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Lower gastrointestinal bleeding in inflammatory bowel disease.

An increasing number of patients with inflammatory bowel disease (IBD) have been observed over the past two to three decades at the Cleveland Clinic. This has allowed extensive follow-up and determination of long-term prognosis. The diseases are chronic, require medication over a long period of time, are frequently associated with the need for operation, and often have complications and recurrences. In addition, a substantial number of patients have onset disease at a young age and thus, the propensity for recurrences and complications makes IBD of significant clinical importance. The symptoms of IBD are chronic and usually include diarrhea and often malnutrition. Rectal bleeding is found in almost all patients with ulcerative colitis and in about 25% of patients with Crohn's disease. However, severe hemorrhage in IBD occurs in a small number (1-5%) of patients. When this occurs, it often does so as an episode which may be associated with severe illness systemically as well as creating diagnostic confusion. For patients with ulcerative colitis, the progressive severity of bleeding may be an important indication for surgery (colectomy); in Crohn's disease, patients with ileocolic location of disease are more likely to have severe hemorrhage, and may require resection as a result. Despite the similarities of Crohn's disease and ulcerative colitis, there are significant differences particularly in the long-term (greater than 10 years) follow-up. For patients with Crohn's disease, the major long-term problem is the need for surgery (2/3-3/4 of patients) and recurrence (+/- 50%).(ABSTRACT TRUNCATED AT 250 WORDS)

Colonic Neoplasms↗

Significance of interleukin-6 in patients with inflammatory bowel disease.

The significance of interleukin-6 (IL-6) in patients with inflammatory bowel disease (IBD) was studied by measuring the IL-6 level in serum and colonic tissue by means of an enzyme-linked immunosorbent assay (ELISA), and by examining its localization using an immunohistochemical method. The serum IL-6 level reflected the degree of disease activity, and the extent of affected area, and was also correlated with the serum C-reactive protein (CRP) level. In the colonic mucosa of active IBD, the tissue IL-6 level was markedly elevated, and immunoreactive products of anti-IL-6 antibody were present in infiltrative mononuclear cells in the lamina propria. This indicates that IL-6 production in these cells is enhanced at the site of affected intestine. These results, together with its biological activity and the type of cell producing it, suggest that IL-6 is an available marker to assess disease conditions of IBD and that it might be also involved in the pathophysiology of IBD.

Adult↗

Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease.

INTRODUCTION: Several new derivatives of sulphasalazine that make use of its active moiety, 5-aminosalicylic acid (5-ASA), have been introduced for the treatment of inflammatory bowel disease (IBD). In rats short term intravenous administration of 5-ASA has been associated with nephrotoxicity. A number of cases of nephrotoxicity have been reported recently in IBD patients taking oral maintenance treatment with 5-ASA compounds. OBJECTIVE: To study the urinary and serum levels of acetylated 5-ASA (Ac-5-ASA) and the unacetylated 5-ASA (5-ASA) in patients with IBD maintained on sulphasalazine, olsalazine and mesalazine (pH dependent release form). We also sought correlation between levels of 5-ASA, clinical disease activity and extent of disease. METHODS: We studied 79 patients (male, n = 30; female, n = 49) with established IBD [ulcerative colitis (UC), n = 48; Crohn's disease (CD), n = 31], 72 maintained on 5-ASA compounds (sulphasalazine = 27; olsalazine = 28; mesalazine = 17) and 7 patients were receiving no medication. Urinary and serum analysis of 5-ASA was performed by high performance liquid chromatography (HPLC). Clinical disease activity was quantified using simple index of Harvey and Bradshaw. RESULTS: Patients receiving mesalazine had significantly higher levels of serum free 5-ASA compared to those who were receiving olsalazine and sulphasalazine (mesalazine mean +/- SEM; range; 2.84 +/- 1.21 (0.00-16.00) vs olsalazine 0.45 +/- 0.18 (0.00-16.20); mumol/L; p < 0.04; sulphasalazine 0.37 +/- 0.25 (0.00-3.74); p < 0.03). Similarly levels of urinary free 5-ASA were significantly higher in patients maintained on mesalazine compared to those on olsalazine or sulphasalazine (mesalazine 219 +/- 80.43 (0.00-1050) vs olsalazine 33.3 +/- 17.23 (0.00-317) mumol/L; p < 0.01; and sulphasalazine 15 +/- 8.86 (0.00-192); p < 0.05). However, no significant difference was observed in the levels of urinary free 5-ASA between olsalazine and sulphasalazine. No significant difference was observed in the levels of free-5-ASA in UC patients with left sided disease and those with extensive disease. Furthermore, no significant difference was observed in the levels of serum and urinary 5-ASA in CD patients with ileo-colic disease and colonic disease. Urinary and serum free-5-ASA did not correlate with the clinical disease activity. CONCLUSION: Systemic absorption of 5-ASA from sulphasalazine and olsalazine is relatively low. However, pH-dependent mesalazine formulations may release their contents rapidly in the small intestine and proximal colon resulting in higher plasma and urinary concentrations of free 5-ASA. The effects of free 5-ASA on renal function in the human require further evaluation.

Adolescent↗

Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitis.

BACKGROUND: Little information is available on the relative contribution of peptide growth factors and leukocyte-derived proteinases to the repair processes in inflammatory bowel disease (IBD). We investigated their possible roles in epithelial cell restitution and proliferation in patients with IBD. METHODS: The expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-beta (TGF-beta), and neutrophil elastase (NE) was examined in colonic mucosal tissues. The effects of organ culture supernatants of mucosal tissues on epithelial cell restitution and proliferation were analyzed in vitro using an intestinal cell line, IEC-6 cells. RESULTS: Most organ cultures detected the presence of measurable levels of HGF, with a relative paucity of KGF and TGF-beta activity. Greater levels of HGF were obtained in the mucosa involved with IBD, especially in patients with ulcerative colitis (UC). The mucosa involved with UC also showed higher amounts of NE. The supernatants from the mucosa involved with UC possessed a prominent stimulatory effect on the restitution of IEC-6 cells. By contrast, significant suppression beyond baseline levels was observed for the proliferation of IEC-6 cells when they were incubated with recombinant HGF plus the supernatants from the mucosa involved with UC. This suppression was diminished considerably by preincubation of the supernatants with the anti-NE antibody. CONCLUSIONS: HGF produced in the intestinal mucosa may be an important stimulator acting on epithelial cell restitution in patients with IBD. However, NE released in situ may impair mucosal repair through inhibiting epithelial cell proliferation in patients with UC.

Adult↗

Major cardiovascular event risk of advanced therapies in inflammatory bowel diseases: systematic review and meta-analysis.

BACKGROUND: Patients with chronic immune-mediated disorders (IMIDs), including inflammatory bowel disease (IBD), are at increased risk of cardiovascular disease. While advanced therapies show cardioprotective effects in other IMIDs, their impact on major adverse cardiovascular events (MACE) in IBD remains unclear. We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating MACE risk with advanced therapies in IBD. METHODS: Systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials identified 43 studies (36 RCTs, including 9 long-term follow-up (LTF) studies, and 7 observational studies) published between 2002 and 2024. Primary analyses estimated odds ratios (OR) for MACE comparing advanced therapy to placebo, with secondary analyses stratifying studies by drug class and length of follow-up. Sensitivity analyses were conducted using alternative methods to account for zero-event data. RESULTS: Placebo-controlled RCTs showed a nonsignificant trend toward reduced MACE risk (OR 0.60; 95% CI 0.24-1.51), with similar findings across sensitivity analyses accounting for sparse and zero-event data. Class-specific trends suggested lower MACE risk with IL-12/IL-23 inhibitors (OR 0.35; 95% CI 0.05-2.21), JAK inhibitors (OR 0.57; 95% CI 0.16-2.06), and a potential increase with Anti-TNF agents (OR: 3.04; 95% CI 0.31-29.47), though none reached statistical significance. LTF studies showed consistent findings. Observational studies suggested lower MACE risk with Anti-TNF therapies (OR 0.29; 95% CI 0.21-0.40), but not with IL-12/IL-23 (OR 4.41; 95% CI 0.49-39.28) or JAK inhibitors (OR 1.57; 95% CI 0.86-2.84). CONCLUSION: Advanced therapies did not demonstrate a clear increase or decrease in cardiovascular risk in IBD. The discrepancies between RCTs and observational studies underscore the urgent need for rigorous-designed observational research with long-term follow-up to evaluate the real-world impact of advanced therapies on MACE risk.

Humans↗

[The German competence network inflammatory bowel disease (KNCED) -- network research leads to the identification of the cause of disease and to the improvement in patient care].

The competence network chronic inflammatory bowel disease (KN-CED) is one of 17 networks of competence initiated by the German Federal Ministry of Education and Research (BMBF). These networks are concerned with disease patterns which are characterized by their high frequency, high mortality rate or which present a large expense factor. The project-executing organization is the German Center for Air and Space Travel (DLR e. V.). The central structure of organization is the Telematic Platform for medical Networks (TMF e. V.). Aim of the KN-CED is to investigate, in their complexity, the incurable chronic diseases ulcerative colitis and Crohn's disease, particularly with regard to the causes of disease, the establishment of new therapy standards as well as patient care. To achieve this goal, the competence network is integrated into both national and international research associations and is also backed by the national self-help group DCCV and the pharmaceutical industry. Principal items of the competence network are the core facilities and their main focus on molecular genetics, animal and cell models and serum markers. Having stored the data of more than 4,000 patients so far, the central database of the competence network is one of the largest databases worldwide with regard to inflammatory bowel disease (IBD). The successful cooperation within the network is reflected in numerous publications. Thus, two of the three known genes of Crohn's disease were identified. Also with the participation of the competence network national guidelines for the diagnosis and therapy of IBD were generated.Furthermore, the competence network operates study centers where significant therapeutic developments in the field of biotechnological drugs are taking place. The analysis of existing structures of care as well as the development of standards of organization for patients with IBD top the research within the competence network and emphasize the claim to find comprehensive answers to the questions connected with IBD.

Clinical Trials as Topic↗

[Immunopathogenesis of inflammatory bowel diseases].

Inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) are chronic inflammatory and frequently relapsing diseases of the gut that ultimately lead to destruction of the intestinal tissue. Recent evidence suggests that a pathologic activation of the mucosal immune system in response to antigens is a key factor in the pathogenesis of IBD. Furthermore, changes in cell migration and cytokine production appear to contribute to the perpetuation of IBD and the postoperative recurrence of Crohn's disease. Based on recent advances in our understanding of the pathogenesis of IBD, several new therapeutic strategies are currently being tested in clinical practice, including recombinant anti-inflammatory cytokines (IFN-alpha, IL-10, IL-11) and inhibitors of cell adhesion molecules (ICAM), proinflammatory cytokines (TNF, IL-12) and their receptors (TNF, IL-6R).

Adjuvants, Immunologic↗

[Chronic inflammatory bowel diseases competence network ].

Inflammatory bowel diseases (IBD) are intermittently appearing, often chronic diseases mostly affecting young people between 20-30 years of age influencing their quality of life and socioeconomic efficiency. The triggering factors for the development of IBD are not completely understood: besides environmental factors there is clear evidence for additional genetic factors influencing the risk of disease and the pattern of gut inflammation in Crohn's disease. Pathopysiological discoveries are leading to new therapeutic opportunities which are conducted in large clinical studies with main participation of the competence network IBD. The disseminated structure of the network comprising universitary and nonuniversitary hospitals and labs, the self-help-organization DCCV and its vertical cooperation with general practitioners nationwide gives opportunity to describe the diseases from the point of view of the scientist and the physician simultaneously. Therefore the competence network IBD yields the basis for the standardized integration of patient information, for the development of guidelines and the establishment of a quality management system thus leading to an improvement of scientific and clinical research.

Biomedical Research↗

Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease.

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappaB (NFkappaB) binding sites in each promoter. Furthermore, NFkappaB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-alpha and transforming growth factor-beta, which could be blocked by NFkappaB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P = 0.003) polymorphism with CD and for MUC4-A585S (P = 0.025), as well as MUC13-R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFkappaB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

Adult↗

Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) have frequently a bone mineral density (BMD) significantly lower than age-matched healthy subjects. The low BMD observed in IBD patients is related also to a higher incidence of bone fractures. In this prospective randomized study we evaluated the effect of 1-year risedronate administration on bone mass and turnover, and on vertebral fractures in osteoporotic postmenopausal women with IBD in remission. Ninety osteoporotic postmenopausal women were randomized to receive oral risedronate 35 mg/week (risedronate group) or placebo tablets (placebo group; one tab/week). The duration of treatment was 12 months. At entry and after treatment, lumbar spine and hip BMD, and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. Vertebral fractures were assessed from thoracic and lumbar lateral and anterior-posterior spinal radiographs taken at baseline, and from lateral spinal radiographs taken at the end of the study. At study entry, no difference between groups was also detected in BMD and in bone turnover markers. At the end of the study, lumbar spine, trochanter and femoral neck BMD was significantly ( p <0.05) higher in comparison with baseline in the risedronate group, whereas a significant ( p <0.05) decrease was observed in the placebo group. For the same visit, a significant ( p <0.05) difference in lumbar spine, trochanter and femoral neck BMD was detected between groups. After 12-month follow-up, serum OC and urinary DPD-Cr levels were significantly ( p <0.05) lower and higher in comparison with basal values in risedronate and placebo group, respectively. At the same time, a significant ( p <0.05) difference in serum OC and urinary DPD-Cr levels was observed between groups. Throughout the study, the incidence of vertebral fractures was significantly ( p <0.05) lower in the risedronate group than in the placebo group (12.5% vs 34.1%). The relative risk (RR) to develop a new vertebral fracture after 1 year of risedronate administration was of 0.36 (95% confidence interval, 0.14-0.85). In conclusion, risedronate administration is an effective anti-osteoporotic treatment in osteoporotic postmenopausal women with IBD in remission.

Bone Density↗

The role of aminosalicylates at the beginning of the new millennium in the treatment of chronic inflammatory bowel disease.

OBJECTIVE: To discuss the pharmacological properties of aminosalicylates and their potential value in the treatment of chronic inflammatory bowel disease (IBD). METHODS: A review of clinical studies on the pharmacokinetics and mode of action of aminosalicylates is provided. In addition, the clinical efficacy and safety of aminosalicylates in the treatment of IBD, according to several recent meta-analyses, is summarised. RESULTS: Whereas aminosalicylates represent drugs of first choice in the acute treatment of ulcerative colitis and also for maintaining those patients in remission, their value for patients with Crohn's disease, either for achieving or maintaining remission, is at best modest. There is a large variability in the clinical results, especially in Crohn's disease, which is probably due to the variable extent and severity of IBD, different instruments in the evaluation of therapeutic outcome, and also at least partly caused by the different preparations and dosages of aminosalicylates used, as well as the high variation in drug disposition and topical availability of the active drug. The popular use of aminosalicylates is most likely due to the low incidence of side effects and the good overall safety records of mesalazine (mesalamine). CONCLUSIONS: Apparently, the full therapeutic potential of aminosalicylates has not yet been evaluated (e.g. upper dosage range, combination therapy, responding subgroups). Consequently, the imperfect treatment might be improved in the new millennium by novel insights in the complex mode of action of mesalazine as well as in the etiopathogenesis of IBD.

Aminosalicylic Acids↗

The potential of digital X-ray radiogrammetry (DXR) in the assessment of osteopenia in children with chronic inflammatory bowel disease.

BACKGROUND: Loss of bone mass is a known complication of chronic inflammatory bowel disease (IBD) in children. The gold standard in the evaluation of bone mineral density (BMD) is dual energy X-ray absorptiometry (DXA). OBJECTIVE: In this preliminary study we evaluated digital X-ray radiogrammetry (DXR) which estimates BMD (DXR-BMD) from hand radiographs in children with IBD. MATERIALS AND METHODS: A total of 26 children with IBD (10 girls, 16 boys; age range 10-18 years) underwent DXR for the calculation of DXR-BMD and metacarpal index (DXR-MCI) using the Pronosco X-posure system. The results were compared with a local reference database and correlated with the results of DXA. RESULTS: DXR-BMD was 0.36-0.56 g/cm(2) (median 0.46 g/cm(2)) in Crohn disease patients and 0.38-0.63 g/cm(2) (median 0.48 g/cm(2)) in ulcerative colitis patients. DXR-MCI was 0.29-0.49 in Crohn disease patients and 0.28-0.53 in ulcerative colitis patients. The Z-scores were reduced to <-1 SD in five Crohn disease patients and in six ulcerative colitis patients. The coefficients (r) for the correlations between DXR-BMD and DXA-BMD were 0.78 for the lumbar spine and 0.61 for the proximal femur (P<0.01), and between DXR-MCI and DXA-BMD were 0.78 for the lumbar spine and 0.51 for the proximal femur (P<0.01). CONCLUSIONS: DXR seems to be able to estimate cortical osteopenia in children with chronic IBD. The DXR results showed a positive correlation with DXA results.

Absorptiometry, Photon↗

Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, including ulcerative colitis (UC) and Crohn's disease (CD). The aim of the study was to determine the prevalence of the tumor necrosis factor alpha (TNF-alpha) promoter polymorphisms at positions -238 and -308, and to measure the serum CRP levels in CD and UC patients and in a healthy population. The TNF-alpha gene polymorphisms were determined by the PCR-RFLP method. Samples of 74 CD and 50 UC patients and 138 healthy Hungarian volunteers were examined. The G-->A substitution at position -308 (designated the TNF2 allele) was significantly less frequent among IBD patients than in the control group (P=0.0009); 15% of the CD patients and 18% of the UC patients carried the mentioned allele, which was significantly less frequent compared with the healthy population (33%, P=0.0035 and P=0.036, respectively). No difference in the G-->A substitution at position -238 was observed. We found the median CRP levels to be significantly higher in the active phase of the disease than in the inactive phase among the -308A allele carriers (P=0.002), while this difference was not significant when the CRP levels in the active and inactive phases were compared among the -308GG homozygous patients (P=0.084). The decreased frequency of the TNF2 allele (known to be associated with elevated TNF-alpha production) in IBD may determine the severity of IBD through its interaction with plasma CRP levels, and may modify the pathogenesis of this chronic inflammatory disease.

Adult↗

Laparoscopy for inflammatory bowel disease: pros and cons.

The role of laparoscopic surgery in the treatment of colorectal malignancies is still under investigation, although it can offer significant benefits to many patients with inflammatory bowel disease (IBD). The aim of this study was to assess the pros and cons of the laparoscopic management of IBD. Data were obtained from a review of the literature published since 1992, when the first report of laparoscopic surgery for IBD appeared in print. From 1992 to 1997 several series of laparoscopic colorectal surgery for the management of IBD have been reported. A close evaluation of these studies revealed that laparoscopy in patients with terminal ileal Crohn's disease or anal Crohn's disease in need of fecal diversion offers significant advantages compared to laparotomy, including decreased pain, length of hospitalization, and disability. An additional bonus is improved cosmesis and a reduction in symptomatic postoperative adhesions. These many benefits can be achieved without any increase in morbidity or expense. Conversely, the use of this technology for restorative proctocolectomy in patients with mucosal ulcerative colitis is associated with a longer operative time and an increased incidence of both intra- and postoperative complications compared to laparotomy. Laparoscopic colorectal surgery can thus be advantageous for treatment of terminal ileal Crohn's disease but cannot be routinely justified for the treatment of mucosal ulcerative colitis.

Adult↗

Abrogated lymphocyte infiltration and lowered CD14 in dextran sulfate induced colitis in mice treated with p65 antisense oligonucleotides.

BACKGROUND AND AIMS: Dextran sulfate sodium (DSS) induced colitis exhibits a predominantly NF-kappaB dependent proinflammatory cytokine profile and shares similarities with human inflammatory bowel disease (IBD). Lamina propria macrophages of IBD patients display elevated levels of NF-kappaB p65. Knowing the role of NF-kappaB in IBD, we investigated the beneficial cellular mechanisms underlying the lasting effect of a single p65 antisense treatment in DSS-colitis mice. METHODS: One local dose of p65 antisense oligonucleotides was administered in DSS colitis mice. Ten days later the mice were killed and examined at cellular and biochemical levels. The level of p65 in lamina propria cells was determined by electrophoretic mobility shift assay and by intracellular immunofluorescent staining of nuclear p65 levels, using laser scanning cytometer. RESULTS: FACS analysis demonstrated a considerable drop in infiltrating lymphocytes and a drastic reduction in CD14+ cells in mice treated with p65 antisense oligonucleotides. Moreover, abrogation of inflammation extended all the way to the cecum in treated mice. Treatment was correlated with decreased DNA binding activity of NF-kappaB. CONCLUSION: Our data strongly support a model in which p65 antisense treatment possesses the capacity to disrupt the pathogenic autocrine loop propagated by NF-kappaB at the chronic phase of IBD.

Animals↗

Questions on life satisfaction (FLZM) in inflammatory bowel disease.

BACKGROUND AND AIMS: When assessing quality of care the outcome in terms of quality of life (QOL) is of major significance. This study examined QOL in IBD outpatients and the contribution of individual expectations and various other factors including disease activity. PATIENTS AND METHODS: The study included 306 outpatients with Crohn's disease and 109 with ulcerative colitis (UC). General and health-related QOL was quantified using the instrument Questions on Life Satisfaction(Modules). Disease activity was assessed by a questionnaire. Data were compared with a normal population sample. RESULTS: Life satisfaction scores on general items and on health-related items were significantly lower than in a control sample (60.5+/-37.3 and 74.4+/-41.5, respectively) among both CD patients (54.3+/-33.2, 59.1+/-38.8) and UC patients (45.4+/-34.0, 52.1+/-40.7). Scores were significantly related to severity of disease activity. IBD patients attributed particular importance to health-related issues. CONCLUSION: Both health-related and general life satisfaction is compromised in IBD outpatients, and health-related topics have major impact. Not surprisingly, inflammatory activity compromises QOL, which underlines the importance of anti-inflammatory strategies. The importance attributed to health-related features is higher in IBD patients than in the normal population.

Adult↗

Bosentan, an endothelin receptor antagonist, reduces leucocyte adhesion and inflammation in a murine model of inflammatory bowel disease.

BACKGROUND AND AIMS: Endothelins, a group of polyfunctional cytokines, induce the adhesion of circulating leucocytes to venous endothelium, an initial step in the pathogenesis of a cellular infiltrate in inflammatory bowel disease (IBD). The effect of bosentan, a non-selective endothelin receptor antagonist, on leucocyte adhesion and inflammation in a murine model of IBD was studied. MATERIALS AND METHODS: Thirty BALB/c mice were divided into three groups of 10 animals: untreated controls, chronic colitis [dextran sodium sulphate (DSS), 3% w/v for 30 days], and treatment with bosentan (30 mg/kg i.p. daily on days 26-30). On day 30, adherent and rolling leucocytes and the average rolling velocity were assessed by intravital microscopy. Clinical and histological activity of inflammation were assessed by the disease activity index and modified Dieleman score, respectively. STATISTICS: Kruskal-Wallis test was used, followed by Dunn's method. A value of p<0.05 was considered significant. RESULTS: Compared to healthy controls, mice treated with DSS showed pronounced clinical and histological inflammation, and a higher number of rolling and adhering leucocytes in colonic submucosal venules. Therapy with bosentan significantly reduced clinical and histological inflammation. Adherent leucocyte levels were markedly lower (1.2+/-0.3 vs 23.7+/-2.8 adherent cells per 0.01 mm2, p<0.05). The number of rolling leucocytes was lower but not significantly different. However, rolling velocity was significantly higher (91.5+/-14.0 vs 19.0+/-1.6 microm/s, p<0.05). CONCLUSIONS: Bosentan reduces the adhesion of leucocytes in colonic submucosal venules and reduces inflammation in this mouse model of IBD. By inhibiting leucocyte adhesion, a crucial step in the recruitment of leucocytes to the inflamed tissue, bosentan is a potent therapeutic drug in this animal model. Further studies are necessary to investigate the role of bosentan as a novel drug in human IBD.

Animals↗

The -237C-->T promoter polymorphism of the SLC11A1 gene is associated with a protective effect in relation to inflammatory bowel disease in the South African population.

The purpose of this study was to assess the likelihood that variation in the promoter region of the solute carrier family 11 member 1 gene (SLC11A1) contributes to inflammatory bowel disease (IBD) susceptibility in the South African population. The study cohort included 102 IBD patients, 47 with Crohn's disease (CD) and 55 with ulcerative colitis, and 192 population-matched controls. Mutation analysis revealed two novel alleles for the 5'-(GT)n repeat polymorphism, t(gt)5ac(gt)5ac(gt)6ggcaga(g)6 (allele 8) and t(gt)5ac(gt)5ac(gt)8ggcaga(g)6 (allele 9), and one previously documented point mutation -237C-->T. A significantly decreased frequency of the -237C-->T promoter polymorphism was observed in the patient group with IBD (p<0.001) and CD (p<0.0006) compared with the population-matched control group. These findings may be related to previous in vitro studies, which demonstrated that the point mutation at nucleotide position -237 represents a functional polymorphism that affects regulation of the upstream 5'-(GT)n repeat polymorphism differentially upon iron loading. Our findings raise the possibility that iron dysregulation mediated by allelic effects of SLC11A1 may contribute to IBD susceptibility.

Black People↗