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PubMed2005

Mechanism of TNF-{alpha} modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression.

TNF-alpha plays a central role in the intestinal inflammation of various inflammatory disorders including Crohn's disease (CD). TNF-alpha-induced increase in intestinal epithelial tight junction (TJ) permeability has been proposed as one of the proinflammatory mechanisms contributing to the intestinal inflammation. The intracellular mechanisms involved in the TNF-alpha-induced increase in intestinal TJ permeability remain unclear. The purpose of this study was to investigate the possibility that the TNF-alpha-induced increase in intestinal epithelial TJ permeability was regulated by myosin light-chain kinase (MLCK) protein expression, using an in vitro intestinal epithelial model system consisting of the filter-grown Caco-2 intestinal epithelial monolayers. TNF-alpha (10 ng/ml) produced a time-dependent increase in Caco-2 MLCK expression. The TNF-alpha increase in MLCK protein expression paralleled the increase in Caco-2 TJ permeability, and the inhibition of the TNF-alpha-induced MLCK expression (by cycloheximide) prevented the increase in Caco-2 TJ permeability, suggesting that MLCK expression may be required for the increase in Caco-2 TJ permeability. The TNF-alpha increase in MLCK protein expression was preceded by an increase in MLCK mRNA expression but not an alteration in MLCK protein degradation. Actinomycin-D prevented the TNF-alpha increase in MLCK mRNA expression and the subsequent increase in MLCK protein expression and Caco-2 TJ permeability, suggesting that the increase in MLCK mRNA transcription led to the increase in MLCK expression. The TNF-alpha increase in MLCK protein expression was also associated with an increase in Caco-2 MLCK activity. The cycloheximide inhibition of MLCK protein expression prevented the TNF-alpha increase in MLCK activity and Caco-2 TJ permeability. Moreover, inhibitors of MLCK, Mg(2+)-myosin ATPase, and metabolic energy prevented the TNF-alpha increase in Caco-2 TJ permeability, suggesting that the increase in MLCK activity was required for the TNF-alpha-induced opening of the Caco-2 TJ barrier. In conclusion, our results indicate for the first time that 1) the TNF-alpha increase in Caco-2 TJ permeability was mediated by an increase in MLCK protein expression, 2) the increase in MLCK protein expression was regulated by an increase in MLCK mRNA transcription, and 3) the increase in Caco-2 TJ permeability required MLCK protein expression-dependent increase in MLCK activity.

Antimetabolites↗
PubMed2003

Mucosal T cells as a target for treatment of IBD.

Interleukin-7 (IL-7) is an indispensable cytokine for the development of lymphocyte lineage cells. However, the potential role of IL-7 in peripheral nonlymphoid tissues was unclear before our study. We have demonstrated that intestinal epithelial cells produce IL-7 and that IL-7 serves as a regulatory factor for proliferation of mucosal lymphocytes expressing IL-7 receptor (IL-7R). Recent studies demonstrated that intestinal epithelial cell-derived IL-7 plays a crucial role in the organization of mucosal lymphoid tissues and regulating the normal immune response in intestinal mucosa. In a previous study, we demonstrated that IL-7 transgenic mice developed chronic colitis. Here, we have demonstrated the essential role of mucosal IL-7/IL-7R-dependent signals in the development of chronic intestinal inflammation. Our results indicate that mucosal IL-7/IL-7R-dependent signals are involved in the development of chronic intestinal inflammation in both the mouse model and human disease of the intestinal mucosa. Therefore, current studies indicate that therapeutic approaches by specific targeting of IL-7R-expressing mucosal T cells may be feasible in the treatment of human ulcerative colitis.

Animals↗
PubMed2000

Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4(+) T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4(+) T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes. METHODS: Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity. RESULTS: The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18(+)CD68(+) macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. IL-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls. CONCLUSIONS: These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.

Cell Division↗
PubMed2001

Mycophenolate mofetil reduces tissue damage and inflammation in an experimental model of colitis in rats.

BACKGROUND: Lymphocytes are widely believed to be responsible for persistent intestinal inflammation in inflammatory bowel diseases. Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits lymphocyte proliferation and has been shown to be effective in preventing allograft rejection after organ transplantation. The purpose of this study was to assess the modulating effects of MMF on intestinal inflammation in an experimental model of colitis in rats. METHODS: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in ethanol in male Sprague-Dawley rats. One group of rats (n = 10) was treated with MMF i.p. (25 mg/kg b.w.) daily for 1 week starting 24 h after induction of colitis. A second group of rats (n = 10) was treated with MMF at the same dose 2 days, I day and 1 h prior to induction of colitis. Control animals (n = 10) received vehicle only. After being killed, colonic tissue was macroscopically evaluated for necrosis and microscopically for ulcerations. Sections were stained and examined for the presence of granulocytes. RESULTS: Administration of MMF after induction of TNBS colitis reduced macroscopic injury by 62% compared to control animals (P = 0.01). Microscopic ulcerations were reduced by 64% compared to controls (P = 0.009). In addition, posttreatment significantly reduced the number of granulocytes. MMF pretreatment did not significantly prevent macroscopic or microscopic tissue damage, or change the number of granulocytes. CONCLUSION: Systemic administration of MMF significantly ameliorates tissue damage in a model of experimental colitis in rats suggesting that this compound may play an important role as an immunosuppressant in the therapy of inflammatory bowel diseases.

Animals↗
PubMed1998

hPepT1-mediated epithelial transport of bacteria-derived chemotactic peptides enhances neutrophil-epithelial interactions.

Intestinal epithelial cells express hPepT1, an apical transporter responsible for the uptake of a broad array of small peptides. As these could conceivably include n-formyl peptides, we examined whether hPepT1 could transport the model n-formylated peptide fMLP and, if so, whether such cellular uptake of fMLP influenced neutrophil-epithelial interactions. fMLP uptake into oocytes was enhanced by hPepT1 expression. In addition, fMLP competitively inhibited uptake of a known hPepT1 substrate (glycylsarcosine) in hPepT1 expressing oocytes. hPepT1 peptide uptake was further examined in a polarized human intestinal epithelial cell line (Caco2-BBE) known to express this transporter. Epithelial monolayers internalized apical fMLP in a fashion that was competitively inhibited by other hPepT1 recognized solutes, but not by related solutes that were not transported by hPepT1. Fluorescence analyses of intracellular pH revealed that fMLP uptake was accompanied by cytosolic acidification, consistent with the known function of hPepT1 as a peptide H+ cotransporter. Lumenal fMLP resulted in directed movement of neutrophils across epithelial monolayers. Solutes that inhibit hPepT1-mediated fMLP transport decreased neutrophil transmigration by approximately 50%. Conversely, conditions that enhanced the rate of hPepT1-mediated fMLP uptake (cytosolic acidification) enhanced neutrophil-transepithelial migration by approximately 70%. We conclude that hPepT1 transports fMLP and uptake of these peptide influences neutrophil-epithelial interactions. These data (a) emphasize the importance of hPepT1 in mediating intestinal inflammation, (b) raise the possibility that modulating hPepT1 activity could influence states of intestinal inflammation, and (c) provide the first evidence of a link between active transepithelial transport and neutrophil-epithelial interactions.

Animals↗
PubMed2001

Phosphoinositide 3-kinases in the gut: a link between inflammation and cancer?

Carcinoma of the gastrointestinal tract is the most common internal malignancy affecting men and women in Western countries. Chronic intestinal inflammation, especially of the colon, is also a Western disease and correlates with a significantly increased risk of developing cancer. This has suggested that the immune processes involved in both conditions might share some common pathways. Indeed, there is increasing evidence that phosphatidylinositol 3-kinases (PI 3-kinases) are involved in both the pathogenesis of colorectal carcinoma and intestinal inflammation. Here, we discuss this rapidly progressing area of research, presenting evidence for a pivotal role of PI 3-kinase(s) in intestinal pathophysiology.

Animals↗
PubMed2006

Ileitis alters neuronal and enteroendocrine signalling in guinea pig distal colon.

BACKGROUND AND AIMS: Intestinal inflammation alters neuronal and enteroendocrine signalling, leading to functional adaptations in the inflamed bowel. Human studies have reported functional alterations at sites distant from active inflammation. Our aims were to determine whether neuronal and enteroendocrine signalling are altered in the uninflamed colon during ileitis. METHODS: We used neurophysiological, immunohistochemical, biochemical and Ussing chamber techniques to examine the effect of 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced ileitis on the properties of submucosal neurones, enteroendocrine cells and epithelial physiology of the distal colon of guinea pigs. RESULTS: Three days after TNBS administration, when inflammation was restricted to the ileum, the properties of colonic enteric neurones were altered. Submucosal AH neurones were hyperexcitable and had reduced after hyperpolarisations. S neurones received larger fast and slow excitatory postsynaptic potentials, due to an increase in non-cholinergic synaptic transmission. Despite the absence of inflammation in the colon, we found increased colonic prostaglandin E(2) content in animals with ileitis. Ileitis also increased the number of colonic 5-hydroxytryptamine (5-HT)- and GLP-2-immunoreactive enteroendocrine cells. This was accompanied by an increase in stimulated 5-HT release. Functional alterations in epithelial physiology occurred such that basal short circuit current was increased and veratridine-stimulated ion transport was reduced in the colon of animals with ileitis. CONCLUSION: Our data suggest that inflammation at one site in the gut alters the cellular components of enteric reflex circuits in non-inflamed regions in ways similar to those at sites of active inflammation. These changes underlie altered function in non-involved regions during episodes of intestinal inflammation.

Animals↗
PubMed1993

Intestinal mucosal inflammation associated with human immunodeficiency virus infection.

The role of the human immunodeficiency virus type-1 (HIV) in producing intestinal disease was studied prospectively in 74 HIV-infected individuals with (43) or without (31) the acquired immunodeficiency syndrome (AIDS). Thirty-one subjects had enteric infections; all but one had AIDS. Alteration in bowel habits was the most common symptom and occurred independently of enteric infections. Abnormal histopathology was present in 69% of cases, and the finding was associated with altered bowel habits. An HIV-associated protein, p24, was detected in 71% of biopsies by ELISA assay. Tissue p24 contents varied with disease stage and were highest in HIV-infected individuals without AIDS (Walter Reed classes 3 and 4). Tissue p24 detection was associated with both altered bowel habits and histologic mucosal abnormalities. Tissue contents of the cytokines, tumor necrosis factor-alpha and interleukin-1 beta, were higher in HIV-infected individuals than in controls and their elevations were independent of enteric infection. We conclude that HIV reactivation in the intestinal mucosa may be associated with an inflammatory bowel syndrome in the absence of other enteric pathogens.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Determination of inflammatory bowel disease activity by breath pentane analysis.

PURPOSE: Quantitative determination of breath pentane, an alkane generated by peroxidation of cellular fatty acids, has been used as a noninvasive determinant of inflammation. Herein we report the first examination of the relationship between breath pentane and intestinal inflammation in humans. METHODS: Patients (N = 33), either with a known history of inflammatory bowel disease (IBD) with symptoms of relapse or with no known history of but having symptoms consistent with IBD, were evaluated with indium-111-labeled leukocyte imaging to assess the presence of active inflammation. At the time of the indium scan, the exhaled breath of the patients was obtained via a collecting tube. Gas chromatography was used to quantify the pentane content, and these values were compared with graded indium scans. RESULTS: The range of breath pentane found in our population (36 determinations in 33 patients) was from 0 to 38.4 nmol/l of exhaled air. For patients with negative scans, the mean pentane was 2.1 nmol/l, for intermediate scans 3.1, for positive scans 4.3, and for nonintestinal nuclide imaging 5.5 [P = 0.005 by analysis of variance (ANOVA)]. CONCLUSIONS: We have previously demonstrated the correlation of breath pentane with gross and histologic evidence of intestinal inflammation in a rodent colitis model. This current study also demonstrates that pentane analysis can be correlated with inflammatory bowel disease activity in humans.

Adult↗
PubMed2002

Changes in the inhibitory responses to electrical field stimulation of intestinal smooth muscle from Trichinella spiralis infected rats.

Functional motor changes and morphological alterations have been associated with intestinal inflammation. The aim of this work was to study functional motor changes in inflamed and non-inflamed intestinal segments of Trichinella spiralis infected rats. Thickness of muscle layers and cell infiltration during infection were also evaluated. Segments of rat jejunum and ileum were placed in organ bath and relaxations of the longitudinal muscle in response to electrical field stimulation (EFS) were recorded. During the post-infection (PI) period EFS-induced relaxations in ileum were decreased. Maximal decreases in relaxation were found on day 14-23 PI for ileum, whereas non significant changes were observed in jejunal samples throughout the experimental period. The sensitivity of the EFS-induced relaxations to the NO synthase inhibitor Nomega-nitro-L-arginine (L-NNA) and to the soluble guanylate cyclase inhibitor oxadiazolo-quinoxalin-1-one (ODQ) was decreased on day 14 PI for jejunum, whereas in the ileum it lasted from day 14-23 PI. The sensitivity of EFS-induced relaxations to apamin (a small conductance calcium activated potassium channel blocker) disappeared between day 6-23 PI for both jejunum and ileum. In contrast, the sensitivity of the EFS-induced relaxations to the K(+) channel blockers tetraethylamonium (TEA) and tetrapenthylammonium (TPEA) chloride was similar for healthy tissue and for tissue obtained form infected animals. Distribution and density of NADPH-diaphorase positive neurons was similar in tissue obtained form healthy and infected animals. In conclusion, intestinal inflammation induces functional and structural changes in both worm-free and worm-positive intestinal segments. Increased muscle thickness was similar for both inflamed and noninflamed segments but the most prominent functional changes i.e. a long-lasting decrease of EFS-induced relaxation was found in non-inflamed ileal segments.

Animals↗
PubMed1999

Role of inducible nitric oxide synthase in trinitrobenzene sulphonic acid induced colitis in mice.

BACKGROUND: Studies using inhibitors of nitric oxide synthase (NOS) to date are inconclusive regarding the role of inducible NOS (iNOS) in intestinal inflammation. AIMS: (1) To examine the role of iNOS in the development of chronic intestinal inflammation; (2) to identify the cellular source(s) of iNOS. METHODS: Colitis was induced by an intrarectal instillation of trinitrobenzene sulphonic acid (TNBS, 60 mg/ml, 30% ethanol), in wild type (control) or iNOS deficient mice. Mice were studied over 14 days; the colons were scored for injury and granulocyte infiltration was quantified. Blood to lumen leakage of (51)Cr-EDTA was measured as a quantitative index of mucosal damage. RESULTS: At 24 and 72 hours, iNOS deficient mice had significantly increased macroscopic inflammation compared with wild type mice. Granulocyte infiltration increased significantly at 24 hours and remained elevated in iNOS deficient mice at 72 hours, but significantly decreased in controls. However, by seven days post-TNBS macroscopic damage, microscopic histology, granulocyte infiltration, and mucosal permeability did not differ between wild type and iNOS deficient mice. A four- to fivefold increase in iNOS mRNA was observed in wild type mice at 72 hours and seven days post-TNBS and was absent in iNOS deficient mice. Immunohistochemistry techniques showed that iNOS expression was predominantly localised in neutrophils, with some staining also in macrophages. CONCLUSIONS: These results suggest that leucocyte derived iNOS ameliorates the early phase, but does not impact on the chronic phase of TNBS induced colitis despite the presence of iNOS.

Acute Disease↗
PubMed2004

Allicin inhibits spontaneous and TNF-alpha induced secretion of proinflammatory cytokines and chemokines from intestinal epithelial cells.

BACKGROUND & AIMS: Allicin, the active substance of fresh crushed garlic has different biological activities and was implicated as an anti-inflammatory agent. Epithelial cells have an important role in intestinal inflammation. The aim of this study was to assess the immunomodulatory effect of allicin on intestinal epithelial cells. METHODS: The spontaneous and TNF-alpha-stimulated secretion of IL-1beta, IL-8, IP-10 and MIG from HT-29 and Caco-2 cells was tested with, or without pretreatment with allicin. Cytokine secretion was assessed using ELISA and expression of mRNA was determined by an RNA protection assay. RESULTS: Allicin markedly inhibited the spontaneous and TNF-alpha -induced secretion of IL-1beta, IL-8, IP-10 and MIG from the two different cell lines in a dose-dependent manner and suppressed the expression of IL-8 and IL-1beta mRNA levels. In addition, allicin suppressed the degradation of IkappaB. No effect on cell viability was noted. CONCLUSIONS: These observations indicate that allicin exerts an inhibitory immunomodulatory effect on intestinal epithelial cells and suggest that allicin may have the potential to attenuate intestinal inflammation.

Anti-Infective Agents↗
PubMed2000

Chronic ingestion of a potential food contaminant induces gastrointestinal inflammation in rats: role of nitric oxide and mast cells.

Chronic ingestion of xenobiotics could be pathogenic in the gastrointestinal tract. Recently, we showed that acute low administration of a food contaminant (diquat) induced intestinal secretion involving mast cells and nitric oxide. This work aimed to determine in rats: (1) the influence of a low level (0.1 mg/kg/day per os) chronic ingestion of diquat on gastrointestinal immune cells, and (2) the participation of nitric oxide synthases (NOS) in these effects. Diquat increased both gastric and jejunal myeloperoxidase activities, tissue histamine in vitro release after stimulation by 48/80, and mast cell numbers. Diquat did not alter gastric NOS but increased intestinal inducible NOS (iNOS) activity. L-NAME prevented diquat-induced gastric and intestinal mastocytosis and gastric but not intestinal inflammation. L-NAME reduced gastric constitutive NOS (cNOS) activity and reestablished control iNOS activity. Chronic low level ingestion of diquat induces a low-grade gastric and intestinal inflammation with mastocytosis and enhancement of intestinal iNOS activity.

Animals↗
PubMed2006

Animal models of inflammatory bowel disease: lessons from enteric infections.

Mouse models of intestinal inflammation have played a key role in understanding the mechanisms that govern the inflammatory response in the intestine, and in designing new therapeutic strategies in the treatment of patients with inflammatory bowel disease (IBD). Most of these models use chemical challenges, whereas relatively few robust models of intestinal inflammation caused by microbial infection are known. Two common models of infectious murine colitis and typhlitis are infection with the murine epithelial-adherent pathogen, Citrobacter rodentium, and infection of streptomycin-pretreated mice with Salmonella typhimurium. Studies in these models have helped to define the interactions between bacterial pathogens and host immune defenses, thus broadening the understanding of host-microbial interactions in the intestinal tract. Furthermore, such models help to determine the physiologic consequences of neutralizing specific mediators and signaling pathways implicated in inflammation on antimicrobial host defense.

Animals↗
PubMed2026

Probiotic Lacticaseibacillus casei 2S-1 Attenuates Escherichia coli-Induced Enteritis via Gut Microbiota Modulation and Host Gene Regulation.

Maintaining gut microbial homeostasis is crucial for host health, whereas infection with Escherichia coli (E. coli) is a major contributor to intestinal inflammation and microbial dysbiosis. Recent research has focused on probiotic strategies for managing enteric inflammatory disorders. Previous studies have shown that beneficial microorganisms show protection through modulating host immune responses, enhancing intestinal epithelial barrier integrity, and inhibiting pathogenic bacteria. To evaluate the prophylactic effectiveness of a recently isolated strain, Lacticaseibacillus casei 2S-1, in a murine model of E. coli-induced enteritis, this study focuses on interactions within the microbiota-intestinal-immune axis, together with host transcriptional responses and pathway enrichment associated with oxidative stress and mitochondrial function. In vitro analysis of probiotic features, including growth dynamics, acidogenic capacity, and tolerance to acidic and bile salt environments, as well as genetic safety profiling, followed the methodical isolation and taxonomic identification of L. casei 2S-1. A preventive intervention protocol was established, and a murine model of enteritis was induced by exposure to E. coli. Histopathological analyses were performed to observe in vivo safety and protective efficacy. Changes in gut microbial structure were characterized by 16S rRNA gene sequencing, while host responses were identified by intestinal immunohistochemistry and transcriptome profiling. L. casei 2S-1 showed probiotic properties. In vitro analyses showed that the strain exhibited tolerance to acidic and bile salt conditions, and its untreated culture supernatant showed antimicrobial activity against pathogenic bacteria. Its safety profile was supported by genomic analysis, which verified the lack of virulence-associated genes and antibiotic resistance factors. In vivo, L. casei 2S-1 pretreatment reduced mortality and intestinal inflammation, modulated gut microbial composition, and preserved intestinal barrier-associated protein expression in infected mice. This study provides experimental evidence supporting the prophylactic effects of L. casei 2S-1 and its associations with gut microbiota modulation and host transcriptional responses, providing a foundation for further investigation of probiotic-based preventive strategies against intestinal infections.

Animals↗
PubMed1997

Cytokine modulation of T-lymphocyte activation by intestinal smooth muscle cells.

BACKGROUND & AIMS: Interleukin 1beta (IL-beta) and tumor necrosis factor alpha (TNF-alpha) are present in the neuromuscular layers during intestinal inflammation and directly affect intestinal smooth muscle function. We investigated whether IL-1beta and TNF-alpha modulate T-cell activation by murine intestinal smooth muscle cells (ISMCs). METHODS: alpha- and gamma- actin expression in ISMCs was confirmed using reverse-transcription polymerase chain reaction (RT-PCR). ISMCs were analyzed for class II major histocompatibility complex (MHC), intercellular adhesion molecule 1 (ICAM-1), and B7 before and after exposure to interferon gamma (IFN-gamma; 100 or 1000 U/ mL) in the presence or absence of IL-1beta (10 ng/mL) or TNF-alpha (5 ng/mL) for 72 hours. T-cell proliferation on cytokine-pretreated ISMCs was measured in the absence or presence of anti-B7 antibodies. RESULTS: In a dose-dependent fashion, IFN-gamma-pretreated ISMCs expressed MHC class II, ICAM-1, and B7-2, and stimulated T-cell proliferation. Pretreatment of ISMCs with IL-1beta and IFN-gamma reduced MHC class II and ICAM-1 expression and inhibited T-cell proliferation. When added with 100 U/mL IFN-gamma, TNF-alpha enhanced MHC class II and ICAM-1 expression on ISMCs and T-cell proliferation. However, TNF-alpha and 1000 U/mL IFN-gamma significantly decreased MHC class II expression and T-cell proliferation. Anti-B7-2 monoclonal antibody but not anti-B7-1 inhibited T-cell proliferative responses by >50%. CONCLUSIONS: Because IL-1beta, TNF-alpha, and T cells are present in the intestinal muscle layers during inflammation, these cytokines may serve to modulate the activation of T cells in this site.

Animals↗
PubMed2000

Interleukin-12 induced interferon-gamma increases inflammation in acute dextran sulfate sodium induced colitis in mice.

There is increasing evidence that IL-12 and Th1-cytokines play an important role in intestinal inflammation. We therefore examined the role of IL-12 and interferon-gamma (IFN-gamma) in our model of dextran sulfate-induced acute colitis in mice. Treatment of mice with rmIL-12 during colitis induction resulted in severe aggravation as demonstrated by a greater loss of body weight, an increase of the histological parameters, and reduction of myeloperoxidase activity in colonic biopsies. Depletion of neutrophils in mice also led to aggravation of colitis. Neutralization of IFN-gamma in IL-12-treated mice with colitis inhibited these effects of IL-12. Neutralization of endogenous IFN-gamma or IL-12 with specific antibodies in DSS-treated mice, however, had only weak ameliorating effects. Since IL-12 and IFN-gamma have been shown to mediate experimental chronic colitis we conclude that the transition from a macrophage/neutrophil determined response to a Th-cell response promotes chronic intestinal inflammation.

Animals↗
PubMed2001

Effects of therapy with lansoprazole on intestinal permeability and inflammation in young cystic fibrosis patients.

BACKGROUND: Defective pancreatic bicarbonate secretion with low intestinal pH or intestinal inflammation of any origin increase intestinal permeability in cystic fibrosis (CF). METHODS: In this open study, the authors evaluated the effect of a proton-pump inhibitor on intestinal permeability and inflammation in 14 young, pancreatic-insufficient CF patients. Permeability was measured by a three-sugar permeability test before and after 1 year of lansoprazole use, and urinary nitric oxide (NO) oxidation products were assessed before and during that year as a marker of inflammation. RESULTS: After 1 year of lansoprazole use, median urinary recovery percentages changed from 2.5% to 1.7% (P = 0.064), from 24.9% to 24.5% (no significance), and from 10.5% to 11.1% (no significance) for lactulose, mannitol, and L-rhamnose, respectively. Despite the fact that the median urinary excretion ratios decreased from 0.108 to 0.083 (P = 0.03) and from 0.246 to 0.176 (P = 0.016) for lactulose and mannitol and for lactulose and rhamnose, respectively, they both remained increased. Median urinary NO products-to-creatinine ratios were 0.287 for CF patients before lansoprazole and 0.130 for healthy control participants (P = 0.002). Although there was a tendency toward a decrease in the NO products-to-creatinine ratio during treatment, this was not significant at the end point. CONCLUSIONS: Intestinal permeability is considerably increased in CF patients and is partly corrected after the use of a proton-pump inhibitor for 1 year, which may point to a harmful effect of the acid luminal contents on the tight junctional related paracellular permeability pathway. The start and end values for the NO products-to-creatinine ratio in CF patients were not significantly different, but were considerably increased when compared with control participants (P = 0.002).

2-Pyridinylmethylsulfinylbenzimidazoles↗