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PubMedDate not supplied

Clinical presentation of Crohn's disease. association between familial disease, smoking, disease phenotype, extraintestinal manifestations and need for surgery.

BACKGROUND/AIMS: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in Crohn's disease (CD). It was also suggested that familial inflammatory bowel disease (IBD) is a homogenous subgroup, phenotypically different from sporadic disease. Our aim was to determine the clinical presentation in a large CD population. METHODOLOGY: 564 CD patients (m/f: 278/286, age: 37.4 (SD 12.7) yrs, duration: 8.4 (7.1) yrs) were included. Disease phenotype was determined according to Vienna classification. Familial disease, extraintestinal manifestations (EIM), need for surgery and smoking habits were also analyzed. RESULTS: Familial IBD was present in 73 (12.9%) patients. Age at onset and presence of EIMs was associated with familial disease. Penetrating (44.6% vs. <10 yrs: 29.1%, P<0.0001) and ileocolonic disease (54.4% vs. 42.8%, P=0.03) were more common in patients with a disease duration of > or =10 yrs. In a logistic regression model female gender, colonic/ileocolonic location, smoking and familial IBD were independent risk factors for EIMs, while ileal and non-inflammatory disease increased the risk for resections. Smoking was also associated with frequent relapses. CONCLUSIONS: Familial IBD was associated with the presence of EIMs, while ileal involvement and noninflammatory behavior independently increased the risk for surgery. Since penetrating and extensive disease was more frequent in patients with longer disease duration our data support a possible change in location and behavior during the course of disease.

Adult↗
PubMed2005

[Inflammatory bowel disease: experience of two Chilean centers].

BACKGROUND: The incidence of Inflammatory Bowel Disease (IBD) has increased, particularly in the developed world, and probably also in Chile. AIM: To report our experience with a large group of patients from two medical centers, Hospital Clinico de la Universidad de Chile (HCUCH) and Clinica Las Condes (CLC) and to characterize the clinical features of IBD in Chile. PATIENTS AND METHODS: Retrospective review of 238 patients with IBD (age range 14-78 years, 143 women) treated at HCUCH and CLC between January 1990 and August 2002. RESULTS: One hundred eighty one patients had ulcerative colitis (UC) and 57 had Crohn's disease (CD), with an UC/CD ratio of 3.2/1. Forty eight percent of patients were aged between 20 and 39 years old and 69% were diagnosed after 1995. Patients from HCUCH had more severe disease, more complications and needed surgery more often. CONCLUSIONS: Clinical features of Chilean patients with IBD are similar to those of other countries. UC is more common than EC. There is a higher proportion of women with the disease. The severity of the disease was higher among HCUCH.

Adolescent↗
PubMed2002

Sentinel lymph node biopsy for cutaneous head and neck melanomas.

OBJECTIVE: To report the results of sentinel lymph node biopsy (SLNB) for cutaneous head and neck melanomas (CMHNs). DESIGN: Consecutive series followed for a median of 20 months. SETTING: Tertiary cancer care center. PATIENTS: Fifty-six individuals with clinically node-negative CMHN, median Breslow thickness, 2.6 mm (range, 0.2-20.0 mm). INTERVENTIONS: Preoperative technetium 99m sulfur colloid lymphoscintigraphy (PLSG) followed within 4 hours by intraoperative handheld gamma probe localization (IHGP). Intraoperative injection of 1% isosulfan blue dye (IBD) was used in 48 patients. Immediate completion nodal dissection was performed for metastatic SLNs on intraoperative frozen section analysis and monitoring for negative SLNs. MAIN OUTCOME MEASURES: Rate of SLN identification, SLN and non-SLN positivity, same-basin recurrence, and disease-specific and recurrence-free survival. RESULTS: Combination of IHGP and IBD improved SLN identification to 96% from 93% for IHGP and 73% for IBD alone. Four patients had a positive SLN on frozen section analysis. A negative SLNB correctly predicted regional nodal control in 47 of 48 patients but missed 1 of 5 patients who had regional lymphatic disease. All 4 patients who failed SLNB remain alive and free of recurrent disease. Two-year Kaplan-Meier disease-specific and relapse-free survival was 91% and 88%, respectively. Two-year disease-specific survival was 93% for SLN-negative patients and 50% for SLN-positive patients (P=.20). CONCLUSIONS: Combining PLSG with IHGP and IBD improves the success rate of SLNB. Although SLNB is a reliable indicator of the status of the draining lymphatic basins in CMHN, patients with negative SLNs must be observed for longer periods to understand the true implications of the procedure.

Adolescent↗
PubMed1998

Effect of surgery on health-related quality of life in patients with inflammatory bowel disease: a prospective study.

BACKGROUND: Health-related quality of life (HRQL) has increasingly become a factor in management decisions in patients with chronic diseases. OBJECTIVE: To measure the effect of surgical resection on quality of life in patients with inflammatory bowel disease (IBD). DESIGN: A consecutive series of patients undergoing surgery for IBD between June 1994 and December 1997 were prospectively investigated as a cohort outcomes study. PATIENTS: Data were obtained in 63 patients. The primary diagnoses were Crohn's disease (n = 36) and ulcerative colitis (n = 27). INTERVENTION: Patients with Crohn's disease underwent resection with or without stricturoplasty for intractable disease; all but 3 patients with ulcerative colitis underwent ileoanal anastomoses with ileoanal reservoir. MAIN OUTCOME MEASURE: Health status was measured using the Health Status Questionnaire preoperatively and every 3 months postoperatively. RESULTS: Preoperative measures of HRQL of the patients were low, with values well below the general population in all 8 scales of the Health Status Questionnaire. Postoperatively, HRQL measures improved significantly (P < .05) in both patients with Crohn's disease and those with ulcerative colitis, with scores equal to the general population in most scales. For example, average raw scores for general health in previously studied patient groups were 59 in patients with asthma, 55 in those with diabetes mellitus, 74 in the general population, and 54 and 73 preoperatively and postoperatively, respectively, in the present study. CONCLUSIONS: The results of this study confirm that HRQL scores are low in many patients with IBD referred for operation and HRQL scores improve postoperatively to levels comparable to those of the general population. We believe these data justify early surgical intervention in many patients with symptomatic IBD.

Adult↗
PubMed2001

The long-term benefit of surgery on health-related quality of life in patients with inflammatory bowel disease.

HYPOTHESES: Health-related quality of life (HRQL) has been shown to improve dramatically shortly after surgery in patients with inflammatory bowel disease (IBD). Our hypotheses were that (1) improved HRQL would be maintained long term in patients after surgery for ulcerative colitis and (2) the improved HRQL in patients with Crohn disease would decline with long-term follow-up. DESIGN: Consecutive series of patients undergoing surgery for IBD between June 1994 and January 2000 prospectively investigated as a cohort outcomes study. PATIENTS: Data were obtained in 139 patients. The diagnoses were Crohn disease (n = 56) and ulcerative colitis (n = 83). INTERVENTION: Patients with Crohn disease underwent resections with or without stricturoplasties; all but 5 patients with ulcerative colitis underwent ileal pouch-anal anastomoses. MAIN OUTCOME MEASURE: Health status was measured using the Health Status Questionnaire (HSQ) preoperatively and then every 3 months postoperatively. RESULTS: Preoperative HSQ scores were very low in all 8 scales of the HSQ. Postoperatively, HRQL measures improved significantly (P<.05) both in patients with Crohn disease and ulcerative colitis, with scores equal to or better than published scores in the general population. In patients with Crohn disease, the scores improved significantly after surgical resection and steadily increased despite disease recurrence and reoperations. The HRQL at last follow-up was equivalent to the general population. The improvements were statistically significant in patients followed up for more than 1 year in 7 of 8 scales of the HSQ. CONCLUSIONS: These results confirm that HRQL is poor in patients with IBD referred for possible operation. Surgical resection resulted in significant improvement in HRQL. More important, the results were durable. With follow-up up to 6 years, the HRQL in this cohort was equal to or better than norms for the general population both in patients with ulcerative colitis and with Crohn disease. We believe these data justify aggressive surgical intervention in many patients with IBD and support the prospective study of HRQL by surgeons treating patients with chronic diseases.

Adult↗
PubMed2000

Clinical features and treatment of peristomal pyoderma gangrenosum.

CONTEXT: Peristomal pyoderma gangrenosum (PPG), an unusual variant of pyoderma gangrenosum, has been reported almost exclusively in patients with inflammatory bowel disease (IBD) and is frequently misdiagnosed. OBJECTIVE: To better characterize the clinical manifestations, diagnosis, and management of PPG. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of 7 patients with PPG observed in a university-affiliated community setting between 1988 and December 1999. MAIN OUTCOME MEASURES: Clinical and histopathologic features, associated disorders, and microbiologic findings. RESULTS: Two patients had Crohn disease, 2 had ulcerative colitis, and 3 had abdominal cancer. Five patients had at least 1 relapse of PPG after initial healing. Although 3 of 4 patients with IBD had active bowel disease, a parallel course with PPG occurred in only 1 patient. Both patients whose stoma was relocated developed an ulcer at the new site. Effective therapies included topical superpotent corticosteroids; intralesional injection of triamcinolone acetonide at the ulcer margin; topical cromolyn sodium; oral dapsone, prednisone, cyclosporine, mycophenolate mofetil; and intravenous infliximab. CONCLUSION: Our experiences demonstrate that although PPG has been most often reported in patients with IBD, it may occur in the absence of IBD. Biopsy of the skin lesion is not diagnostic but excludes other causes. Relocation of the stoma may be associated with a new ulceration and should be avoided. Trauma to the skin of a predisposed patient may elicit the pustules or ulcerations associated with pathergy. JAMA. 2000;284:1546-1548.

Adult↗
PubMed2000

Anticipation in inflammatory bowel disease: a phenomenon caused by an accumulation of confounders.

Inflammatory bowel disease (IBD) has a definite genetic component as documented by epidemiological and linkage evidence. It shows an earlier onset of disease in children of affected patients than in their parents. This has lead to speculations about genetic anticipation in this disorder. 2,007 IBD patients with sporadic disease and 472 multiplex familial cases (including 103 affected parents and 99 children of affected patients) were evaluated with a multi-item questionnaire as part of a study of inflammatory bowel disease genetics. The Mann-Whitney U-test and the general linear model were used for analysis. Clinical characteristics such as presence of fistulae, stenoses, extraintestinal manifestations, and other parameters, which are related to the severity of the disease, were found to be similar between familial and sporadic cases of IBD (corrected P > or = 0.31 for all tests). The mean-age-of onset in children of affected patients was 19.4 years earlier than in their parents. However, the age of the parental cohort was significantly higher (27 years) and the diagnostic interval also longer (1.7 years). If these confounders are corrected in a general linear model, no significant difference is evident for the age-of-onset between the groups (P > or = 0.52). There is no evidence for genetic anticipation in inflammatory bowel disease. The absence of genetic anticipation is consistent with the clinical similarity of familial and sporadic inflammatory bowel disease. This finding justifies the primary genetic analysis of familial disease under the assumption that their genetic background will be representative for all presentations of IBD.

Adult↗
PubMed1996

Differential in situ expression of the genes encoding the chemokines MCP-1 and RANTES in human inflammatory bowel disease.

Two chemotactic cytokines, monocyte chemoattractant protein-1 (MCP-1) and RANTES, possibly contribute to the recruitment and activation of leukocytes in inflamed tissues. The expression of these cytokine genes was evaluated in tissue sections from resected bowel segments of 14 patients with inflammatory bowel disease (IBD) and seven control patients by use of 35S-labelled antisense RNA probes. MCP-1 and RANTES transcripts were generally increased in the intestinal mucosa of patients with IBD, compared with controls. Whereas MCP-1 gene expression in the mucosa was restricted to the lamina propria, the gene coding for RANTES was expressed in intraepithelial lymphocytes and in the subepithelial lamina propria. Furthermore, MCP-1 mRNA, but not RANTES mRNA, was abundant in vessel-associated cells, such as endothelial cells, medial smooth muscle cells, and intraluminal cells; in smooth muscle cells of the intestinal tunica muscularis; and in cells of the myenteric plexus. Compared with controls, a significant increase of MCP-1-expressing cells was observed in tissue specimens from patients with IBD, in endothelial cells of venules, and in cells present in the lumen of intestinal vessels. Conversely, the expression of MCP-1 mRNA in smooth muscle cells and myenteric plexus cells appeared to be comparable in control and diseased intestines. The increased number of MCP-1 and RANTES mRNA-expressing cells in mucosa from patients with IBD suggests that these cytokines play a role in the pathogenesis of mucosal inflammation. Furthermore, the expression of the MCP-1 gene in vessel-associated cells may indicate its involvement in mechanisms regulating the adhesion of blood monocytes to endothelial cells.

Adult↗
PubMed2000

The IL-10 gene is not involved in the predisposition to inflammatory bowel disease.

Although genetic predisposition for inflammatory bowel disease (IBD) is well established, little is known about the accountable genes. The pathogenesis of IBD is characterized by an imbalanced activation of Th1- and Th2-lymphocytes. IL-10 represents an anti-inflammatory cytokine which downregulates the production of Th1-derived cytokines. To evaluate the role of the IL-10 gene in IBD, two polymorphisms in the promoter region (G/A at position -1082 and C/A at position -592) were genotyped in 142 patients with Crohn's disease (CD), 104 patients with ulcerative colitis (UC), and 400 healthy controls. Significant differences were not apparent, neither in the allele frequencies of either polymorphism, nor in the haplotype frequencies. Screening of the coding region of the IL-10 gene by polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) analysis revealed a rare sequence variation in exon 1 leading to an amino acid exchange (G-->A; G15R) in two patients with CD and five healthy controls. Therefore, polymorphisms of the IL-10 gene are not demonstrably involved in the predisposition of IBD in our cohorts of patients.

Colitis, Ulcerative↗
PubMed1980

The spondylitis of inflammatory bowel disease. Evidence for a non-HLA linked axial arthropathy.

Of 12 patients with inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) or sacroiliitis (SI), only 4 (32%) had HLA-B27. Family studies revealed 3 B27-negative relatives with AS, 1 with SI, 1 with SI and IBD, and 1 with IBD alone. HLA haplotypes did not segregate with disease. These data suggest a non-HLA linked genetic predisposition to IBD which also confers susceptibility to spondylitis, even in the absence of expression of bowel disease.

Adult↗
PubMed1992

The CD56 adhesion molecule is the major determinant for detecting non-major histocompatibility complex-restricted cytotoxic mononuclear cells from the intestinal lamina propria.

In this study, specific antibodies against natural killer (NK) cell surface markers identify these cells to be commonly present in normal intestinal mucosa of inflammatory bowel disease (IBD) and carcinoma patients. Cells expressing the CD56 adhesion molecule were found to be far more abundant than CD16+ cells. Functional studies revealed that cells mediating non-major histocompatibility complex-restricted cytotoxicity (NK activity) in the lamina propria express the CD56 surface antigen, whereas only a minority of this activity resides in the population with CD16 expression. This is in contrast with peripheral blood NK cells, which were found to be almost exclusively both CD16+ and CD56+. Moreover, in the lamina propria of the intestine we found CD3+ T lymphocytes not to be involved in spontaneous cell-mediated killing of tumor cells. Considerably higher numbers of cells with the CD16 or CD56 surface markers were found to be present in normal mucosa of IBD patients compared with normal mucosa of carcinoma patients, which was also reflected in higher levels of cytotoxicity detected in lamina propria mononuclear cell preparations from normal IBD mucosa. Because of the disease-related localization of the mucosa studied from both patient groups, i.e. ileum vs. colon, the observed differences may be related to tissue characteristics. Within the IBD group, relatively high levels of cytotoxicity were found in cell preparations from normal mucosa of Crohn's disease patients compared with ulcerative colitis patients, which might support the current concept that Crohn's disease affects the whole of the gastrointestinal tract.

Adult↗
PubMed1996

Polyclonal expansion of adoptively transferred CD4+ alpha beta T cells in the colonic lamina propria of scid mice with colitis.

The adoptive transfer of low numbers of peripheral, non-fractionated CD4+ alpha beta T cells into histocompatible, severely immunodeficient (scid) hosts induces a colitis. This disease developed in C.B-17 scid/scid hosts after the injection of 10(5) CD4+ T cells purified from different peripheral lymphoid organs of immunocompetent C.B.-17 +/+ or BALB/cdm2 donor mice. Irrespective of their tissue origin, transferred CD4+ T cells selectively repopulated the scid host with gut-seeking CD4+ T cells. A chronic inflammatory bowel disease (IBD) developed as polyclonal populations of mucosa-seeking memory/effector CD4+ T cells accumulated in the gut lamina propria and epithelial layer of the adoptive host. The manifestation of colitis in the scid host correlated with the in situ polyclonal activation and expansion of adoptively transferred CD4+ T cells in the colonic lamina propria. Attempts were unsuccessful to select in vivo an oligoclonal CD4+ T cell population with an enhanced IBD-inducing potential by repeatedly reinjecting 10(5) donor-type CD4+ T cells from the colonic lamina propria of transplanted scid mice with an early and severe IBD into new scid hosts. The data indicate that the preferential repopulation of gut-associated lymphoid tissues with immunocompetent CD4+ T cells, and their polyclonal activation and in situ expansion in the lamina propria of the histocompatible, immunodeficient host are critical events in the pathogenesis of an IBD in this model.

Animals↗
PubMed2003

Testing linkage and gene x environment interaction: comparison of different affected sib-pair methods.

The aim of this study was to compare, under different models of gene-environment (G x E) interaction, the power to detect linkage and G x E interaction of different tests using affected sib-pairs. Methods considered were: 1) the maximum likelihood lod-score (MLS), based on the distribution of parental alleles identical by descent (IBD) in affected sibs; 2) the sum of the MLS (sMLS) calculated in affected sib-pairs with 2, 1, or 0 sibs exposed; 3) the predivided sample test (PST), which compares the IBD distribution between affected sib-pairs with 2, 1, or 0 sibs exposed; 4) the triangle test statistic (TTS), which uses the IBD distribution among discordant affected sib-pairs (one exposed, one unexposed); and 5) the mean interaction test (MIT), based on the regression of the proportion of alleles shared IBD among affected sib-pairs on the exposure among sib-pairs. The MLS, sMLS, and MIT allow detection of linkage. However, the sMLS and MIT account for a possible G x E interaction without testing it. In contrast, the PST and the TTS allow detection of both linkage and G x E interaction. Results showed that when exposure cancels the effect of the gene, or changes the direction of this effect (i.e., the protective allele becomes the risk allele), the PST, sMLS, and MIT may provide, under some models, greater power to detect linkage than the MLS. Under models where exposure changes the direction of the effect of the gene, the TTS test may also be more powerful than the other tests accounting for G x E interaction. Under the other models, the MLS remains the most powerful test to detect linkage. However, only the PST and TTS allow the detection of G x E interaction.

Environment↗
PubMed2005

Genome-wide identity-by-descent sharing among CEPH siblings.

The concept of genetic identity-by-descent (IBD) has markedly advanced our understanding of the genetic similarity among relatives and triggered a number of developments in epidemiological genetics. However, no empirical measure of this relatedness throughout the whole human genome has yet been published. Analyzing highly polymorphic genetic variations from the Centre d'études du polymorphisme humain (CEPH) database, we report the first genome-wide estimation of the mean and variation in IBD sharing among siblings. From 1,522 microsatellite markers spaced at an average of 2.3 cM on 498 sibling pairs, we estimated a mean of 0.4994 and a standard deviation of 0.0395. In order to account for the impact of varying chromosomal lengths and recombination rates, the analysis was also performed at the chromosomal and marker levels and for paternal and maternal DNA separately. Based on the variation, we estimate an "effective number of segregating loci" of around 80 for sibling pairs over the whole genome (i.e., the number of loci that would yield the same standard deviation in IBD sharing if all loci were segregating independently). Finally, we briefly assess the impact of genotyping errors on IBD estimations, compare our results to published theoretical and simulated expectations, and discuss some implications of our findings.

Chromosome Mapping↗
PubMed2006

Potential bias in Generalized Estimating Equations linkage methods under incomplete information.

The mean identity-by-descent (IBD) specification used in the Generalized Estimating Equations (GEE) methodology for linkage is only valid, strictly speaking, under the assumption of fully polymorphic markers. In practice, markers often provide only partial IBD information, which can potentially result in inconsistency of the locus location and gene effect estimates obtained by the GEE method. Using both simulations and theory, we identify some realistic conditions about marker information under which the validity of the GEE linkage methods may be arguable. Namely, researchers should not trust the GEE parameters' estimates and their associated confidence intervals in areas of the genome where IBD information is sparse or when this information changes abruptly. We show that properly standardized statistics based on IBD sharing provide a valid alternative.

Alleles↗
PubMed2007

Active and passive smoking in childhood is related to the development of inflammatory bowel disease.

BACKGROUND: The highest prevalence of smoking in the United States is in Kentucky, where smoking typically begins in childhood. The state has many patients who suffer from inflammatory bowel diseases (IBD). The primary aim of this study was to assess whether exposure to active and/or passive tobacco smoke in childhood is related to the likelihood of developing IBD. METHODS: Recruited into this prospective study were a total of 672 participants (253 patients with Crohn's disease [CD], 177 patients with ulcerative colitis [UC], and 242 controls), all of whom were asked to complete the Behavioral Risk Factor Surveillance Survey modified by the addition of 4 questions on childhood passive smoke exposure. RESULTS: Survey response rate was 84%. CD and UC patients were more likely than controls to begin smoking regularly by ages 10 and 15, respectively, suggesting that becoming a regular smoker at a younger age may be associated with a subsequent diagnosis of IBD. Smoking by age 10 was associated with an earlier age at diagnosis with UC, but not with CD. CD patients were more likely than controls to have prenatal smoke exposure (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.1-2.71) and were more likely to have passive smoke exposure during childhood, with 1 or both parents or other household members being smokers (OR, 2.04; 95% CI, 1.28-3.31). CONCLUSIONS: Passive and active smoke exposure in childhood influences the development of IBD. A high incidence of this disease in a state with a high rate of cigarette smoking underscores the profound role of environmental factors in the etiology of these illnesses.

Adult↗
PubMed2005

Effects of dietary fiber on inflammatory bowel disease.

The chronic idiopathic inflammatory bowel diseases (IBDs), namely Crohn's disease and ulcerative colitis, appear to be derived from an inappropriate reaction towards a luminal agent, most probably driven by the intestinal microflora, which upregulates the synthesis and release of different pro-inflammatory mediators, thus contributing to tissue damage that characterizes these intestinal conditions. Several studies have reported that IBD is associated with impairment in short-chain fatty acid (SCFA) production, mainly acetate, propionate, and butyrate. They are produced in the large bowel by anaerobic bacterial fermentation of undigested dietary carbohydrates and fiber polysaccharides, with butyrate being considered as the major fuel source for colonocytes. These SCFAs have been proposed to play a key role in the maintenance of colonic homeostasis. Therefore, it is reasonable to consider therapeutic approaches that increase colonic SCFA production, as it can be achieved by administration of dietary fiber to IBD patients. Unfortunately, there is quite limited documentation of efficacy of dietary fiber in properly designed trials. This review discusses the rationale, available evidence for the use of dietary fiber and its mechanisms of action in the treatment and prevention of IBDs.

Animals↗
PubMed2003

Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease.

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.

Adult↗