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PubMed1997

Inflammatory bowel disease and predisposition to osteopenia.

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energy x ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p < 0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids.

Adolescent↗
PubMed2003

Variations in initial assessment and management of inflammatory bowel disease across Great Britain and Ireland.

BACKGROUND: There are no published data from Great Britain and Ireland detailing the initial management of children with inflammatory bowel disease (IBD). AIMS: To prospectively record the initial investigation and treatment of children aged less than 16 years with newly diagnosed IBD. METHODS: For 13 months, between June 1998 and June 1999, 3247 paediatricians, adult gastroenterologists, and surgeons across the UK and Ireland were prospectively surveyed each month and asked to report every newly diagnosed case of childhood IBD. Reporters subsequently completed a postal questionnaire about each case. RESULTS: A total of 739 new IBD cases were reported from 172 institutions. Significant variations were observed in the investigation and treatment of these cases, when examined by number of cases reported per institution, or by the specialists providing care. There were wide regional variations in the proportion of children having access to paediatric gastroenterology services. Overall, one third of children received care from an adult service, and a tenth care exclusively from an adult gastroenterologist. Children with Crohn's disease who had some or all of their care from adult services were more likely to receive systemic steroids and less likely to receive dietary therapy; those with ulcerative colitis were more likely to receive rectal steroids and to have surgery. Height and weight were also less likely to be recorded in those whose care involved adult services. CONCLUSION: Current specialist provision, and initial investigation and treatment of IBD, is heterogeneous. Optimisation of care is likely to be achieved by greater access to specialist paediatric gastroenterology services for all those with suspected IBD.

Adolescent↗
PubMed2004

Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County.

BACKGROUND: Several placebo controlled studies have demonstrated the efficacy of infliximab in inflammatory bowel disease (IBD) but the potential toxicity of this new biological compound has been less studied. AIM: To assess the use of infliximab in IBD in a population based cohort, with special emphasis on the occurrence of severe adverse events and mortality. PATIENTS: All patients with IBD treated with infliximab between 1999 and 2001 in Stockholm County were evaluated. METHODS: Prospective registration of clinical data was carried out. Retrospective analyses were made of possible adverse events occurring in relation to infliximab treatment. Adverse events requiring pharmacological treatment or hospitalisation were defined as severe. Clinical response was assessed as remission, response, or failure. RESULTS: A cohort comprising 217 patients was assembled: 191 patients had Crohn's disease (CD), and infliximab was used off label for ulcerative colitis (UC) in 22 patients. Four patients were treated for indeterminate colitis (IC). Mean age was 37.6 (0.9) years (range 8-79). The mean number of infliximab infusions was 2.6 (0.1) (range 1-11). Forty two severe adverse events were registered in 41 patients (CD, n = 35). Eleven of the severe adverse events occurred postoperatively (CD, n = 6). Three patients with CD developed lymphoma (of which two were fatal), opportunistic infections occurred in two patients (one with UC, fatal), and two patients with severe attacks of IBD died due to sepsis (one with CD, one postoperatively with UC). One additional patient with UC died from pulmonary embolism after colectomy. Mean age in the group with fatal outcome was 62.7 years (range 25-79). The overall response rate was 75% and did not differ between the patient groups. CONCLUSIONS: Infliximab was efficacious as an anti-inflammatory treatment when assessed in a population based cohort of patients with IBD. However, there appear to be a significant risk of deleterious and fatal adverse events, particularly in elderly patients with severe attacks of IBD. Off label use of infliximab in UC and IC should be avoided until efficacy is proven in randomised controlled trials. The underlying risk of developing malignancies among patients with severe or chronically active CD in need of infliximab treatment is not known but the finding of a 1.5% annual incidence of lymphoma emphasises the need for vigilant surveillance with respect to this malignant complication.

Adult↗
PubMed2004

Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is known to be associated with reduced bone density but the extent to which this results in an increased risk of fracture and the contribution of corticosteroid therapy are unclear. We have conducted a large cohort study to address these issues. METHODS: We selected subjects within the General Practice Research Database (GPRD) with a diagnosis of IBD and up to five matched controls for each patient. We derived dates of recorded hip fractures and also information on smoking, use of corticosteroids, and a number of other drugs. We calculated the absolute risk of fracture and the relative risk as a hazard ratio corrected for available confounders by Cox regression. RESULTS: Seventy two hip fractures were recorded in 16 550 IBD cases and 223 in 82 917 controls. Cox modelling gave an unadjusted relative risk of hip fracture of 1.62 (95% confidence interval (CI) 1.24-2.11) for all IBD, 1.49 (1.04-2.15) for ulcerative colitis (UC) and 2.08 (1.36-3.18) for Crohn's disease (CD). Multivariate modelling showed that both current and cumulative use of corticosteroids and use of opioid analgesics confounded this relationship. After adjusting for confounding, the relative risk was 1.41 (0.94-2.11) for UC and 1.68 (1.01-2.78) for CD. CONCLUSION: The risk of hip fracture is increased approximately 60% in IBD patients. Corticosteroid use is a contributor to this, both in the long term as previously recognised and also in an acute reversible manner. The majority of hip fracture risk in IBD patients however cannot be attributed to steroid use.

Adult↗
PubMed2006

Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease.

BACKGROUND: Clinical and experimental observations in animal models indicate that intestinal commensal bacteria are involved in the initiation and amplification of inflammatory bowel disease (IBD). No paediatric reports are available on intestinal endogenous microflora in IBD. AIMS: To investigate and characterise the predominant composition of the mucosa-associated intestinal microflora in colonoscopic biopsy specimens of paediatric patients with newly diagnosed IBD. METHODS: Mucosa-associated bacteria were quantified and isolated from biopsy specimens of the ileum, caecum and rectum obtained at colonoscopy in 12 patients with Crohn's disease, 7 with ulcerative colitis, 6 with indeterminate colitis, 10 with lymphonodular hyperplasia of the distal ileum and in 7 controls. Isolation and characterisation were carried out by conventional culture techniques for aerobic and facultative-anaerobic microorganisms, and molecular analysis (16S rRNA-based amplification and real-time polymerase chain reaction assays) for the detection of anaerobic bacterial groups or species. RESULTS: A higher number of mucosa-associated aerobic and facultative-anaerobic bacteria were found in biopsy specimens of children with IBD than in controls. An overall decrease in some bacterial species or groups belonging to the normal anaerobic intestinal flora was suggested by molecular approaches; in particular, occurrence of Bacteroides vulgatus was low in Crohn's disease, ulcerative colitis and indeterminate colitis specimens. CONCLUSION: This is the first paediatric report investigating the intestinal mucosa-associated microflora in patients of the IBD spectrum. These results, although limited by the sample size, allow a better understanding of changes in mucosa-associated bacterial flora in these patients, showing either a predominance of some potentially harmful bacterial groups or a decrease in beneficial bacterial species. These data underline the central role of mucosa-adherent bacteria in IBD.

Adolescent↗
PubMed2005

Mu opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation.

BACKGROUND AND AIMS: Recent studies with mu opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti-inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. PATIENTS AND METHODS: Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8+ T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor kappaB (NFkappaB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti-inflammatory effect was investigated in mucosal explants from controls and IBD patients. RESULTS: MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8+ T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active IBD patients. CONCLUSIONS: Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation.

Adult↗
PubMed2006

Altered colonic glycoprotein expression in unaffected monozygotic twins of inflammatory bowel disease patients.

BACKGROUND AND AIMS: Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose beta1, 3 N-acetylgalactosamine alpha-), among the same IBD twins. MATERIALS AND METHODS: Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn's disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor kappaB (NFkappaB) activation with investigators blinded to the diagnosis. RESULTS: Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p<0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NFkappaB was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p=0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NFkappaB. CONCLUSIONS: Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect "preinflammatory" NFkappaB activation.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1980

Inflammatory bowel disease associated circulating immune complexes.

Circulating immune complexes have been detected in patients with inflammatory bowel disease (IBD). To determine if these complexes are related specificially to IBD or more generally to loss of intestinal mucosal integrity, we compared circulating immune complex levels in the sera of 86 IBD patients, nine pseudomembranous and nine bacterial colitis patients, and 42 healthy controls. Immune complexes were measured by a Raji cell radioimmunoassay. Raji detectable circulating immune complex levels were significantly higher in the IBD group than in the healthy controls (P<0.001). Circulating immune complex levels in the pseudomembranous-bacterial colitis group and the healthy controls were essentially identical. While nearly 20% of the IBD patients (16 of 86) had abnormally high levels, none of the patients with the other forms of intestinal inflammation (0 of 18) had abnormal levels. These data suggest that the circulating immune complexes present in inflammatory bowel disease patients are related to the IBD process rather than to non-specific mucosal cell (barrier) damage. Patients with intestinal inflammation and normal peripheral immune complex levels also had normal mesenteric vein levels. These data suggest that lack of formation, rather than more efficient hepatic reticuloendothelial clearance, was primarily responsible for the absence of detectable complexes in Raji negative individuals. Circulating immune complex levels did not correlate with type, location, severity, or extraintestinal manifestations of inflammatory bowel disease. The absence of Raji detectable circulating immune complexes in the majority of patients, even in those with extraintestinal manifestations, raises serious doubts about the pathogenic significance of such complexes. Nevertheless, as the circulating immune complexes appear to be disease related, they may be used to isolate and identify disease specific antigen(s) of possible aetiological importance.

Antigen-Antibody Complex↗
PubMed1980

Inflammatory bowel disease: study of cell mediated cytotoxicity for isolated human colonic epithelial cells.

A better understanding of the mechanism(s) of cell mediated toxicity for colon cells in vitro may help clarify the pathogenesis of inflammatory bowel disease (IBD). We have examined both the cytotoxicity of IBD peripheral blood mononuclear cells and the kinetics of induction of such toxicity by soluble plasma factors. Peripheral blood mononuclear cells from IBD patients were found to be cytotoxic for the colon cells. With the use of Chang cells, this cytotoxicity was shown not to be due to an increase in spontaneous cell mediated cytotoxicity. Colon cell toxicity in vitro did not correlate with site of disease or severity, but decreased toxicity appeared to be associated with in vivo steroid administration. Plasma from some IBD patients was capable of inducing normal peripheral blood mononuclear cells to be toxic to colon cells. This ability was not affected by steroid therapy. The induction capacity of IBD plasma was not associated with the presence of circulating immune complexes, as measured by Raji RIA, suggesting that large complement fixing complexes are not the inducing and directing factors. Unlike findings in other systems, induction could be demonstrated after a one hour preincubation of mononuclear cells with IBD plasma. The kinetics of induction are consistent with the hypothesis that either cytophilic antibody or small circulating immune complexes arm K cells for specific colon cell lysis.

Antigen-Antibody Complex↗
PubMed1980

Lymphocyte subpopulations of intestinal mucosa in inflammatory bowel disease.

Lymphocyte subpopulations in peripheral blood (PBL) and intestinal mucosa (IML) of 10 patients with inflammatory bowel disease (IBD) were compared with those of 11 non-IBD controls. PBL were separated on Ficoll/hypaque gradients, and IML were isolated by incubation in dithiothreitol, EDTA, and collagenase. These methods yielded cells of good viability and with intact HLA A and B-antigens. T-cells, identified by neuraminidase-treated sheep RBC rosettes and non-specific esterase staining, comprised approximately 91% of the IML from normal mucosa of all groups. B-cells, identified by erythrocyte-antibody-complement rosettes and surface immunoglobulins, were only 7% of these IML populations. Cell yields were two-fold or more greater from abnormal IBD mucosa, with T-cells ranging from 55 to 95% and B-cells from 2 to 36%. The percentage of Fc receptor bearing cells was low in all specimens. By these methods, T-lymphocytes predominated in intestinal mucosa of both IBD and non-IBD patients, but there is marked increase in the percentage of B-cells isolated from abnormal mucosa in IBD.

Adult↗
PubMed1996

Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria.

In contrast with normal subjects where IgA is the main immunoglobulin in the intestine, patients with active inflammatory bowel disease (IBD) produce high concentrations of IgG from intestinal lymphocytes, but the antigens at which these antibodies are directed are unknown. To investigate the specificities of these antibodies mucosal immunoglobulins were isolated from washings taken at endoscopy from 21 control patients with irritable bowel syndrome, 10 control patients with intestinal inflammation due to infection or ischaemia, and 51 patients with IBD: 24 Crohn's disease (CD, 15 active, nine quiescent), 27 ulcerative colitis (UC, 20 active, seven inactive). Total mucosal IgG was much higher (p < 0.001) in active UC (median 512 micrograms/ml) and active CD (256 micrograms/ml) than in irritable bowel syndrome controls (1.43 micrograms/ml), but not significantly different from controls with non-IBD intestinal inflammation (224 micrograms/ml). Mucosal IgG bound to proteins of a range of non-pathogenic commensal faecal bacteria in active CD; this was higher than in UC (p < 0.01); and both were significantly greater than controls with non-IBD intestinal inflammation (CD p < 0.001, UC p < 0.01) or IBS (p < 0.001 CD and UC). This mucosal IgG binding was shown on western blots and by enzyme linked immunosorbent assay (ELISA) to be principally directed against the bacterial cytoplasmic rather than the membrane proteins. Total mucosal IgA concentrations did not differ between IBD and controls, but the IgA titres against faecal bacteria were lower in UC than controls (p < 0.01). These experiments show that there is an exaggerated mucosal immune response particularly in active CD but also in UC directed against cytoplasmic proteins of bacteria within the intestinal lumen; this implies that in relapse of IBD there is a breakdown of tolerance to the normal commensal flora of the gut.

Adolescent↗
PubMed1996

Soluble Fc gamma receptor III (CD 16) and eicosanoid concentrations in gut lavage fluid from patients with inflammatory bowel disease: reflection of mucosal inflammation.

BACKGROUND: Activated neutrophils cause tissue injury in inflammatory bowel disease (IBD). Upon activation, they shed soluble Fc gamma IIIb receptors (sFc gamma RIIIb). The subsequent inflammatory response is modulated by several mediators, including neutrophil derived leukotriene B4 (LTB4), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2). The aim of this study was to determine the value of gut lavage sFc gamma RIII and eicosanoid measurements for the assessment of mucosal inflammation in IBD. METHODS: A total of 18 patients with active IBD, 10 ulcerative colitis (UC), and eight Crohn's disease (CD), and 12 control patients underwent whole gut lavage. Disease activity, endoscopic appearance, and histopathology were graded. Samples were processed for the determination of sFc gamma RIIIb, LTB4, PGE2, and TXB2. RESULTS: Soluble Fc gamma RIIIb concentrations were increased in both IBD groups. Significant correlations were seen between sFc gamma RIIIb and LTB4 values with histology scores. Mean eicosanoid lavage fluid concentrations in control patients were 14.1 pg/ml for LTB4, 5.6 pg/ml for PGE2, and 397 pg/ml for TXB2. Concentrations of all eicosanoids in IBD patients were significantly increased: LTB4 in UC: mean 73.2 pg/ml, in CD: 96.4 pg/ml (both p < 0.01 v controls). PGE2 in UC: 20.2 pg/ml, in CD: 43.4 pg/ml (p < 0.01). TXB2 in UC: 719.3 pg/ml, in CD: 180.6 pg/ml (both p < 0.05). CONCLUSIONS: Whole gut lavage fluid analysis is an effective method to study mucosal eicosanoid production. Soluble Fc gamma RIIIb concentrations in gut lavage fluid closely correlate with histological signs of mucosal inflammation and with lavage LTB4 concentration. These data suggest that lavage Fc gamma RIIIb assessment may be used as a simple assay to estimate mucosal neutrophil infiltration in IBD.

Colitis, Ulcerative↗
PubMed1996

Phospholipase A2 activating protein and idiopathic inflammatory bowel disease.

BACKGROUND: Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel diseases (IBD) involving synthesis of eicosanoids from arachidonic acid (AA), which is released from membrane phospholipids by phospholipase A2 (PLA2). A potentially important regulator of the production of these mediators is a protein activator of PLA2, referred to as PLA2 activating protein (PLAP). AIMS: The purpose of this investigation was to discover if PLAP values might be increased in the inflamed intestinal tissue of patients with IBD and in intestinal tissue of mice with colitis. PATIENTS: Biopsy specimens were taken from patients with ulcerative colitis and Crohn's disease undergoing diagnostic colonoscopy, and normal colonic mucosa was obtained from patients without IBD after surgical resection. METHODS: Immunocytochemistry with affinity purified antibodies to PLAP synthetic peptides was used to locate PLAP antigen in sections of intestinal biopsy specimens from IBD patients compared with that of normal intestinal tissue. Northern blot analysis with a murine [32P] labelled plap cDNA probe was performed on RNA extracted from the colons of mice fed dextran sulphate sodium (DSS) and cultured HT-29 cells exposed to lipopolysaccharide (LPS). RESULTS: PLAP antigen was localised predominantly within monocytes and granulocytes in intestinal tissue sections from IBD patients, and additional deposition of extracellular PLAP antigen was associated with blood vessels and oedema fluid in the inflamed tissues. In contrast, tissue sections from normal human intestine were devoid of PLAP reactive antigen, except for some weak cytoplasmic reaction of luminal intestinal epithelial cells. Similarly, colonic tissue from DSS treated mice contained an increased amount of PLAP antigen compared with controls. The stroma of the lamina propria of the colonic mucosa from the DSS treated mice reacted intensely with antibodies to PLAP synthetic peptides, while no reaction was observed with control mouse colons. These data were supported by northern analysis which showed that PLAP mRNA was increased in the colons of DSS treated mice and cultured HT-29 cells exposed to LPS. CONCLUSIONS: As PLAP values were increased in the intestinal mucosa of IBD patients and mice with colitis, as well as in LPS treated cultured HT-29 cells, a role was postulated for PLAP in increasing PLA2 activity, which leads to the increased synthesis of eicosanoids in intestinal tissues of patients with these inflammatory diseases.

Animals↗
PubMed1997

Inflammatory bowel disease: re-evaluation of the diagnosis in a prospective population based study in south eastern Norway.

BACKGROUND: The incidence figures for ulcerative colitis (UC) and Crohn's disease (CD) have been difficult to interpret, and geographical variations may be due to differences in classification criteria and study design. Few studies have based the incidence on prospective systematic follow up to confirm the initial diagnosis. METHODS: Between 1990 and 1993, in a prospective incidence study of inflammatory bowel disease (IBD) in south eastern Norway, 527 cases of UC, 228 cases of CD, 36 cases of indeterminate colitis (IND), and 55 cases of possible IBD were identified, yielding an annual incidence of 13.6, 5.9, 0.9, and 1.4 per 10(5) respectively. The diagnosis and all clinical data were reviewed by two gastroenterologists independently of each other. One to two years after diagnosis, all patients were offered a clinical follow up in which the initial diagnosis was assessed. RESULTS: Between the time of diagnosis and the follow up, 16 patients had died, four of complications related to IBD. Of the remaining 830 patients, 98% (814/830) were available for follow up, 93% (772/830) attended a clinical examination which included a colonoscopy in 77% (637/830), and the remainder had had a telephone interview, or reassessment based on hospital records, or both. Twenty seven patients were reclassified as not having IBD (3%), and 65 patients were characterised as possible IBD (8%). Of the patients initially classified as UC, 88% had their diagnosis confirmed, compared with 91% with an initial diagnosis of CD. In patients with indeterminate colitis, 33% were classified as definite UC and 17% as CD. This reclassification of patients yielded a corrected annual incidence of 12.8 for UC and 6.0 for CD. CONCLUSION: At follow up one to two years after the diagnosis of IBD, the initial incidence was only marginally altered. This is probably due to uniform inclusion criteria and careful diagnostic methods. The study also illustrates the importance of the re-evaluation of the initial diagnosis as close to 10%, both among patients with UC and CD, were reclassified at follow up.

Colitis, Ulcerative↗
PubMed1998

Activation of nuclear factor kappa B inflammatory bowel disease.

BACKGROUND: Expression of pro-inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease (IBD). Nuclear factor kappa B (NF kappa B) controls transcription of inflammation genes. On activation, NF kappa B is rapidly released from its cytoplasmic inhibitor (I kappa B), transmigrates into the nucleus, and binds to DNA response elements in gene promoter regions. AIMS: To investigate whether increased activation of NF kappa B is important in IBD and may be down-regulated by anti-inflammatory treatment. METHODS: Activation of NF kappa B was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells. RESULTS: Nuclear levels of NF kappa B p65 are increased in lamina propria biopsy specimens from patients with Crohn's disease in comparison with patients with ulcerative colitis and controls. Increased activation of NF kappa B was detected in lamina propria mononuclear cells from patients with active IBD. Corticosteroids strongly inhibit intestinal NF kappa B activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor I kappa B alpha against activation induced degradation. CONCLUSIONS: In both IBDs, but particularly Crohn's disease, increased activation of NF kappa B may be involved in the regulation of the inflammatory response. Inhibition of NF kappa B activation may represent a mechanism by which steroids exert an anti-inflammatory effect in IBD.

Adolescent↗
PubMed1998

Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease.

BACKGROUND: Reactive oxygen species contribute to tissue injury in inflammatory bowel disease (IBD). The tripeptide glutathione (GSH) is the most important intracellular antioxidant. AIMS: To investigate constituent amino acid plasma levels and the GSH redox status in different compartments in IBD with emphasis on intestinal GSH synthesis in Crohn's disease. METHODS: Precursor amino acid levels were analysed in plasma and intestinal mucosa. Reduced (rGSH) and oxidised glutathione (GSSG) were determined enzymatically in peripheral blood mononuclear cells (PBMC), red blood cells (RBC), muscle, and in non-inflamed and inflamed ileum mucosa. Mucosal enzyme activity of gamma-glutamylcysteine synthetase (gamma GCS) and gamma-glutamyl transferase (gamma GT) was analysed. Blood of healthy subjects and normal mucosa from a bowel segment resected for tumor growth were used as controls. RESULTS: Abnormally low plasma cysteine and cystine levels were associated with inflammation in IBD (p < 10(-4)). Decreased rGSH levels were demonstrated in non-inflamed mucosa (p < 0.01) and inflamed mucosa (p = 10(-6)) in patients with IBD, while GSSG increased with inflammation (p = 0.007) compared with controls. Enzyme activity of gamma GCS was reduced in non-inflamed mucosa (p < 0.01) and, along with gamma GT, in inflamed mucosa (p < 10(-4)). The GSH content was unchanged in PBMC, RBC, and muscle. CONCLUSIONS: Decreased activity of key enzymes involved in GSH synthesis accompanied by a decreased availability of cyst(e)ine for GSH synthesis contribute to mucosal GSH deficiency in IBD. As the impaired mucosal antioxidative capacity may further promote oxidative damage, GSH deficiency might be a target for therapeutic intervention in IBD.

Adult↗
PubMed2002

Expression of the regenerating gene family in inflammatory bowel disease mucosa: Reg Ialpha upregulation, processing, and antiapoptotic activity.

BACKGROUND: The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury related to an ongoing inflammatory process and mucosal reparative mechanisms. Proreparative mucosal factors may offer new therapeutic paradigms. Transcriptional profiling can be applied to identify candidate gene products involved in colonic mucosal regeneration. METHODS: Resection specimens from patients who underwent colonic resection for IBD or non-IBD indications were analyzed by performing Affymetrix GeneChip hybridization (Affymetrix, Inc., Santa Clara, Calif) and histopathologic scoring. Expression and physiologic processing of Reg Ialpha, the most highly expressed member of the regenerating (Reg) gene family, was further studied by performing specific immunohistochemistry, protein sequencing, and mass spectroscopy. RESULTS: Foregut-derived tissues normally express human Reg proteins with minimal expression in the colon. In the setting of tissue injury associated with IBD, Reg Ialpha Reg Ibeta, and Reg III mRNA were highly expressed in colonic mucosa. Paired histopathologic scoring demonstrated that Reg expression was not related to the presence or the degree of mucosal inflammation. Studies of the Reg Ialpha protein revealed evidence of proteolytic cleavage at the N-terminus. In IBD, intact Reg Ialpha protein was expressed by the metaplastic Paneth granular cell population. Whereas Reg Ialpha cleaved at the N-terminus, it was also deposited throughout the lamina propria. Reg Ialpha treatment was shown to reduce epithelial apoptosis that occurred in response to treatment with hydrogen peroxide. CONCLUSION: Ectopic expression, physiologic processing, and directed tissue deposition of Reg Ialpha are components of the colonic mucosal regenerative response in IBD. Reg Ialpha may serve to reduce epithelial apoptosis in inflammation.

Apoptosis↗
PubMed1994

Vaccination of commercial layer chicks against infectious bursal disease with maternally derived antibodies.

Day-old commercial layer chicks with maternally derived antibody to infectious bursal disease (IBD) were reared in four pens on a commercial farm, and chicks from the same flock were reared at the laboratory and examined for the decay of the maternal antibody and the development of susceptibility to IBD. The chicks in the pens on the farm were vaccinated with different combinations of commercial inactivated and live vaccines against IBD, transferred to the laboratory, and challenged with virulent IBD virus to assess the efficacy of the vaccination programmes. The chicks from one pen, given a live IBD vaccine only, did not develop antibodies and were fully susceptible to challenge by seven weeks old; only one to two weeks later than the unvaccinated control chicks reared at the laboratory. The chicks in the other three pens were inoculated with an inactivated vaccine, and the chicks in two of these pens were inoculated later with a live vaccine. All these chicks developed IBD antibodies and were protected by between 91 and 100 per cent against challenge. There was no demonstrable benefit in administering a live vaccine either alone or in addition to an inactivated oil emulsion vaccine.

Animals↗