
PubMed2005

Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis.

BACKGROUND & AIMS: Basic fibroblast growth factor (bFGF) is a promising therapeutic agent for various diseases. It remains unclear, however, whether bFGF is effective for the treatment of inflammatory bowel disease. The aim of this study was to examine the efficacy of bFGF on 2 experimental murine colitis models and to investigate its molecular mechanisms. METHODS: We evaluated the effects of human recombinant bFGF (hrbFGF) on mice with dextran sulfate sodium (DSS)-induced colitis and mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis as well as normal mice. Body weight, survival rate, and histologic findings of the colonic tissues were examined. Gene expression of tumor necrosis factor (TNF)-alpha, cyclooxygenase (COX)-2, transforming growth factor (TGF)-beta, mucin 2 (MUC2), intestinal trefoil factor (ITF), and vascular endothelial growth factor (VEGF) in the colonic tissues was determined. The proliferation activity of hrbFGF on the colonic epithelium was evaluated by immunohistochemistry. RESULTS: Rectal administration of hrbFGF ameliorated DSS-induced colitis in a dose-dependent manner. Gene expression of TNF-alpha was significantly reduced in the colonic tissues of mice with DSS-induced colitis treated with hrbFGF, whereas MUC2 and ITF messenger RNA expression was up-regulated. Rectal administration of hrbFGF significantly improved the survival rate of mice with TNBS-induced colitis and partially ameliorated colitis. hrbFGF significantly increased the number of Ki-67-positive cells in the colonic epithelium of normal mice, and up-regulated the gene expression of COX-2, TGF-beta, MUC2, ITF, and VEGF in the colonic tissues. CONCLUSIONS: Rectal administration of bFGF might be a promising option for the treatment of inflammatory bowel disease.

Administration, Rectal↗
PubMed2005

Colitis in mice lacking the common cytokine receptor gamma chain is mediated by IL-6-producing CD4+ T cells.

BACKGROUND & AIMS: Mice that have a truncated mutation of the common cytokine receptor gamma chain (CR gamma -/Y) are known to spontaneously develop colitis. To identify the pathologic elements responsible for triggering this localized inflammatory disease, we elucidated and characterized aberrant T cells and their enteropathogenic cytokines in CR gamma -/Y mice with colitis. METHODS: The histologic appearance, cell population, T-cell receptor V beta usage, and cytokine production of lamina propria lymphocytes were assessed. CR gamma -/Y mice were treated with anti-interleukin (IL)-6 receptor monoclonal antibody to evaluate its ability to control colitis, and splenic CD4 + T cells from the same mouse model were adoptively transferred into SCID mice to see if they spurred the appearance of colitis. RESULTS: We found marked thickening of the large intestine, an increase in crypt depth, and infiltration of the colonic lamina propria and submucosa with mononuclear cells in the euthymic CR gamma -/Y mice, but not in the athymic CR gamma -/Y mice, starting at the age of 8 weeks. Colonic CD4 + T cells with high expressions of antiapoptotic Bcl-x and Bcl-2 were found to use selected subsets (V beta 14) of T-cell receptor and to exclusively produce IL-6. Treatment of CR gamma -/Y mice with anti-IL-6 receptor monoclonal antibody prevented the formation of colitis via the induction of apoptosis in IL-6-producing CD4 + T cells. Adoptive transfer of pathologic CD4 + T cells induced colitis in the recipient SCID mice. CONCLUSIONS: Colonic IL-6-producing thymus-derived CD4 + T cells are responsible for the development of colitis in CR gamma -/Y mice.

Adoptive Transfer↗
PubMed2005

Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis.

BACKGROUND & AIMS: Constitutive signal transducer and activator of transcription (STAT) 3 activation promotes chronic inflammation and epithelial proliferation in murine colitis and human inflammatory bowel disease. SHP-2, through binding to the glycoprotein 130 signaling receptor, negatively regulates STAT3 activation. Growth hormone reduces disease activity and promotes mucosal healing in colitis and can activate SHP-2. METHODS: We hypothesized that growth hormone administration would reduce disease activity in experimental colitis and that this would involve modulation of SHP-2/glycoprotein 130 association and STAT3 activation. RESULTS: Growth hormone administration improved weight gain and colon histology in interleukin 10-null mice with colitis. Growth hormone reduced apoptosis and increased proliferation of crypt epithelial cells while increasing apoptosis of lamina propria mononuclear cells. Growth hormone increased SHP-2/glycoprotein 130 association and reduced colonic STAT3 activation in interleukin 10-null mice and in biopsy samples from patients with Crohn's colitis. Expression of the antiapoptotic protein bcl-2 was increased in crypt epithelial cells after growth hormone treatment. Growth hormone increased SHP-2/glycoprotein 130 binding and reduced interleukin 6-dependent STAT3 activation in the T84 human colon carcinoma and Jurkat human T-cell leukemia lines. CONCLUSIONS: Growth hormone administration improves weight gain and reduces disease activity in interleukin 10-null mice with colitis. The improvement in disease activity is associated with increased SHP-2/glycoprotein 130 binding and reduced STAT3 activation in both murine and Crohn's colitis. Growth hormone may be a useful therapy in inflammatory bowel disease, in terms of both improving anabolic metabolism and enhancing mucosal healing.

Animals↗
PubMed2006

Antidepressants attenuate increased susceptibility to colitis in a murine model of depression.

BACKGROUND & AIMS: Psychiatric factors may determine gastrointestinal health outcomes. Here, we used a model of depression based on neonatal maternal separation (MS) to identify alterations in gut physiology and to assess its association with increased sensitivity to experimental colitis in adulthood. We also examined whether antidepressant therapy attenuates the increased susceptibility to colitis. METHODS: C57BL/6 mouse pups were separated from mothers for 3 hours per day at 1-21 days of age. Maternally unseparated (US) litters served as controls. At 8 weeks of age mice were examined for changes in behavior, intestinal permeability, and sensitivity to colitis. Separate sets of MS and US mice were given either saline or the antidepressant desipramine 15 mg/kg once daily at 23-36 days of age. Testing of mice occurred at 8 weeks of age. RESULTS: Adult MS mice showed evidence of depressive-like behavior and enhanced intestinal permeability but showed no evidence of spontaneous inflammation. A more severe colitis was seen in MS compared with US mice. Antidepressant therapy improved parameters of depressive-like behavior and reduced the vulnerability to dextran sulphate sodium colitis in MS mice but had no effect on colitis in US mice. CONCLUSIONS: MS may lead to depression and increased responsiveness to stress, to impaired intestinal barrier function, and to enhanced vulnerability to colitis in adulthood. This vulnerability is reversed by antidepressant therapy. Depression increases vulnerability to intestinal inflammation. We speculate that pre-existing depression may facilitate the expression of inflammatory bowel diseases.

Animals↗
PubMed2005

Lansoprazole-associated collagenous colitis: a case report.

A 57-year-old man developed chronic, watery diarrhea four weeks after Helicobacter pylori eradication therapy including lansoprazole followed by lansoprazole monotherapy for gastroesophageal reflux disease. Four weeks later the patient was admitted to our hospital. By repeated testing other causes of diarrhea, e. g., infectious diarrhea including Clostridium difficile colitis were excluded. Endoscopy showed a normal colon, histopathology of random biopsies of all sections of the colon demonstrated the characteristic features of collagenous colitis. Withdrawal of lansoprazole lead to prompt and sustained relief. Two months later repeat colonoscopy with biopsies showed no evidence of collagenous colitis. Collagenous colitis as a subtype of microscopic colitis is a rare cause of chronic diarrhea with unknown pathogenesis. The reported case represents an unusual association between medication with the proton pump inhibitor lansoprazole and the development of collagenous colitis suggesting the importance of evaluation of drug use in patients with microscopic colitis.

2-Pyridinylmethylsulfinylbenzimidazoles↗