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PubMed2004

Mouse mast cell protease-1 is required for the enteropathy induced by gastrointestinal helminth infection in the mouse.

BACKGROUND & AIMS: The relationship between intestinal pathology and immune expulsion of gastrointestinal nematodes remains controversial. Immune expulsion of gastrointestinal helminth parasites is usually associated with Th2 responses, but the effector mechanisms directly responsible for parasite loss have not been elucidated. Mast cell hyperplasia is a hallmark of infection with gastrointestinal nematodes, in particular Trichinella spiralis. Although the precise mechanism by which mast cells induce expulsion of these parasites has not been elucidated, it has been proposed that mast cell mediators, including cytokines and granule chymases, act to create an environment inhospitable to the parasite, part of this being the induction of intestinal inflammation. Therefore, the aims of this study were to dissect the role of mast cells and mast cell proteases in the induction of parasite-induced enteropathy. METHODS: Mast cell-deficient W/Wv and mouse mast cell protease-1 (mMCP-1)-deficient mice were infected with T. spiralis, and parasite expulsion, enteropathy, and Th2 responses were determined. RESULTS: Expulsion of the parasite was delayed in both strains of mice compared with wild-type controls; additionally, in both cases, the enteropathy was significantly ameliorated. Although Th2 responses were significantly reduced in mast cell-deficient W/Wv mice, those from mMCP-1-deficient mice were similar to wild-type mice. Additionally, levels of TNF-alpha and nitric oxide were significantly reduced in both W/Wv and mMCP-1 deficient mice. CONCLUSIONS: These results imply that mast cells may contribute to the induction of protective Th2 responses and, importantly, that the intestinal inflammation associated with gastrointestinal helminths is partly mediated by mMCP-1.

Animals↗
PubMedDate not supplied

Therapy of spondylarthropathy in inflammatory bowel disease.

Musculoskeletal manifestations represent the most common extra-intestinal complication of inflammatory bowel diseases (IBD) and are usually included in the clinical spectrum of the spondyloarthropathies (SpA). Although control of intestinal inflammation often ameliorates articular symptoms, sometimes arthropathy is independent of the gut disease course and may require the same therapeutic options which apply to primary SpA diseases, but with caution so as not aggravate the IBD. At the moment, salicylates (sulphasalazine and mesalazine) and selective COX-2 inhibitors (which are preferable to traditional NSAIDs although they cannot be assumed to be safe for the gastrointestinal tract) are the first choice treatment. Several immunosuppressive and biological agents including methotrexate, thalidomide and TNFalpha antagonists have efficacy for both articular and intestinal inflammation and are currently in use for the induction of remission and for maintenance in more severe cases. New combination therapies and novel biologically-driven treatments, targeted to specific pathophysiological processes, might offer less toxicity and the potential for better treatment outcomes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Virulence of broad- and narrow-host-range Salmonella enterica serovars in the streptomycin-pretreated mouse model.

Salmonella enterica subspecies I serovars are common bacterial pathogens causing diseases ranging from enterocolitis to systemic infections. Some serovars are adapted to specific hosts, whereas others have a broad host range. The molecular mechanisms defining the virulence characteristics and the host range of a given S. enterica serovar are unknown. Streptomycin pretreated mice provide a surrogate host model for studying molecular aspects of the intestinal inflammation (colitis) caused by serovar Typhimurium (S. Hapfelmeier and W. D. Hardt, Trends Microbiol. 13:497-503, 2005). Here, we studied whether this animal model is also useful for studying other S. enterica subspecies I serovars. All three tested strains of the broad-host-range serovar Enteritidis (125109, 5496/98, and 832/99) caused pronounced colitis and systemic infection in streptomycin pretreated mice. Different levels of virulence were observed among three tested strains of the host-adapted serovar Dublin (SARB13, SD2229, and SD3246). Several strains of host restricted serovars were also studied. Two serovar Pullorum strains (X3543 and 449/87) caused intermediate levels of colitis. No intestinal inflammation was observed upon infection with three different serovar Paratyphi A strains (SARB42, 2804/96, and 5314/98) and one serovar Gallinarum strain (X3796). A second serovar Gallinarum strain (287/91) was highly virulent and caused severe colitis. This strain awaits future analysis. In conclusion, the streptomycin pretreated mouse model can provide an additional tool to study virulence factors (i.e., those involved in enteropathogenesis) of various S. enterica subspecies I serovars. Five of these strains (125109, 2229, 287/91, 449/87, and SARB42) are subject of Salmonella genome sequencing projects. The streptomycin pretreated mouse model may be useful for testing hypotheses derived from this genomic data.

Animals↗
PubMed1995

[Activation of the major omentum-associated lymphoid tissue in Crohn disease].

The mucosa associated lymphoid tissues of the intestinal lamina propria or the bronchial mucosa, respectively, represent a separated and well defined immunologic compartment. Due to highly specialized functions, subpopulations of lymphoid cells are distributed unevenly between the compartments and unique regulatory mechanisms developed to sustain integrity of mucosal surfaces. With this study we investigate whether an omentum associated lymphoid tissue exists and whether it partakes in immunologic processes involved in the perpetuative intestinal inflammation in Crohn's disease. Mononuclear cells from surgically resected omentum tissue (10 patients with Crohn's disease, 10 patients with malignomas or inflammatory control diseases (diverticulitis)) were isolated by collagenase digestion and subsequent serial density centrifugation. Phenotypic analysis was carried out by immunofluorescent labeling with a panel of monoclonal antibodies as well as peanut agglutinin. Most interestingly, the percentage of CD4-T(Helper) cells among omentum mononuclear cells was decreased in comparison with peripheral blood mononuclear cells, whereas the percentage of monocytes/macrophages and of natural killer cells appeared to be increased. In comparison with normal peripheral blood a higher percentage of normal omentum mononuclear cells were activated. It thus appears that a defined immunologic compartment exists which is different in its cellular composition from peripheral blood as well as from intestinal mucosa associated lymphoid tissue and which may be called omentum associated lymphoid tissue. In Crohn's disease subpopulations of omentum mononuclear cells did not change in number, however immunologic activation increased further and appears to be highly increased in comparison to both omentum cells from disease specificity controls (diverticulitis) and Crohn's disease peripheral blood cells. We conclude that omentum associated lymphoid tissue may be described as an unique immunologic compartment which may play a role in activating events in chronic intestinal inflammation in Crohn's disease. Further studies will address functional characteristics of the omentum associated lymphoid tissue and will investigate regulatory mechanisms which may contribute to the inflammatory process in Crohn's disease.

Adult↗
PubMed2003

Upregulation of interleukin-12 and -17 in active inflammatory bowel disease.

BACKGROUND: Cytokines are essential mediators of the intestinal inflammation during active episodes of inflammatory bowel disease (IBD). Interleukin (IL)-12 and IL-17 are potent immunoregulatory cytokines whose roles in the pathogenesis of IBD are unknown. The aim of this study was to evaluate the colonic expression of IL-12 and IL-17 genes in IBD. METHODS: Fifty-one patients (22 with ulcerative colitis (UC), 17 with Crohn disease (CD), and 12 controls) who underwent colonoscopy were included. IBD disease activity was determined using a clinical grading scale. The degree of inflammation, as well as the content of CD4+ T cells (synthesizing IL-17) and CD68+ macrophages (synthesizing IL-12) in colonic biopsies, was determined. The amounts of IL-12 and IL-17 mRNA were assessed by RT-PCR, using GAPDH as an internal standard. RESULTS: In colonic specimens, IL-17 mRNA expression was increased in moderately and severely active UC (P = 0.03) and in all degrees of activity in CD (P < 0.04). Levels of IL-12 mRNA were upregulated in both active UC and active CD compared to controls (P < 0.02). In cases of remission, IL-12 mRNA expression was similar to that found in control samples. Compared to controls, histological examination showed significant differences in signs of chronic and acute inflammation in UC (P < 0.01) and CD (P < 0.02), revealing a high correlation between clinical disease activity and histological scoring (r2 = 0.92, P < 0.005). Whereas CD4+ T cells were observed in lymphocyte aggregates located profound in the lamina propria, CD68+ macrophages were primarily found just underneath the surface epithelium. The density of CD4+ and CD68+ cells correlated significantly with the amounts of IL-17 and IL-12 mRNA, respectively (P < 0.05). CONCLUSION: The expression of both IL-12 and IL-17 mRNA is induced in active UC and CD and may thus be involved in sustaining the intestinal inflammation in IBD. Inhibition of IL-12 or IL-17 might be future therapeutic targets in IBD.

Adult↗
PubMed2000

Butyrate upregulates stromelysin-1 production by intestinal mesenchymal cells.

Nutritional factors and resident bacteria participate in the pathogenesis of intestinal inflammation. However, the ways in which bacteria and complex diets might modulate matrix metalloproteinase (MMP) production are unknown. We hypothesized that butyrate might enhance production of MMPs, thus amplifying their response to signals in inflammatory conditions. Human mesenchymal cells were incubated with butyrate and then stimulated with cytokines. MMPs and inhibitors were studied by Western blotting and quantitative RT-PCR. Acetylation of histones was examined in Triton X acetic acid-urea gels by PAGE. We showed that butyrate selectively enhanced the protein production and mRNA expression of stromelysin-1 in tumor necrosis factor-alpha- or interleukin-1beta-stimulated mesenchymal cells. Butyrate alone did not induce any change in MMP production or mRNA expression. It increased the acetylation of histones in mesenchymal cells. Furthermore, acetylation of histones (induced by trichostatin A) reproduced the effects of butyrate. Although butyrate is a major source of nutrient for the colonic epithelial cells, it modulates intestinal inflammation through the secretion of stromelysin-1 in stimulated stromal cells via the inhibition of histone deacetylase.

Acetylation↗
PubMed1996

Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice.

Chronic intestinal inflammation induced by 2,4,6,-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn's disease. Here, we show that the transcription factor NF-kappa B p65 was strongly activated in TNBS-induced colitis and in colitis of interleukin-10-deficient mice. Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease.

Adrenal Cortex Hormones↗
PubMed2003

Targeting enteric bacteria in treatment of inflammatory bowel diseases: why, how, and when.

PURPOSE: This review discusses the role of bacterial adjuvants and antigens in induction and reactivation of chronic intestinal inflammation in susceptible hosts; discusses the results of recent therapeutic trials of antibiotics, probiotics, and prebiotics; and suggests future treatment strategies. RECENT FINDINGS: Bacterial adjuvants, including peptidoglycan, lipopolysaccharide, and DNA (CpG) bind to membrane-bound toll-like receptors (TLR-2, 4, and 9. respectively) or cytoplasmic (NOD1 and NOD2) receptors (pattern recognition receptors) that activate nuclear factor-kappaB and transcription of many proinflammatory cytokines and adhesion, costimulatory, and major histocompatibility complex class II molecules. Experimental enterocolitis does not occur in a sterile (germ-free) environment and is prevented and treated by broad-spectrum antibiotics. Individual nonpathogenic intestinal bacterial species selectively induce experimental colitis, with host specificity. Crohn disease and ulcerative colitis patients exhibit pathogenic immune responses (loss of immunologic tolerance) to multiple normal enteric bacterial species and serologic responses to Mycobacterium paratuberculosis. Metronidazole and ciprofloxacin selectively treat colonic Crohn disease, but not ulcerative colitis or ileal Crohn disease, and may prevent recurrence of postoperative Crohn disease. Certain probiotic species decrease relapse of ulcerative colitis and chronic pouchitis and delay onset of pouchitis. SUMMARY: Normal, nonpathogenic enteric bacteria induce and perpetuate chronic intestinal inflammation in genetically susceptible hosts with defective immunoregulation, bacterial clearance, or mucosal barrier function. Altering the composition and decreasing mucosal adherence/invasion of commensal bacteria with antibiotics, probiotics, and prebiotics can potentially prevent and treat Crohn disease, pouchitis, and possibly ulcerative colitis, but optimal treatments have not yet been identified.

Journal Article↗
PubMed2000

Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice.

BACKGROUND & AIMS: CD1d is a major histocompatibility complex class I-like molecule that presents glycolipid antigens to a subset of natural killer (NK)1.1(+) T cells. These NK T cells exhibit important immunoregulatory functions in several autoimmune disease models. METHODS: To investigate whether CD1d and NK T cells have a similar role in intestinal inflammation, the effects of the glycolipid, alpha-galactosylceramide (alpha-GalCer), on dextran sodium sulfate (DSS)-induced colitis were examined. Wild-type (WT), CD1d(-/-), and RAG(-/-) mice were examined for their response to either alpha-GalCer or the control analogue, alpha-mannosylceramide (alpha-ManCer). RESULTS: WT mice, but not CD1d(-/-) and RAG(-/-) mice, receiving alpha-GalCer had a significant improvement in DSS-induced colitis based on body weight, bleeding, diarrhea, and survival when compared with those receiving alpha-ManCer. Elimination of NK T cells through antibody-mediated depletion resulted in a reduction of the effect of alpha-GalCer. Furthermore, adoptive transfer of NK T cells preactivated by alpha-GalCer, but not alpha-ManCer, resulted in diminished colitis. Using a fluorescent-labeled analogue of alpha-GalCer, confocal microscopy localized alpha-GalCer to the colonic surface epithelium of WT but not CD1d(-/-) mice, indicating alpha-GalCer binds CD1d in the intestinal epithelium and may be functionally active at this site. CONCLUSIONS: These results show an important functional role for NK T cells, activated by alpha-GalCer in a CD1d-restricted manner, in regulating intestinal inflammation.

Animals↗
PubMed2004

Effect of corticosteroids on nitric oxide production in inflammatory bowel disease: are leukocytes the site of action?

Nitric oxide (NO) production is increased in the human colonic mucosa in intestinal inflammation. We examined the effect of corticosteroids and the role of mononuclear cells in this production. Colonic biopsies from patients with ulcerative colitis and normal controls were cultured with either budesonide or prednisolone in the presence of proinflammatory cytokines. Human mixed mononuclear cells (MMCs) were cocultured with HT-29 cells stimulated with IFN-gamma and LPS in the presence or absence of corticosteroids. Nitrite production was measured in supernatants by a modification of the Griess reaction, and inducible NO synthase (iNOS) mRNA expression was studied in colonic tissue by RT-PCR. Both steroids significantly suppressed the nitrite production and iNOS mRNA expression in inflamed colonic biopsies from ulcerative colitis patients and in cytokine-stimulated normal colonic biopsies but not in cytokine-stimulated HT-29 cells. Nitrite production by HT-29 cells was significantly increased (P < 0.01) in cocultures with MMCs stimulated with IFN-gamma and LPS. The presence of either prednisolone or budesonide significantly (P < 0.01) suppressed nitrite production from cocultures of HT-29 cells and MMCs but not from cultures of HT-29 cells stimulated with conditioned media from activated MMCs. Interestingly, stimulation of HT-29 with conditioned media from MMCs pretreated with steroids before stimulation with LPS and IFN-gamma induced a significantly (P < 0.01) lower nitrite production. These results suggest that the inhibitory effect of corticosteroids on the NO production in the intestinal inflammation might be via the inhibition of MMC-produced mediators responsible for NO production by colonic epithelial cells.

Budesonide↗
PubMed2000

Detection of ICAM-1 in experimentally induced colitis of ICAM-1-deficient and wild-type mice: an immunohistochemical study.

Adhesion molecules (e.g. ICAM-1, CD 54) are known to be upregulated on activated vascular endothelial cells during inflammatory reactions. To study the role of ICAM-1 in intestinal inflammation in vivo, we induced acute experimental colitis in wild-type (C57BL/6) mice and ICAM-1-deficient mice, by feeding the animals with 3% dextran sodium sulphate (DSS) in drinking water for 7 days. In the control strain the immunohistochemical staining showed a very pronounced endothelial upregulation of ICAM-1 after the DSS treatment observed in areas of inflammatory infiltrate, especially in venules or arterioles of the propria and submucosa, and partly in the mesocolon. DSS-fed ICAM-1-deficient mice showed no endothelial enhancement and only faint staining of venules or capillaries approaching that encountered in the control ICAM-1-deficient animals. Our data indicate that ICAM-1 may play a crucial role in the development of acute intestinal inflammation, consistent with our finding that ICAM-1 deficiency can obviate severe forms of experimentally induced colitis in mice.

Animals↗
PubMed2004

Hyperexpression of inducible costimulator on lamina propria mononuclear cells in rat dextran sulfate sodium colitis.

BACKGROUND AND AIMS: The authors have previously shown that a third member of the CD28 family, inducible costimulator (ICOS), was increased in the inflamed intestinal mucosa of murine experimental colitis, and that the blockade of ICOS ameliorated the development of colitis. However, the role of ICOS in rat intestinal inflammation and its expression profile remains unclear. In the present study, the authors investigated the involvement of ICOS in the development of rat dextran sulfate sodium (DSS)-induced colitis, and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in colitis. METHODS: The authors first examined expression of ICOS protein in normal rat by immunohistochemistry and flow cytometry. Sprague-Dawley rats were fed 3.0% DSS. The expression of ICOS on infiltrating lamina propria mononuclear cells and splenocytes were examined. The DSS-fed rats were then administered anti-ICOS mAb to test its effect on the development of colitis. RESULTS: Unlike mice and human, ICOS was expressed on a part of CD4+ T-cells from the thymus, spleen, mesenteric lymph nodes and lamina propria. Levels of ICOS on CD4+ T-cells from the spleen and colonic lamina propria were significantly upregulated after Concanavalin A (Con A) stimulation. In addition, ICOS was also upregulated on CD4+ T-cells from DSS-fed rats compared with those from non DSS-fed rats. However, anti-ICOS mAb did not ameliorate the development of both acute and chronic DSS colitis. CONCLUSION: These results suggest that the different expression of ICOS in rats plays a distinct role in rat intestinal inflammation.

Animals↗
PubMedDate not supplied

Effect of short-term topical corticosteroid treatment on mucosal enzyme systems in patients with distal inflammatory bowel disease.

BACKGROUND/AIMS: Glucocorticoids, even when administered topically, have a known early benefit on diarrheal symptoms in inflammatory bowel diseases which may not be explained exclusively by their anti-inflammatory effect. Therefore, we evaluated a possible early effect of topically administered glucocorticosteroids on the mucosal function of patients with distal inflammatory bowel disease in a prospective, controlled study, which was blinded for histological evaluation. METHODOLOGY: Eleven patients with distal ulcerative colitis or Crohn's disease, and 8 patients without intestinal inflammation were studied. A sigmoidoscopy with biopsy sampling (8-10) was performed before and 3 days after rectal administration of a hydrocortisone acetate foam preparation (100 mg b.i.d.). Prior to and after topical steroid treatment, basolateral (Na++K+)-ATPase activity (coupled optical assay), specific 3H ouabain binding (rapid filtration method), 5'-nucleotidase (microdetection method of phosphorus), and mucosal DNA levels (diphenylamine reaction) were determined from biopsy homogenates. Morphological and clinical characteristics were assessed according to established scores. RESULTS: Short-term topical GCS treatment significantly (p<0.05) stimulated (Na++K+)-ATPase activity (103%) as well as the number of active (Na++K+)-ATPase molecules (190%). In the healthy mucosa, only (Na++K+)-ATPase activity was stimulated (124%, p<0.05; specific 3H ouabain binding: 33%; p=0.09). As an unspecific GCS effect, apical 5'-nucleotidase was also stimulated (p<0.05; IBD: 50%; controls: 200%). As assessed by endoscopic and histological scores, as well as by mucosal DNA levels, morphological signs of intestinal inflammation remained unchanged during the study, whereas the daily stool frequency decreased significantly (p<0.05). CONCLUSIONS: In patients with distal inflammatory bowel disease, short-term treatment with topical GCS leads to a quick recovery from diarrheal symptoms, due to the early improvement of mucosal function prior to the occurrence of the well-known anti-inflammatory GCS effect.

5'-Nucleotidase↗
PubMed2000

Sulfasalazine in the prevention of anterior uveitis associated with ankylosing spondylitis.

PURPOSE: To assess the effects of sulfasalazine in preventing recurrences and reducing the severity of anterior uveitis associated with ankylosing spondylitis and chronic intestinal inflammation. METHODS: Twenty-two patients with anterior uveitis associated with ankylosing spondylitis were studied. Ten patients were randomised to receive oral sulfasalazine (group 1) and 12 patients randomised to no treatment (group 2); all were followed for 3 years. Blood-aqueous barrier permeability was determined by fluorophotometry and bowel biopsies were taken. RESULTS: A statistically significant difference was observed between the two groups regarding the number of recurrences of uveitis (p = 0.016). The blood-aqueous barrier permeability was significantly higher during acute attacks in group 2 (group 1: 31.3 +/- 26.4 x 10(-4) min-1 vs group 2: 66.2 +/- 28.5 x 10(-4) min-1; p = 0.019) but not during the disease-free period. We observed a higher incidence of chronic intestinal inflammation at the end of the study in group 2 (group 1: 3/8 vs group 2: 7/9, p = 0.153). No relation was observed between blood-aqueous barrier permeability and the number of recurrences. The number of patients with severe persistent posterior synechiae at the end of the study was higher in group 2 (group 1: 4 patients before and 4 patients at the end; group 2: 4 patients before and 8 patients at the end; p = 0.65). CONCLUSION: Sulfasalazine may be beneficial in preventing recurrences and reducing the severity of anterior uveitis associated with ankylosing spondylitis.

Adult↗
PubMed2005

Effects of bile reflux on gastric mucosal lesions in patients with dyspepsia or chronic gastritis.

AIM: To investigate the influences of bile reflux on profiles of gastric mucosal lesions in patients with dyspepsia or chronic gastritis. METHODS: A total of 49 patients diagnosed with dyspepsia and chronic gastritis underwent 24-h ambulatory and simultaneous monitoring of intragastric bilirubin absorbance and pH values, and then they were divided into bile reflux positive group and bile reflux negative group. Severity of pathological changes in gastric mucosa including active inflammation, chronic inflammation, intestinal metaplasia, atrophy and dysplasia as well as Helicobacter pylori (H pylori) infection at the corpus, incisura and antrum were determined respectively according to update Sydney system criteria. The profiles of gastric mucosal lesions in the two groups were compared, and correlations between time-percentage of gastric bilirubin absorbance >0.14 and severity of gastric mucosal lesions as well as time-percentage of gastric pH >4 were analyzed respectively. RESULTS: Thirty-eight patients (21 men and 17 women, mean age 44.2 years, range 25-61 years) were found existing with bile reflux (gastric bilirubin absorbance >0.14) and 11 patients (7 men and 4 women, mean age 46.2 years, range 29-54 years) were bile reflux negative. In dyspepsia patients with bile reflux, the mucosal lesions such as active inflammation, chronic inflammation, intestinal metaplasia, atrophy or H pylori infection in the whole stomach, especially in the corpus and incisura, were significantly more severe than those in dyspepsia patients without bile reflux. Moreover, the bile reflux time was well correlated with the severity of pathological changes of gastric mucosa as well as H pylori colonization in the near-end stomach, especially in the corpus region. No relevance was found between the time of bile reflux and pH >4 in gastric cavity. CONCLUSION: Bile reflux contributes a lot to mucosal lesions in the whole stomach, may facilitate H pylori colonization in the corpus region, and has no influence on acid-exposing status of gastric mucosa in patients with dyspepsia or chronic gastritis.

Adult↗
PubMed1994

Metronidazole inhibits leukocyte-endothelial cell adhesion in rat mesenteric venules.

BACKGROUND/AIMS: The beneficial effects of metronidazole in intestinal inflammation are generally attributed to the drug's antimicrobial actions. The objective of this study was to determine whether metronidazole exerts an anti-inflammatory action by inhibiting leukocyte-endothelial cell adhesion in postcapillary venules. METHODS: Short-term (leukotriene B4 superfusion) and long-term (subcutaneous indomethacin injections) inflammatory responses were elicited in rat mesentery). The number of adherent and emigrated leukocytes, leukocyte rolling velocity, erythrocyte velocity, blood flow, and shear rate were monitored in normal and inflamed postcapillary venules. RESULTS: Eightfold and 2.7-fold increases in leukocyte adherence and comparable increments in leukocyte emigration were observed 48 hours and 14 days after indomethacin treatment, respectively. Metronidazole, but not its vehicle (methylcellulose), reversed the leukocyte adherence and emigration responses elicited by indomethacin. The antibiotic was equally effective in preventing the reduction in leukocyte rolling velocity and increased leukocyte adherence/emigration elicited by acutely exposing venules to leukotriene B4. CONCLUSIONS: These results indicate that some of the beneficial effects of metronidazole in intestinal inflammation may be related to its influence on leukocyte-endothelial cell adhesion.

Animals↗
PubMed2001

IL-1beta and IL-10 have dual effects on enteric glial cell proliferation.

Inflammatory bowel disease is typically accompanied by functional and structural changes of the enteric nervous system. In pathological studies, cellular loss and axonal degeneration have been described in the myenteric plexus. However, more recent studies suggest that the proliferation rate of myenteric glial cells is enhanced in animal models of intestinal inflammation. Therefore, we have investigated the effect of different cytokines on the proliferative response of enteric glial cells (EGCs), comparing transformed enteric glial cell lines, primary astrocyte cultures and transformed oligodendrocytes. Cells were incubated in serum-free chemically defined medium in the presence or absence of either interleukin (IL)-1beta or IL-10 at concentrations ranging between 0.1 and 100 ng mL(-1) for 48 h. Subsequently, [3H]thymidine was added to each culture dish for an additional 6 h, and the amount of incorporated [3H] was assessed. IL-1beta significantly and dose-dependently suppressed [3H]-uptake by EGCs. In contrast, IL-10 induced a biphasic response; IL-10 at low concentrations (0.1 ng mL(-1)) caused a significant suppression of [3H]-uptake, whereas high concentrations (5-100 ng mL(-1)) significantly enhanced [3H] uptake. These results indicate that EGC proliferation can be modulated by cytokines. The differential effects of IL-1beta and IL-10 suggest that during intestinal inflammation there may be a regulatory interplay between different classes of cytokines modulating EGC proliferation.

Animals↗
PubMed2001

Increased concentration of fecal alpha1-antitrypsin is associated with cow's milk allergy in infants with atopic eczema.

BACKGROUND: The use of fecal alpha1-antitrypsin in the monitoring of intestinal inflammation in infants with atopic eczema and food allergy was evaluated. METHODS: The study material comprised 26 atopic infants with confirmed food allergy. Fecal samples were collected before an elimination diet and 3 months later for the determination of alpha1-antitrypsin. RESULTS: Nine (35%) of the 26 patients demonstrated an increased fecal concentration of alpha1-antitrypsin (median 3 mg/g; range 2.8-6.4 mg/g). In all nine patients (100%) the oral cow's milk challenge was positive as opposed to only six (35%) in those with normal alpha1-antitrypsin concentration (P = 0.0024). No further connections between alpha1-antitrypsin and other food allergies were detected. As a result of an adequate elimination diet, the fecal concentration of alpha1-antitrypsin was normalized in seven patients, with a favourable clinical response in atopic eczema in six and no improvement in one patient. CONCLUSIONS: Our results indicate that serial determinations of fecal alpha1-antitrypsin provide a useful non-invasive tool for the detection and follow-up of intestinal inflammation in a certain group of atopic infants with cow's milk allergy and severe inflammation of the gut.

Dermatitis, Atopic↗