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PubMedDate not supplied

Immunopharmacology of 5-aminosalicylic acid and of glucocorticoids in the therapy of inflammatory bowel disease.

Glucocorticoids as well as 5-aminosalicylic acid have been used successfully in different formulations during the past 40 years for the treatment of both acute and chronic inflammation in inflammatory bowel disease. The mechanism by which the drugs exert their actions are only partially known. Recent studies of the immunoregulation in the lamina propria provide evidence that numerous therapeutic mechanisms contribute to the efficacy of these drugs including the inhibition of arachidonic acid metabolism, a decrease in radical formation by oxygen radical scavenging, an inhibition of both in vivo and in vitro activation of peripheral and intestinal lymphocytes. Moreover direct immunoregulatory effects exerted by the drug may be important in influencing the complex balance of pro-inflammatory mechanisms during active intestinal inflammation. Such effects are the inhibition of both peripheral and intestinal B lymphocyte immunoglobulin secretion as well as the inhibition of pro-inflammatory cytokine production and their binding to receptors. Some of these immunoregulatory effects appear to be mediated by an inhibition of the activation of the nuclear factor kappa B transcription factor family by steroids and (less potent) aminosalicylic acid. Activation of nuclear factor kappa B appears to be pivotal for the sustained upregulation of inflammation molecule expression in many inflammatory diseases. It seems, therefore, most likely that the enormous therapeutic potency of steroids, as well as the anti-inflammatory properties of 5-aminosalicylic acid, are not achieved by a single action of the drug. The complex orchestration of numerous inhibitory interactions with pro-inflammatory principles will add to the therapeutic potential of steroids and of 5-aminosalicylic acid in the treatment of both acute and chronic intestinal inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2007

Blockade of colony stimulating factor-1 (CSF-I) leads to inhibition of DSS-induced colitis.

BACKGROUND: Intestinal inflammation associated with inflammatory bowel disease (IBD) is typically characterized by an inflammatory cell infiltrate and pro-inflammatory cytokine production. Of particular interest, the frequency of colony stimulating factor-1 (CSF-l)-expressing cells is increased in active lesions. In this study, we have investigated the role of CSF-1 in mucosal inflammation, using a murine model of colitis induced by dextran sulfate sodium (DSS). METHODS: A neutralizing anti-CSF-1 antibody was administered to Balb/c mice that received DSS in their drinking water. Signs of colitis, such as clinical disease score, cellular infiltrate, and cytokine production, were assessed. RESULTS: Administration of a neutralizing anti-CSF-1 antibody significantly inhibited DSS-induced colitis. Clinical symptoms, such as weight loss and the appearance of diarrhea or fecal blood, were reduced by CSF-1 blockade; histologic scores were also improved. The cellular infiltrate of macrophages and T cells was inhibited and a trend toward reduced production of pro-inflammatory cytokines was noted. CONCLUSIONS: This is the first study to demonstrate that CSF-1 plays an important role in mediating intestinal mucosal inflammation and therefore may prove to be an attractive therapeutic target for intestinal diseases such as inflammatory bowel disease.

Animals↗
PubMed1998

Childhood Crohn's disease and the efficacy of enteral diets.

Enteral diets, both elemental and, more recently, polymeric (whole protein), are used as primary therapy in Crohn's disease and can induce disease remission without the concomitant use of immunosuppressive drugs. Controlled trials comparing enteral nutrition with corticosteroid therapy have given mixed results but suggest, at least in children, that they are as effective as corticosteroids in inducing remission. There is no clear consensus as to which dietary therapy is best. Elemental diets do not seem to be superior to polymeric whole protein-based diets, although further work is necessary. The effect of enteral diets does not seem to be related to the site of intestinal inflammation. Enteral nutrition is particularly appropriate in children and adolescents with Crohn's disease, improving nutrition and promoting growth and pubertal development, and avoiding the systemic toxicity of corticosteroid therapy. Most centers will use it as a first line of treatment. Supplementary enteral nutrition after primary therapy and remission induction may be associated with the prolongation of remission and promotion of linear growth. Pathways by which enteral diets may affect mucosal inflammation are discussed. Enteral diets may inhibit intestinal immune responses by reducing the number of cytokine-producing cells. Enteral nutrition may also boost immunosuppressive pathways, which then endogenously suppress ongoing inflammation. Enteral diets may promote epithelial healing and reepithelialization of Crohn's ulcers and may also reduce the bacterial load in the small bowel.

Adolescent↗
PubMed2001

Down-regulation of inducible nitric-oxide synthase (NOS-2) during parasite-induced gut inflammation: a path to identify a selective NOS-2 inhibitor.

Nitric oxide (NO) possesses potent anti-inflammatory properties; however, an over-production of NO will promote inflammation and induce cell and tissue dysfunction. Thus, the ability to precisely regulate NO production could prove beneficial in controlling damage. In this study, advantage was taken of the well characterized inflammatory response caused by an intestinal parasite, Trichinella spiralis, to study the relationship between intestinal inflammation and the regulation of nitric oxide synthase-type 2 (NOS-2) expression. Our study revealed that a specific gut inflammatory reaction results in inhibition of NOS-2 expression. Characteristics of this inhibition are: 1) local jejunal inflammation induced by T. spiralis systemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity; 2) the inhibition blunts endotoxin-stimulated NOS-2 expression; 3) the inhibition does not extend to the expression of other isoforms of NOS, to paxillin, a housekeeper protein, or to cyclooxygenase-2, another protein induced by proinflammatory cytokines; 4) the inhibition is unlikely related to the formation of specific anti-parasite antibodies; and 5) the inhibition may involve substances other than stress-induced corticosteroids. Elucidation of such potent endogenous NOS-2 down-regulatory mechanisms could lead to the development of new strategies for the therapy of inflammatory conditions characterized by the overproduction of NO.

Animals↗
PubMed2000

Absorption of iron in rats with experimental enteritis.

Inflammatory conditions of the gastrointestinal tract and iron-deficiency anemia are very common in humans. Acute intestinal inflammation was pathologically established in rats by intraluminal administration of acetic acid into the duodenum and the proximal jejunum. The study included two control groups of intact (untreated) rats and sham-operated (saline-treated) rats for each intestinal segment. A third group of rats received acetic acid. The acetic acid-induced inflammatory process was established histopathologically and biochemically. Two days after treatment, iron absorption was measured using ligated 10-cm loops of proximal jejunum or ligated duodenum in which 59Fe was injected intraluminally (n = 6 in each group). In another four control groups (intact and sham-operated for each intestinal segment) and two acetic acid-treated groups, serosal-luminal secretion of 59Fe was measured after intravenous injection (n = 5 in each group). 59Fe transfer from the lumens of the duodenum and jejunum to the portal system was significantly lower in those rats in whom inflammation was induced by acetic acid. There was no apparent serosal-luminal secretion of intravenously injected 59Fe in any of the studied groups. We conclude that acetic acid-induced intestinal inflammation significantly reduces iron absorption by the duodenum and the proximal jejunum.

Acetic Acid↗
PubMed2003

Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn's disease and experimental colitis.

BACKGROUND & AIMS: Rho proteins are involved in the regulation of several cellular functions. Data from in vitro studies suggest that RhoA could be involved in the inflammatory response. We investigated the role of RhoA and its downstream effector Rho kinase in intestinal inflammation. METHODS: Activation of RhoA was assessed by pull-down assays. A specific inhibitor of Rho kinase, Y-27632, was used to examine the role of Rho kinase in inflammatory response in vivo and in vitro by molecular biology and by immunological and biochemical approaches. RESULTS: Increased activation of RhoA was found in inflamed intestinal mucosa of patients with Crohn's disease and of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Oral administration of Y-27632 in rats significantly reduced the colonic inflammation. In vitro, activation of RhoA alone was sufficient to induce tumor necrosis factor production. Y-27632 inhibited production of tumor necrosis factor-alpha and interleukin-1 beta by lamina propria and peripheral blood mononuclear cells. Rho kinase inhibition prevented nuclear factor kappa B activation and I-kappa B phosphorylation and degradation. We showed that Rho kinase associates with and activates I-kappa B kinase alpha and that Y-27632 prevents I-kappa B kinase activation. CONCLUSIONS: Our study provides the first evidence that Rho kinase activates I-kappa B kinase and, thus, nuclear factor kappa B, suggesting a key role of Rho kinase in inflammatory responses and intestinal inflammation. Specific inhibition of Rho kinase may be a promising approach for the treatment of patients with Crohn's disease.

Adolescent↗
PubMed2004

Enteric glia.

The enteric nervous system is composed of both enteric neurones and enteric glia. Enteric glial cells were first described by Dogiel and are now known to outnumber neurones approximately 4 : 1. In the past, these cells were assumed to subserve a largely supportive role; however, recent evidence indicates that enteric glial cells may play a more active role in the control of gut function. In transgenic mouse models, where enteric glial cells are selectively ablated, the loss of glia results in intestinal inflammation and disruption of the epithelial barrier. Enteric glia are activated specifically by inflammatory insults and may contribute actively to inflammatory pathology via antigen presentation and cytokine synthesis. Enteric glia also express receptors for neurotransmitters and so may serve as intermediaries in enteric neurotransmission. Thus, enteric glia may serve as a link between the nervous and immune systems of the gut and may also have an important role in maintaining the integrity of the mucosal barrier and in other aspects of intestinal homeostasis.

Animals↗
PubMed2006

Oral exposure to cadmium chloride triggers an acute inflammatory response in the intestines of mice, initiated by the over-expression of tissue macrophage inflammatory protein-2 mRNA.

Intestinal inflammation is an indispensable protective response of the gut immune system to aggressive injury from pathogens and/or chemicals. Although the major route of exposure to cadmium for most people is via food, causing the gastrointestinal tract to become the first target organ, very little information is available on whether cadmium exposure triggers the intestinal inflammatory response. We investigated in the present study the acute inflammatory response in the intestines of mice orally challenged with a single dose of cadmium chloride (CdCl(2)) by determining the gene expression of pro-inflammatory mediators with real-time PCR, and by examining the infiltration of inflammatory cells with a myeloperoxidase (MPO) assay and histological analysis of hematoxylin and eosin (H&E)-stained intestinal sections. The results show that CdCl(2) significantly increased the expression of macrophage inflammatory protein-2 mRNA (30-40 times the normal level) 3h and the activity of MPO (about 2 times the normal level) 24h after the challenge in the duodenal and proximal jejunal tissue. Furthermore, these increases were dose-dependent over a dosage range of 25-100mg/kg of body weight. The histological analysis confirmed that CdCl(2) induced mild to moderate villus damage and infiltration of inflammatory cells into the lamina propria. All these results demonstrate that oral exposure to CdCl(2) triggered an acute inflammatory response in the proximal intestine of mice, suggesting that the gut immune system was involved in the toxic effects of Cd on the gastrointestinal tract.

Administration, Oral↗
PubMed2006

Intestinal neuro-epithelial interactions modulate neuronal chemokines production.

Human enteric neurons have recently been shown to produce chemokines during intestinal inflammation. However, whether (1) neuro-epithelial interactions modulate neuronal chemokines production and (2) neurons can induce the chemotaxis of immune cells remain unknown. Neuro-epithelial interactions were studied using a coculture model composed of human neurons (NT2-N) and intestinal epithelial cells (Caco-2). IL-8 or MIP-1beta expression was analyzed by quantitative-PCR, ELISA or immunohistochemistry. Neuronally induced chemotaxis was studied using a coculture model composed of NT2-N and human peripheral blood mononuclear cells (PBMC). Following Caco-2 inflammation with IFNgamma/TNFalpha, neuronal IL-8 and MIP-1beta mRNA expression was significantly increased compared to control. This increase was significantly reduced by IL-1 receptor antagonist. IL-1beta-pretreated NT2-N induced the chemotaxis of PBMC, which was significantly reduced by anti-IL-8, but not by anti-MIP-1beta neutralizing antibody. Our results demonstrate that, under inflammatory conditions, neuro-epithelial interactions can modulate neuronal chemokines production through IL-1beta-dependent pathways. Furthermore, neuronal IL-1beta-induced chemotactic properties could favor the development of immune cells infiltrates within the enteric nervous system, as is observed during intestinal inflammation.

Cell Communication↗
PubMed2001

Nutrition in inflammatory bowel disease.

Nutritional derangements are frequent in inflammatory bowel disease. In the past year significant work has been published examining the mechanisms of impaired food intake in animal models of inflammatory bowel disease, which allow a better understanding of these processes. Data from the same laboratory have shed further light on the relative role of underfeeding and inflammation on the growth retardation associated with intestinal inflammation. Other studies have provided further data on the risk factors and predictive biomarkers of bone loss in patients with inflammatory bowel disease. The potential role of enteral nutrition as primary therapy for Crohn's disease is particularly addressed in this review. Recent contributions to the field emphasized the special importance of this modality of therapy in paediatric patients. The possible mechanisms for such a therapeutic action are not well understood. Other nutrients may have a therapeutic potential in inflammatory bowel disease. In particular, recent data on the in-vivo anti-inflammatory actions of butyrate merit special mention. Finally, novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta2-enriched enteral feeding, or hydrothermally processed cereals have recently been explored.

Adult↗
PubMed2001

Nutrition in inflammatory bowel disease: impact on disease and therapy.

Nutritional derangements are frequent in inflammatory bowel disease. In the last year, significant work was published examining the mechanisms of impaired food intake in animal models of inflammatory bowel disease, which allow a better understanding of these processes. These data have shed new light on the relative role of underfeeding and inflammation on the growth retardation associated with intestinal inflammation. Other studies have provided further information on the risk factors and predictive biomarkers of bone loss in patients with inflammatory bowel disease. The potential role of enteral nutrition as primary therapy for Crohn disease is particularly addressed in the present review. Recent contributions emphasized the special importance of this therapeutic modality in pediatric patients, but the possible mechanisms for such therapeutic effect are still not well understood. Other nutrients may have a therapeutic potential in inflammatory bowel disease. In particular, recent data on the in vivo antiinflammatory action of butyrate merit special mention. Finally, novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta2-enriched enteral feeding or hydrothermally processed cereals, have recently been explored.

Journal Article↗
PubMed2004

beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis.

mRNA expression of two recently described human beta-defensins (hBD-3 and hBD-4) in epithelial cells of normal small and large intestine and the impact of chronic intestinal inflammation on their expression levels was investigated. Intestinal specimens from patients with ulcerative colitis (UC), Crohn's disease (CD) and controls with no history of inflammatory bowel disease were studied. hBD-3 and hBD-4 mRNAs were determined in freshly isolated epithelial cells by real-time quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and by in situ hybridization. The effect of proinflammatory cytokines on hBD-3 and hBD-4 mRNA expression in colon carcinoma cells was also investigated. Purified epithelial cells of normal small and large intestine expressed both hBD-3 and hBD-4 mRNA, with higher expression levels of hBD-3 mRNA. In situ hybridization revealed higher levels of mRNA expression in the crypt- compared to the villus/luminal-compartment. Interferon (IFN)-gamma, but not tumour necrosis factor (TNF)-alpha or IL-1beta, augmented hBD-3 mRNA expression. None of these agents stimulated hBD-4 expression. Colonic epithelial cells from patients with UC displayed a significant increase in hBD-3 and hBD-4 mRNA compared to epithelial cells of controls. In contrast, small intestinal epithelial cells from CD patients did not show increased expression levels compared to the corresponding control cells. Moreover, Crohn's colitis did not show increased expression of hBD-4 mRNA, while the data are inconclusive for hBD-3 mRNA. We conclude that the chronic inflammatory reaction induced in the colon of UC patients enhances hBD-3 and hBD-4 mRNA expression in the epithelium, whereas in CD this is less evident.

Adult↗
PubMed2003

Dietary fructo-oligosaccharides and lactulose inhibit intestinal colonisation but stimulate translocation of salmonella in rats.

BACKGROUND AND AIMS: It is frequently assumed that dietary non-digestible carbohydrates improve host resistance to intestinal infections by stimulating the protective gut microflora. However, compelling scientific evidence from in vivo infection studies is lacking. Therefore, we studied the effect of several non-digestible carbohydrates on the resistance of rats to Salmonella enteritidis infection. METHODS: Rats (n=8 per group) were fed "humanised" purified diets containing 4% lactulose, fructo-oligosaccharides (FOS), resistant starch, wheat fibre, or cellulose. After an adaptation period of 2 weeks the animals were orally infected with S enteritidis. Supplement induced changes in faecal biochemical and microbiological parameters were studied before infection. Colonisation of salmonella was determined by studying the faecal excretion of this pathogen and translocation by analysis of urinary nitric oxide metabolites over time and classical organ cultures. Intestinal mucosal myeloperoxidase activity was determined to quantify intestinal inflammation after infection. RESULTS: Despite stimulation of intestinal lactobacilli and bifidobacteria and inhibition of salmonella colonisation, FOS and lactulose significantly enhanced translocation of this pathogen. These supplements also increased cytotoxicity of faecal water and faecal mucin excretion, which may reflect mucosal irritation. In addition, caecal and colonic, but not ileal, mucosal myeloperoxidase activity was increased in infected rats fed FOS and lactulose. In contrast, cellulose, wheat fibre, and resistant starch did not affect the resistance to salmonella. CONCLUSIONS: In contrast to most expectations, FOS and lactulose impair the resistance of rats to intestinal salmonella infection. Obviously, stimulation of the endogenous lactobacilli and bifidobacteria is no guarantee of improved host defence against intestinal infections.

Administration, Oral↗
PubMed1998

Butyrate enhances interleukin (IL)-8 secretion by intestinal epithelial cells in response to IL-1beta and lipopolysaccharide.

Intestinal epithelial (Caco-2) cells secrete the chemokine, IL-8, after stimulation with IL-1beta, but not after lipopolysaccharide. Butyrate is a short chain fatty acid derived from the metabolism of intestinal contents by gut bacteria. Butyrate concentrations reflect, therefore, the bacterial microenvironment established within the intestine. We hypothesized that butyrate may alter the secretion of IL-8 by intestinal epithelial cells in response to stimulation by IL-1beta or lipopolysaccharide. Caco-2 cells were incubated in varying concentrations of sodium butyrate (0-20 mM) for 24 h before stimulation with lipopolysaccharide or IL-1beta. IL-8 secretion was measured over 24 h by ELISA. IL-8 mRNA accumulation was detected by Northern blots. Lipopolysaccharide induced the secretion of IL-8 only after Caco-2 cells cells had been cultured with sodium butyrate. Furthermore, butyrate significantly enhanced IL-8 secretion by cells stimulated with IL-1beta. Butyrate also increased IL-8 mRNA accumulation in stimulated Caco-2 cells. Intestinal epithelial cells can, therefore, be primed by butyrate to become activated by lipopolysaccharide and proinflammatory cytokines. This may represent a mechanism by which intestinal epithelial cells can regulate intestinal inflammation in response to changes in the intestinal milieu.

Blotting, Western↗
PubMed1998

CGRP upregulation in dorsal root ganglia and ileal mucosa during Clostridium difficile toxin A-induced enteritis.

We have previously reported that pretreatment of rats with capsaicin (an agent that ablates sensory neurons) or CP-96345 (a substance P receptor antagonist) dramatically inhibits fluid secretion and intestinal inflammation in ileal loops exposed to Clostridium difficile toxin A. The aim of this study was to determine whether calcitonin gene-related peptide (CGRP), a neuropeptide also found in sensory afferent neurons, participates in the enterotoxic effects of toxin A. Administration of toxin A was also found to increase CGRP content in dorsal root ganglia and ileal mucosa 60 min after toxin exposure. Furthermore, immunohistochemical studies demonstrated increased neuronal staining for CGRP 2 h after toxin A treatment. Pretreatment of rats with CGRP-(8-37), a specific CGRP antagonist, before instillation of toxin A into ileal loops significantly inhibited toxin-mediated fluid secretion (by 48%), mannitol permeability (by 83%), and histological damage. We conclude that CGRP, like substance P, contributes to the secretory and inflammatory effects of toxin A via increased production of this peptide from intestinal nerves, including primary sensory afferent neurons.

Animals↗
PubMed2006

COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation.

The discovery of a second form of cyclooxygenase, COX-2, led to a burst of research aimed at the development of nonsteroidal anti-inflammatory drugs that would not damage the gastrointestinal tract. In the years since, this promise has only been partially fulfilled. Selective COX-2 inhibitors cause less gastric damage than conventional, nonselective COX inhibitors, but their use is still associated with significant gastrointestinal injury, and with toxicity in the renal and cardiovascular systems. COX-2 is now recognized as a source of mediators that produce many beneficial and detrimental effects in the digestive system. In this review, the roles of COX-2 in mucosal defense and injury are discussed. Furthermore, contributions of COX-2-derived products to the long-term consequences of intestinal inflammation, including cancer, are reviewed.

Animals↗
PubMed1990

Effects of neutrophil-derived oxidants on intestinal permeability, electrolyte transport, and epithelial cell viability.

There are several pathophysiologic conditions in which intestinal inflammation is associated with enhanced mucosal permeability, fluid loss, and epithelial cell injury. The objective of this study was to determine the effects of polymorphonuclear leukocyte (PMN)-derived oxidants on ileal mucosal permeability in vivo as well as electrolyte transport and epithelial cell viability in vitro. Using blood-to-lumen clearance of [51Cr]EDTA as a measure of mucosal permeability, we found that luminal perfusion with hydrogen peroxide (H2O2), hypochlorous acid (HOCl), or monochloramine (NH2Cl) produced a dose-dependent increase in mucosal permeability. Perfusion with 0.1 mM, 0.5 mM, and 1.0 mM oxidant produced a 2 +/- 1, 5 +/- 2, and 11 +/- 5-fold increase in mucosal permeability for H2O2, a 2 +/- 1, 8 +/- 3, and 36 +/- 12-fold increase for HOCl, and a 3 +/- 1, 11 +/- 2, and 30 +/- 7-fold increase for NH2Cl. Taurine monochloramine (TauNHCl) was ineffective in enhancing the blood-to-lumen clearance of [51Cr]EDTA. Furthermore, 0.01 mM and 0.1 mM NH2Cl and H2O2 produced significant increases in short-circuit current across rat ileum in vitro, whereas HOCl and TauNHCl were without effect. Tissue resistance and potential difference were not altered, suggesting that NH2Cl, HOCl, and H2O2 were not cytotoxic under these conditions. Cultured intestinal epithelial cells exposed to NH2Cl and HOCl were injured in a dose-dependent manner in vitro, whereas H2O2 and Tau NHCl were nontoxic. Taken together, our data suggest that PMN-derived oxidants may mediate the enhanced mucosal permeability, electrolyte transport, and epithelial cell injury associated with acute inflammation of the bowel.

Animals↗
PubMed2006

Peyer's patches and M cells as potential sites of the inflammatory onset in Crohn's disease.

Clinical observations suggest that the sites of initial inflammation in ileal Crohn's disease (CD) are the lymphoid follicles, where the aphtoid lesions originate from small erosions of the follicle-associated epithelium (FAE). Lymphoid follicles and Peyer's patches (PPs) consist of a number of B-cell follicles with intervening T cell areas. The T cell follicular area is also populated by dendritic cells (DCs) and macrophages. A single layer of epithelial cells covering each follicle forms a dome between the surrounding villi. This FAE differs from normal villus epithelium in several ways that make the epithelial cells of the FAE more exposed to the luminal contents, more accessible to antigens, and in closer contact with the immune system. The most prominent feature is the presence of specialized M cells, which are optimized for antigen adherence and transport. M cells play an important role in the surveillance of the intestinal lumen, but also provide a route of entry for various pathogens. In this article we review the current knowledge on the epithelial phenotype of the human FAE, and changes of the FAE and M cells in intestinal inflammation, leading to a hypothesis of the role of the FAE and M cells in the pathogenesis of CD.

Animals↗