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PubMed2006

Contribution of polymeric immunoglobulin receptor to regulation of intestinal inflammation in dextran sulfate sodium-induced colitis.

BACKGROUND: Inflammatory bowel disease (IBD) affects approximately 4 million people worldwide and can be caused by dysregulated mucosal immune responses to the intestinal commensal microflora. Immunoglobulin A (IgA) is considered to be the principal antibody in intestinal secretions and functions to prevent commensals and pathogenic organisms from gaining access to epithelial cell surfaces. Immunoglobulin A deficiency in humans has been associated with celiac disease and ulcerative colitis. However, the precise role of IgA in the pathogenesis of these disorders is yet to be fully understood. METHODS: Mice with a targeted disruption in IgA production (IgA(-/-) mice) and polymeric immunoglobulin receptor (pIgR(-/-) mice) were analyzed for the contribution of secretory immunity in the pathogenesis of dextran sulfate sodium (2.5%)-induced colitis. RESULTS: It was found that dextran sulfate sodium-treated pIgR(-/-) mice displayed greater loss of bodyweight and had severe clinical illness compared to similarly treated IgA(-/-) mice and wild-type animals. Additionally, colonic tissues from the pIgR(-/-) mice exhibited progressively and significantly greater degrees of mucosal edema, ulceration, crypt abscesses and macrophage infiltration when compared to similarly treated IgA(-/-) mice and wild-type animals. CONCLUSIONS: The results indicate that secretory immunoglobulins contribute to protection of the colonic mucosa against dextran sulfate sodium-induced epithelial injury, although the isotype of the secretory immunoglobulin (IgA or IgM) may not be a decisive factor in such protection. Collectively, the pIgR and/or the secretory component are important for the maintenance of epithelial integrity and mucosal homeostasis in the colonic epithelium.

Animals↗
PubMed1991

[Colicinogeny in nonspecific intestinal inflammations and colorectal cancer].

Colicins are proteinaceous substances produced by Escherichia coli strains and related bacteria of Enterobacteriaceae family. They are considered to be an important factor in preserving the balance of the intestinal microflora. Their antibiotic action on susceptible bacteria is supplemented with cytotoxicity for several pro- and eukaryotic cells. The large bowel is a natural site of their action. Besides of enhancing oxidoreductive activity of leukocytes in vitro, colicins are also believed to influence inflammatory reaction in vivo. For these reasons, the first part of the present work was concerned with studying colicinogeny in nonspecific inflammatory bowel diseases (IBD). No significant difference has been found out in colicinogeny between a total of 93 IBD-related and 160 healthy controls. In testing leukocyte migration inhibition, colicins of autologous E. coli were used as antigens. The migration index out of normal range showed 36% patients with ulcerative colitis (5/14), 80% patients with Crohn's disease (12/15), and only one clinically healthy control subject (1/16; 6%). The obtained results are considered to be proof of cellular hypersensitivity of IBD patients to colicins of their own E. coli strains. In several colicins the antitumorous effect has been reported in both the in vitro and in vivo experimentation. The second part of this work was concerned with colicinogeny in colorectal cancer. Colicinogenic E. coli were evidenced in 42 subjects (40%) from 105 patients with colorectal carcinoma. Controls showed colicinogenic E. coli in 102/160 clinically healthy subjects (64%), and the difference was as significant as p less than 0.05. In colorectal cancer group, the subjects with proved colicinogeny showed lesser amounts of colicinogenic E. coli strains in contrast with non-colicinogenic ones. In colorectal cancer patients with colicinogenic E. coli strains, B and M colicins were of most frequent occurrence in them no antitumorous effect has been experimentally stated. If changes of colicinogeny were only either the manifestation or consequence of tumor disease, so both the presence or absence of colicinogenic E. coli would have been dependent of clinical patients's condition, stage of disease (in accord with Dukes) or correlated with the tumor markers. For these accounts, a total of 28 colorectal cancer patients underwent a colicinogenic study. However, no colicinogeny dependence was evidenced of either clinical condition or Dukes stage, showing no correlation with any of cancer markers investigated (carcinoembryonic antigen, CA 19-9, alfa-1-fetoprotein, alfa-1-orosomucoid, Cancer serum index, sialic acid, lysozyme).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1998

Local and systemic effects of macrophage cytokines in intestinal inflammation.

The activation of macrophages and newly recruited monocytes appears to be common to both Crohn's disease and ulcerative colitis, despite different inductive stimuli. Similar activation occurs acutely during the course of invasive intestinal infections such as shigellosis, but is then usually downregulated. The macrophage cytokines tumor necrosis factor-alpha and interleukin-1 (IL-1) are centrally involved in the local inflammatory response, and blockade of either cytokine greatly attenuates the inflammatory lesion. Induction of focal vascular thrombosis and matrix degradation are thought to be an important component of this focal damage. Both cytokines and IL-6 are now recognized to contribute to the systemic effects of intestinal disease, including growth suppression, anorexia, and chronic anemia. Disturbance of sleep patterns, mood, and affect may also occur, and recent evidence points towards bidirectional interplay between macrophage cytokines and central nervous system function.

Colitis, Ulcerative↗
PubMed2001

The role of polyunsaturated fatty acid supplementation in intestinal inflammation and neonatal necrotizing enterocolitis.

Dietary polyunsaturated fatty acid (PUFA) supplementation has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in a recent randomized, controlled trial. These compounds are known to modulate the inflammatory cascade and to influence intestinal health in a variety of ways. Although the pathophysiology of NEC is not well understood, recent evidence suggests that platelet-activating factor (PAF) is a key endogenous mediator of intestinal necrosis in animals. Using a neonatal rat model of NEC that includes the key risk factors of asphyxia and formula feeding, we investigated the role of dietary PUFA supplementation on the incidence and pathophysiology of NEC. Our findings suggest that PUFA reduce the incidence of NEC by modulating PAF metabolism and endotoxin translocation.

Animals↗
PubMed2000

Intestinal inflammation in cystic fibrosis.

BACKGROUND: There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS: To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS: Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha(1) antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1beta) were measured. RESULTS: Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS: These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.

Adolescent↗
PubMed1998

Leucocyte endothelial cell adhesion in indomethacin induced intestinal inflammation is correlated with faecal pH.

BACKGROUND: Recent studies indicate that faecal pH is acidified in patients with inflammatory bowel disease compared with healthy controls. In healthy volunteers, stool pH, faecal flora, and bile acid concentration could be affected by means of elemental diets. AIMS: To assess the role of variations of faecal pH on leucocyte endothelial cell adhesion in indomethacin induced long lasting ileitis in rats. METHODS: Indomethacin (7.5 mg/kg subcutaneously) was injected twice, 24 hours apart. Rats were either fed with the identical diet before and 10 days after the induction of inflammation until the experiment, or the diet was changed at the time of induction. Ten postcapillary mesenteric venules (30 microns diameter) per animal were observed using intravital microscopy. Macroscopic visible intestinal ulceration was scored and faecal pH of different sections of the small bowel was determined. RESULTS: Small intestinal faecal pH was 8.5 in controls and 8.0 in indomethacin treated animals. Indomethacin significantly changed microcirculatory parameters: there was a 2.3-fold increase in leucocyte adherence, a 3.2-fold increase in leucocyte emigration, and a 20% reduction in shear rate. Application of various diets or diet combinations resulted in variations in faecal pH ranging from 7.8 to 8.8 which were inversely correlated with macroscopic ulcerations (r = -0.67). Leucocyte adherence was attenuated with increased pH and augmented with decreased pH (r = -0.55). Venular wall shear rate was positively correlated with faecal pH (r = 0.48) while leucocyte emigration showed no correlation. Leucocyte rolling velocity was not significantly altered. Normalisation of faecal pH by different alkalising drugs induced a significant decrease in leucocyte adherence in standard fed, indomethacin treated rats. CONCLUSIONS: Faecal pH is lowered in the indomethacin model of long lasting ileitis in rats, which is similar to human inflammatory bowel disease. Alkalisation of faecal pH due to different diets or alkalising drugs reduces indomethacin induced leucocyte endothelial cell adhesion and macroscopic intestinal damage. These results may provide a rationale for the therapeutic effect of enteral diets in Crohn's disease.

Animals↗
PubMedDate not supplied

Intestinal inflammation and the gut microflora.

The idea that the enteric microflora play a role in the pathogenesis or pathophysiology of inflammatory bowel disease (IBD) is not new. Indeed, identification of an infective cause for chronic IBD, and particularly for Crohn's disease, has been the focus of extensive research efforts. During the 1990s, there has been a noticeable re-emergence of interest in the link between bacteria and functional bowel disorders, and the value of antibiotic therapy to treat gut inflammatory disorders. A variety of experimental evidence from both laboratory model systems and clinical investigations is reviewed with respect to a pivotal role for enteric bacteria in gut inflammation. The voluminous scientific literature on this subject precludes any comprehensive synopsis of the area; instead, pertinent studies are cited to illustrate the ability of bacteria and their products to evoke or exacerbate gut inflammation.

Animals↗
PubMed1999

An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.

A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

Animals↗
PubMed2003

Relative roles of ICAM-1 and VCAM-1 in the pathogenesis of experimental radiation-induced intestinal inflammation.

PURPOSE: Cell adhesion molecules mediate leukocyte recruitment into the irradiated organs; modulation of this process may protect from radiation damage. Our objective was to characterize the requirement for intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in intestinal inflammatory response after abdominal irradiation. METHODS AND MATERIALS: Endothelial ICAM-1 and VCAM-1 expression was determined using radiolabeled antibodies in mice 24 h and 14 days after irradiation with 10 Gy, or sham radiation. Leukocyte-endothelial cell interactions in intestinal venules were assessed using intravital microscopy, and the function of ICAM-1 and VCAM-1 in this process by using blocking antibodies and ICAM-1(-/-) mice. RESULTS: The number of adherent leukocytes significantly increased 24 h after irradiation and remained elevated at 14 days. Treatment with anti-ICAM-1 antibodies and ICAM-1 genetic deficiency significantly reduced leukocyte adhesion 24 h after irradiation. At 14 days after irradiation, both wild-type and ICAM-1(-/-) mice had an upregulation of VCAM-1, expression, and VCAM-1 immunoneutralization, but not ICAM-1 immunoneutralization, significantly reduced leukocyte adhesion. In ICAM-1(-/-) mice, regeneration of the intestinal epithelium was enhanced relative to wild-type mice. CONCLUSIONS: ICAM-1 plays a key role in leukocyte recruitment at early time points after abdominal irradiation, whereas VCAM-1 is the main molecular determinant of leukocyte recruitment at late time points.

Animals↗
PubMed2006

Posttranslationally modified proteins as mediators of sustained intestinal inflammation.

Oxidative and carbonyl stress leads to generation of N(epsilon)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-kappaB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-kappaB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-kappaB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-kappaB activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-kappaB activation, lasting 5 days, was primarily inhibited by either depletion of CML-mps or by the addition of sRAGE, p44/42 and p38 MAPKinase-specific inhibitors. Consistently, CML-mps isolated from inflamed gut areas and rectally applied into mice caused NF-kappaB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE-/- mice. A comparable up-regulation of NF-kappaB and inflammation on rectal application of CML-mps was observed in IL-10-/- mice. Thus, CML-mps generated in inflammatory lesions have the capacity to elicit a RAGE-dependent intestinal inflammatory response.

Adult↗
PubMed1997

[Hepatobiliary complications of idiopathic intestinal inflammations].

Extraintestinal manifestations and metabolic complications are very frequent in patients with idiopathic inflammations of the gut and are encountered in at least 35% of these patients. In Crohn's disease extraintestinal manifestations are more frequent than in ulcerative colitis, in particular when the large bowel is affected. Metabolic complications are the result of inflammatory changes of the small intestine or develop as a result of the reduced reabsorption surface of the gut. As to the relationship to the activity of the idiopathic inflammation of the gut, extraintestinal manifestations can be differentiated into those which depend on the activity of the basic disease and those which lack this dependence. From the aspect of a long-term prognosis extraintestinal manifestation independent on the activity of the inflammation of the gut are much more serious, because as a rule they have a long-term and usually progressive trend. The most serious extraintestinal complication is primary sclerotizing cholangitis which in the majority of patients leads to destruction of the biliary pathways and the development of biliary cirrhosis. Depending on the predominantly affected site of the biliary system, primary sclerotizing cholangitis is divided into three types. It is encountered much more frequently in ulcerative colitis than in Crohn's disease. Treatment of primary sclerotizing cholangitis is not very effective. At present it appears that the only drug with an effect on the course of the disease is long-term administration of urodesoxycholic acid. For patients with manifestations of hepatic insufficiency the only solution is transplantation of the liver. In all patients where the diagnosis of primary sclerotizing cholangitis was established, at the same time the possibility of inclusion in a transplantation programme should be considered. The relationship between sclerotizing cholangitis and pericholangitis has not been resolved conclusively. At present the majority of authors is inclined to believe that pericholangitis is part of changes associated with sclerotizing cholangitis. Other hepatobiliary complications of idiopathic inflammations of the gut such as cholelithiasis and parenchymatous liver damage, steatosis of the liver and chronic autoimmune hepatitis are not such a serious problem as sclerotizing cholangitis.

Biliary Tract Diseases↗
PubMed2001

Stress and the Gastrointestinal Tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance.

The stress response in a healthy organism is generally viewed as a warning and thus a protective reaction to a threat. However, the response may be deleterious if it is linked to an inflammatory stimulus or if it proceeds an inflammatory event. Prior stress enhances the response to an inflammatory stimulus by a mechanism that is independent of the release of hypothalamic corticotropin-releasing factor (CRF) or arginine vasopressin. Putative mechanisms include an increase in intestinal permeability as well as the release of the proinflammatory neuropeptide substance P. Stress may also reactivate previous inflammation when applied in conjunction with a small luminal stimulus. This reactivation involves increased permeability and requires the presence of T lymphocytes. Inflammatory mediators activate hypothalamic pathways, and a negative feedback loop, mediated by CRF release, has been proposed because animals with impaired hypothalamic CRF responses are more susceptible to inflammatory stimuli. Together, these experimental observations provide insights into the expression of inflammatory disorders in humans, including inflammatory bowel disease and postinfective irritable bowel syndrome.

Animals↗
PubMed2004

Induced nitric oxide promotes intestinal inflammation following hemorrhagic shock.

In hemorrhagic shock (HS), increased cytokine production contributes to tissue inflammation and injury through the recruitment of neutrophils [polymorphonuclear cells (PMN)]. HS stimulates the early expression of inducible nitric oxide synthase (iNOS) that modulates proinflammatory activation after hemorrhage. Experiments were performed to determine the contribution of iNOS to gut inflammation and dysmotility after HS. Rats subjected to HS (mean arterial pressure 40 mmHg for 2.5 h followed by resuscitation and death at 4 h) demonstrated histological signs of mucosal injury, impairment of intestinal smooth muscle contractility, extravasation of PMN, and increased gut mRNA levels of ICAM-1, IL-6, and granulocyte colony-stimulating factor (G-CSF). In addition, DNA binding activity of NF-kappaB and Stat3, an IL-6 signaling intermediate, was significantly increased. In shocked rats treated with the selective iNOS inhibitor l-N(6)-(1-iminoethyl)lysine at the time of resuscitation, histological signs of intestinal injury and PMN infiltration were reduced and muscle contractility was almost completely restored. Selective iNOS inhibition in shocked animals reduced the binding activity of NF-kappaB and Stat3 and reduced mRNA levels of ICAM-1, IL-6, and G-CSF. The results of studies using iNOS knockout mice subjected to HS were similar. We propose that early upregulation of iNOS contributes to the inflammatory response in the gut wall and participates in the activation of signaling cascades and cytokine expression that regulate intestinal injury, PMN recruitment, and impaired gut motility.

Animals↗
PubMed1995

[Anders Jahre Prize for young researchers 1994. Chronic intestinal inflammation studies with multi-colored immunohistochemistry].

Multi-colour immunofluorescence can be a potent tool in investigating the cause of chronic inflammation of unknown etiology. The immune system uses two main mechanisms for target destruction; antibody-induced, complement-mediated or cell-mediated lysis. Immunohistochemical tracing of complement activation and immunoglobulin deposition in intestinal lesions from patients with ulcerative colitis and Crohn's disease show that ulcerative colitis may be an autoimmune disease characterized by an autoantibody of the IgG1 subclass to an apically located colonic autoantigen, which induce in situ complement activation and cellular lysis. The apical immune complex deposits co-localized with a previous identified putative autoantigen of 40kD, with peptide sequence homology with tropomyosin. Coeliac disease is a mucosal hypersensitivity to the wheat protein gluten. The intestinal lesion shows a peculiar disease specific increased percentage of T cell receptor (TCR)gamma/delta cells in the epithelium; differential use of CD45-isoforms and proliferative activation of intraepithelial T cells. T-helper(CD4) cells in the lamina propria show a non proliferative activation (CD25) which can be induced after gluten challenge in vitro. Immunomagnetic isolation of such in vitro activated T cells renders it possible to establish gluten reactive T cell clones that respond to gluten presented in the context of the disease associated human leucocyte antigen HLA-DQ2.

Autoantibodies↗
PubMed2004

Glutamine decreases lipopolysaccharide-induced intestinal inflammation in infant rats.

Using a gastrostomy-fed (GF) rat infant "pup-in-a-cup" model, the effects of protein deprivation and supplemental glutamine (Gln) and glutamate (Glu) were examined to test the hypothesis that Gln decreases the proinflammatory response induced by LPS in the developing infant rat small intestine. Four groups of 6- to 7-day-old pups were fed a rat milk substitute (RMS), one providing 100% and three providing 25% of normal protein intake for another 6 days. Two of the 25% protein-fed groups received supplemental Gln or Glu. GF and LPS treatment blunted body growth and intestinal villus height and increased intestinal cytokine-induced neutrophil chemoattractant (CINC) mRNA in the protein-deprived, non-Gln-treated group compared with mother-fed pups (P < 0.05). Gln blunted intestinal CINC mRNA (P < 0.05), but Glu did not. Intestinal CINC peptide in the LPS-treated pups provided 100 and 25% protein was elevated approximately 13-fold compared with the mother-reared pups (P < 0.001). Gln and Glu decreased intestinal CINC peptide by 73 and 80%, respectively. GF, LPS-treated pups also had a higher level of plasma CINC peptide (P < 0.05). Gln but not Glu decreased plasma CINC peptide (P < 0.05). An approximate sixfold elevation of intestinal MPO activity in the GF, LPS-treated rats was decreased by Gln and Glu by 92% (P < 0.001) and 54% (P < 0.05), respectively. Intestinal and plasma TNF-alpha were increased in GF, LPS-treated pups (P < 0.01), and Gln and Glu both blunted this increase (P < 0.05) in the intestine but not in the plasma. The results indicate that Gln decreases the LPS-induced inflammatory response in infant rat intestine under different conditions of protein intake.

Animals↗