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At least 955 records · Page 53Linked to original sources
PubMed2004

Connexin 26-mediated gap junctional intercellular communication suppresses paracellular permeability of human intestinal epithelial cell monolayers.

In some cell types, gap junctional intercellular communication (GJIC) is associated with tight junctions. The present study was performed to determine the roles of GJIC in regulation of the barrier function of tight junctions. Caco-2 human colonic cells were used as a monolayer model, and barrier function was monitored by measuring mannitol permeability and transepithelial electrical resistance (TER). The monolayers were chemically disrupted by treatment with oleic acid and taurocholic acid. Western blotting analyses were performed to evaluate the protein levels of connexins, which are components of gap junctional intercellular channels. Cx26 expression was detected in preconfluent Caco-2 cells, and its level increased gradually after the monolayer reached confluency. These results prompted us to examine whether overexpression of Cx26 affects barrier function. Monolayers of Caco-2 cells stably expressing Cx26 showed significantly lower mannitol permeability and higher TER than mock transfectants when the monolayers were chemically disrupted. The levels of claudin-4, an important component of tight junctions, were significantly increased in the stable Cx26 transfectant. These results suggest that Cx26-mediated GJIC may play a crucial role in enhancing the barrier function of Caco-2 cell monolayers.

Caco-2 Cells↗
PubMed1995

Colitis and colonic mucosal barrier dysfunction.

Trauma, infection, neoplasia, and inflammation can all disrupt the intact intestinal mucosal barrier to intraluminal bacteria and bacterial antigens. This study investigated the relation between colonic inflammation and colonic mucosal barrier function in three experimental models of colitis. There were significantly increased systemic endotoxin concentrations in rats with acetic acid (7.5 (1.7-119.5) pg/ml), ethanol (13.7 (0-111.2) pg/ml), and hapten induced (14.4 (5-31.1) pg/ml) colitis compared with saline controls (3.3 (0-13.7) pg/ml). Data expressed as median (range). There were significant correlations between the systemic endotoxin concentration and both the severity of colitis and of illness in acetic acid induced colitis. A significant increase in colonic permeability to 14C-polyethylene glycol was shown in rats with acetic acid (3.42 (1.36-5.63)%) and hapten induced colitis (2.86 (1.03-8.10)%) compared with saline controls (1.20 (0.67-1.36)%). Data expressed as median (range) of percentage of the intracolonic bolus excreted in urine. There was a significant positive correlation between the severity of colitis and % colonic permeability to 14C-polyethylene glycol. This and other studies provide evidence that mucosal barrier dysfunction is a feature of colitis irrespective of aetiology or species. Such barrier dysfunction may be responsible for the systemic inflammatory response and complications seen in patients with inflammatory bowel disease.

Acetates↗
PubMed2003

Antimicrobial peptides in innate immunity of the human intestine.

The intestinal mucosa has to withstand exposure to a variety of substances, challenges in pH, temperature, and osmolarity; and, finally, bacterial products which might induce local and systemic inflammatory responses. The mucosal integrity is conserved by a defense system which consisting of constitutive and inducible mechanisms. These include the physical barrier function; the secretion of factors into the lumen, such as mucins and antibacterial substances; the mucosal immune system; and, finally, the ability of the mucosa to reconstitute once damage has occurred. The homeostasis and integrity of the gastrointestinal mucosa ultimately depends upon the balance between defensive and aggressive factors. While the physical barrier function was formerly believed to play the major role in mucosal protection against luminal bacteria, the recent discovery of Toll-like receptors and antimicrobial peptides in the intestinal epithelium has modified the concept of intestinal defense towards a more active character, which will be discussed in this review.

Antimicrobial Cationic Peptides↗
PubMed2005

Hyperresponsiveness of the mucosal barrier in Crohn's disease is not tumor necrosis factor-dependent.

BACKGROUND: Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. We studied whether reducing inflammation and restoring gut barrier dysfunction with anti-tumor necrosis factor (TNF) antibody treatment also antagonizes the permeability increase by oral nonsteroidal anti-inflammatory drug intake in patients with CD. METHODS: Thirty-one healthy control subjects and 25 patients with active CD were studied. The 31 controls performed intestinal permeability testing for Cr-EDTA before (baseline) and after oral intake of indomethacin (50 + 75 mg). Twenty-five patients carried out a baseline and indomethacin-mediated permeability test before infliximab infusion. The patients repeated either the indomethacin test (12/25) or baseline and indomethacin tests (13/25), 1 month after this treatment. Intestinal permeability was studied by measurement of urinary excretion of Cr-EDTA after oral intake. RESULTS: Increased whole gut permeation before treatment (3.16%; interquartile range [IQR], 2.92-5.72) was restored to normal values (2.47%; IQR, 1.97-2.78) by anti-TNF treatment. Indomethacin increased whole gut permeability significantly more in patients with CD (before anti-TNF: 6.50%; IQR, 4.84-10.38; after anti-TNF: 5.50%; IQR, 3.97-10.09) compared with the healthy subjects (4.66%; IQR, 3.51-5.64). Eleven of 25 patients (44%) had an abnormal whole gut permeability response to indomethacin before anti-TNF, and 9 of them remained hyperresponsive after infusion, despite clinical remission. CONCLUSIONS: Although anti-TNF treatment suppresses inflammation and restores gut barrier function in patients with CD, it does not antagonize the barrier hyperresponsiveness to indomethacin. These data support the notion of an underlying intestinal mucosal barrier hyperresponsiveness in a subset of patients with CD, independent of inflammation.

Adult↗
PubMed1996

Heparan preserves intestinal perfusion after hemorrhage and resuscitation.

BACKGROUND: Multiple system organ failure (MOF) remains a major source of morbidity and mortality in trauma patients. Despite restoration of central hemodynamics, intestinal hypoperfusion can persist. Mucosal ischemia and barrier breakdown are factors in the genesis of MOF. Heparan sulfate is a gycosaminoglycan similar to heparin, but with minimal anticoagulant properties. As an adjunct to resuscitation, it improves immunologic function and restores mucosal oxygenation and function. We hypothesized that resuscitation with heparan following hemorrhage wound prevents intestinal hypoperfusion. MATERIALS AND METHODS: In vivo videomicroscopy was used to study small intestine microcirculation in rats. Animals were hemorrhaged to 50% of baseline mean arterial pressure (MAP) and maintained there. Resuscitation was initiated when the return of 10% shed blood was required to keep MAP at 50%. Animals received either heparan (7 mg/kg/1 ml saline) or saline (1 ml) followed by the remaining shed blood and an equal volume of saline. MAP, cardiac output (CO), A1 arteriole diameters, and flow were determined. RESULTS: Resuscitation of the saline control group resulted in normal MAP with elevation of CO to 25-40% above baseline. The heparan group had return of MAP but only a moderate increase in CO (7-15%). Saline resuscitation led to progressive deterioration in A1 diameters and flow. The addition of heparan prevented delayed A1 constriction and significantly improved perfusion. CONCLUSIONS: Heparan prior to resuscitation improved intestinal perfusion, despite a relative reduction in CO. Improvement in nutrient blood flow may protect the mucosal barrier, reducing the incidence of MOF, and suggests that heparan may be useful in resuscitation of trauma patients.

Animals↗
PubMed2005

Assessment of a bioactive compound for its potential antiinflammatory property by tight junction permeability.

Lactobacillus probiotic strains are proving to be abundant sources of bioactive components, including antiinflammatory components. Lifree was made of fruits fermented by Lactobacillus paracasei, Lactobacillus reuterrii and Saccharomyces cerevisiae. This study was designed to test these compounds in cell assays measuring epithelial barrier function and proliferation in the first instance. Cell proliferation was measured in mouse fibroblasts cells (3T3NIH) and rat intestinal epithelial cells (IEC-6), and tight junction activity in the kidney epithelial cell line (MDCK). Tight junction permeability was assessed by measuring transepithelial electrical resistance (TER) across confluent monolayers, following the addition of Lifree with or without a challenge with EGTA. Lifree promoted tight junction formation and recovery following loss of TER from challenge with EGTA. On the other hand, Lifree did not stimulate cell growth in either 3T3NIH and IEC-6 cells. Lifree stimulates tight junction maintenance and formation, suggesting it may have potential antiinflammatory properties.

Animals↗
PubMed1993

Murine intestinal mucins inhibit rotavirus infection.

BACKGROUND: Mucin, a population of polymeric glycoproteins, constitutes the primary component of the mucus layer that overlies the gastrointestinal tract. These studies aimed to determine whether murine intestinal mucins inhibit rotavirus infection. METHODS: Murine intestinal mucins were obtained by scraping segments of mouse intestine and purification via CsCl gradient centrifugation and sepharose 4B chromatography. Inhibition of infection was determined by quantitation of immunoperoxidase-stained cells after infection with mucin-rotavirus mixtures. RESULTS: Crude and purified intestinal mucins from suckling and adult mice are potent inhibitors of replication of a simian rotavirus, rhesus rotavirus (RRV), but weak inhibitors of other rotaviruses. In all preparations, colonic mucins were more potent inhibitors of RRV than small intestinal mucins. Suckling mucins neutralized RRV more effectively than adult mucins. In a panel of rotavirus reassortants, susceptibility to mucin inhibition correlated with the ability to hemagglutinate human type O erythrocytes and with RRV gene 4. Murine intestinal mucin inhibited RRV binding to MA104 cells, suggesting inhibition of virus-cell attachment to be the mechanism for neutralization. Mercaptoethanol or neuraminidase inhibited mucins' anti-RRV activities, implying the functional importance of mucins' polymeric structure and sialic acid content. CONCLUSIONS: These findings suggest that intestinal mucins represent a barrier to certain rotavirus infections.

Animals↗
PubMed2006

Coupling between apical and paracellular transport processes.

Transcellular transport affects the paracellular flux through 2 distinct mechanisms: by determining the driving force and by altering the permeability of the paracellular pathway. Such coordination ensures efficient transepithelial transport by preventing the build-up of large electrical and osmotic gradients. The regulation of paracellular permeability was originally recognized as increased paracellular flux of water and solutes upon the activation of the intestinal Na+-coupled glucose uptake. Despite great advances in the molecular characterization of the tight junctions that form the structural basis of epithelial barrier functions, the mechanisms whereby apical transporters alter the paracellular pathways remains unresolved. Recent studies suggest that myosin-based contractility is central to this coupling. In this minireview, we summarize our current knowledge of paracellular permeability, its regulation by contractility, and the various signaling events that link apical Na+-glucose cotransport to myosin phosphorylation. While the role of myosin phosphorylation appears to be universal, the mechanism(s) whereby apical transport triggers this process is likely cell specific. The current model suggests that in intestinal cells, a key factor is a p38 MAP kinase-induced Na+/H+-exchanger-mediated alkalinization. We propose an alternative, nonexclusive mechanism in kidney tubular cells, in which the key event may be a Na+-cotransport-triggered plasma membrane depolarization, which in turn leads to Rho-mediated myosin phosphorylation.

Biological Transport↗
PubMed2001

Intracellular organization of insulin signaling and GLUT4 translocation.

Glucose is cleared from the bloodstream by a family of facilitative transporters (GLUTs), which catalyze the transport of glucose down its concentration gradient and into cells of target tissues, primarily striated muscle and adipose. Currently, there are five established functional facilitative glucose transporter isoforms (GLUT1-4 and GLUTX1), with GLUT5 being a fructose transporter. GLUT1 is ubiquitously expressed with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. GLUT3 is expressed primarily in neurons and, together, GLUT1 and GLUT3 allow glucose to cross the blood-brain barrier and enter neurons. GLUT2 is a low-affinity (high Km) glucose transporter present in liver, intestine, kidney, and pancreatic beta cells. This transporter functions as part of the glucose sensor system in beta cells and in the basolateral transport of intestinal epithelial cells that absorb glucose from the diet. A new facilitative glucose transporter protein, GLUTX1, has been identified and appears to be important in early blastocyst development. The GLUT4 isoform is the major insulin-responsive transporter that is predominantly restricted to striated muscle and adipose tissue. In contrast to the other GLUT isoforms, which are primarily localized to the cell surface membrane, GLUT4 transporter proteins are sequestered into specialized storage vesicles that remain within the cell's interior under basal conditions. As postprandial glucose levels rise, the subsequent increase in circulating insulin activates intracellular signaling cascades that ultimately result in the translocation of the GLUT4 storage compartments to the plasma membrane. Importantly, this process is readily reversible such that when circulating insulin levels decline, GLUT4 transporters are removed from the plasma membrane by endocytosis and are recycled back to their intracellular storage compartments. Therefore, by establishing an internal membrane compartment as the default localization for the GLUT4 transporters, insulin-responsive tissues are poised to respond rapidly and efficiently to fluctuations in circulating insulin levels. Unfortunately, the complexity of these regulatory processes provides numerous potential targets that may be defective and eventually result in peripheral tissue insulin resistance and possibly diabetes. As such, understanding the molecular details of GLUT4 expression, GLUT4 vesicle compartment biogenesis, GLUT4 sequestration, vesicle trafficking, and fusion with the plasma membrane has become a major focus for many laboratories. This chapter will focus on recently elucidated insulin signal transduction pathways and GLUT4 vesicle trafficking components that are necessary for insulin-stimulated glucose uptake and GLUT4 translocation in adipocytes.

Adipose Tissue↗
PubMed1997

Intestinal protein leakage in the acquired immunodeficiency syndrome.

Body wasting, protein catabolism, and hypoalbuminemia are complicating features of the acquired immunodeficiency syndrome (AIDS). Given their multifactorial causes, the contributing role of intestinal protein loss has not yet been fully elucidated. To quantify enteric protein leakage, determination of fecal alpha 1-antitrypsin (AAT) excretion has been established as an accurate and reliable endogenous marker. We estimated AAT concentration by standard immune nephelometry in duplicate random stool samples of 49 patients with AIDS, and we compared it to that of 43 patients with chronic inflammatory bowel disease and to 34 healthy controls. When compared with healthy persons, patients with AIDS had increased fecal AAT excretion regardless of current opportunistic intestinal infections and fecal AAT excretion similar to that of patients with quiescent chronic inflammatory bowel disease. The ratio of fecal and serum AAT concentration was not different between AIDS patients and healthy controls, although it was consistently increased in those with chronic inflammatory bowel disease. Significant intestinal protein leakage occurs in patients with AIDS, probably due to primary impairment of gut permeability. Enteric protein loss may be an important feature of human immunodeficiency virus-associated enteropathy with altered mucosal barrier function.

AIDS-Related Opportunistic Infections↗
PubMed1991

Neutrophil-epithelial cell interactions in the intestine.

PMN transmigration across intestinal epithelia and into crypt lumens is a hallmark of active intestinal disease. Models of the transmigratory event indicate that movement of PMN across intercellular tight junctions transiently increases junctional permeability, thus decreasing epithelial barrier function. Once accumulated in the lumen, activated PMN may release unidentified mediators which activate the epithelial transport mechanisms responsible for secretory diarrhea. Further characterization of such epithelial-PMN interactions may allow identification of rational treatment strategies aimed at intervening in the epithelial dysfunction characterizing this type of cell-cell interaction.

Cell Communication↗
PubMed2006

Can nutraceuticals affect the structure of intestinal mucosa? Qualitative and quantitative microanatomy in L-glutamine diet-supplemented weaning piglets.

Weaning piglets were fed an L-glutamine-supplemented diet with the aim of monitoring the effects on gut mucosal turnover and barrier function, to elucidate the potential preventive or therapeutic roles of glutamine as a nutraceutical or 'functional food'. Sixteen female weaning piglets were divided into two groups, which were fed a control diet (Ctr group: n = 8) or a Ctr + 0.5% L-glutamine diet (G group: n = 8) for 28 days. In the ileum of group G piglets the villus height (V) and crypt depth (C) were increased, and the V:C ratio was decreased (p < 0.01). The PCNA and TUNEL immunoreactivities were also tested. The number of mitotic mucosal cells (M) was increased, and that of mucosal cells with apoptotic nuclei (A) decreased in such a way that the A:M index diminished (p < 0.01). The A:M index also decreased at the level of some components of the gut-associated lymphatic tissue (GALT), thus indicating a positive effect on the gut barrier function. This trial showed that L: -glutamine supplementation influenced some morphofunctional characteristics of piglet ileal mucosa. These data corroborate the nutraceutical role of glutamine as a trophic agent for mucosal repair, improvement of barrier function and gut adaptation in the swine per se and as an animal model.

Animal Feed↗
PubMed2000

Charge-dependent interaction of self-emulsifying oil formulations with Caco-2 cells monolayers: binding, effects on barrier function and cytotoxicity.

A positively charged self-emulsifying oil formulation (SEOF), aimed to enhance oral bioavailability of drugs poorly soluble in water, was recently developed. In the present study the Caco-2 cell model was used for the investigation of the charge-dependent interactions of this SEOF with human intestinal epithelial cells. The positively charged emulsions affected the barrier properties of the cell monolayer at high concentrations and reduced the cell viability. However, at the dilution with aqueous phase used in the present study (1:2000), the positively charged SEOF did not induce any detectable cytotoxic effect. The binding of the fluorescent dye DiIC(18)(3) was much higher from the positively charged SEOF, compared to the negatively charged formulation, suggesting an increased closer adhesion of the droplets to the cell surface due to the electrostatic attraction. No transepithelial transport of this compound across Caco-2 cell monolayers was observed with any SEOF formulation.

Amines↗
PubMed1999

Cow's milk and type 1 diabetes: the real debate is about mucosal immune function.

The hypothesis that early exposure of the infant to cow's milk (or lack of breast-feeding) predisposes the child to type 1 diabetes dates from the 1980s. It has important implications, but remains controversial because the evidence on which it is based has been indirect and is open to criticism. Two meta-analyses of multiple studies in which diabetes prevalence was associated retrospectively with infant feeding revealed only a marginal increase in relative risk. Two recent prospective studies found no apparent association between development of antibodies to islet antigens and feeding patterns in high-risk infants with a first-degree type 1 diabetic relative. Studies reporting increased humoral and cellular immunity to cow's milk proteins in children with type 1 diabetes often lack appropriate controls and standardization and do not, in themselves, establish a causal connection to disease pathogenesis. A review of published data leads to the conclusion that increased immunity to cow's milk proteins is not disease-specific, but reflects genetic predisposition to increased immunity to dietary proteins in general, associated with the HLA haplotype A1-B8-DR3-DQ2 (A1*0501, B1*0201), which also predisposes to celiac disease and selective IgA deficiency. We suggest that the cow's milk hypothesis could be productively reframed around mucosal immune function in type 1 diabetes. Breast milk contains growth factors, cytokines, and other immunomodulatory agents that promote functional maturation of intestinal mucosal tissues. In the NOD mouse model, environmental cleanliness may influence diabetes incidence through mucosal mechanisms, and exposure of the mucosa to insulin (present in breast milk) induces regulatory T-cells and decreases diabetes incidence. The mucosa is a major immunoregulatory barrier, and cow's milk happens to be the first dietary protein it encounters. The basic question is whether impaired mucosal immune function predisposes to type 1 diabetes.

Animals↗
PubMed1998

Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells.

The high concentration of foreign antigen in the lumen of the gastrointestinal tract is separated from the underlying lymphocytes by a single cell layer of polarized epithelium. Intestinal epithelial cells can express HLA class II antigens and may function as antigen-presenting cells to CD4(+) T cells within the intestinal mucosa. Using tetanus toxoid specific and HLA-DR-restricted T lymphocytes, we show that polarized intestinal epithelial cells directed to express HLA-DR molecules are able to initiate class II processing only after internalization of antigen from their apical surface. Coexpression of the class II transactivator CIITA in these cells, which stimulates highly efficient class II processing without the characteristic decline in barrier function seen in polarized monolayers treated with the proinflammatory cytokine gamma-IFN, facilitates antigen processing from the basolateral surface. In both cases, peptide presentation to T cells via class II molecules was restricted to the basolateral surface. These data indicate a highly polarized functional architecture for antigen processing and presentation by intestinal epithelial cells, and suggest that the functional outcome of antigen processing by the intestinal epithelium is both dependent on the cellular surface at which the foreign antigen is internalized and by the underlying degree of mucosal inflammation.

Anti-Bacterial Agents↗
PubMed2001

Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse.

The pathogenesis of Crohn's disease likely involves multifactorial interactions between genetic factors and environmental triggers. The most recent studies suggest that luminal bacteria are a significant factor in the onset and chronicity of inflammation. In interleukin-10 (IL-10) gene-deficient mice a Crohn's-like colitis develops when the mice are raised under conventional animal care facilities but fails to develop when they are raised under germ-free conditions. These mice demonstrate significant alterations in the species and the levels of bacteria colonizing the colon, suggesting that genetic factors in the host may be critical in controlling bacterial colonization. In addition, early treatment of IL-10 gene-deficient mice with antibiotics can prevent the development of colitis in later life, suggesting that early events during the neonatal period can influence later disease progression. Recent work has focused on using probiotic bacterial mixtures to alter the microbial balance in the colon in attempts to reduce inflammation. The use of the VSL-3 probiotic mixture in the IL-10 gene-deficient mouse resulted in a complete normalization of physiological transport function and barrier integrity, in conjunction with a reduction in mucosal secretion of TNF-alpha and IFN-gamma. Further, it would appear that a soluble factor is released from a bacterium found in the VSL-3 mixture that can act directly on the epithelium to enhance barrier integrity. Results from animal models of inflammatory bowel disease suggest that genetically susceptible hosts can mount a pathogenic cellular immune response to specific nonpathogenic bacterial species, as a consequence of defective immunologic tolerance and lack of appropriate mucosal defences. Probiotic bacteria appear to be a promising new alternative for the treatment of clinical conditions that are associated with alterations in gut barrier function, including Crohn' s disease.

Animals↗
PubMed1998

The influence of intestinal ischemia and reperfusion on bidirectional intestinal barrier permeability, cellular membrane integrity, proteinase inhibitors, and cell death in rats.

Intestinal ischemia and reperfusion injury (I/R) is probably involved in the pathogenesis of intestinal barrier dysfunction, associated with the concomitant translocation of enteric bacteria and toxins and the potential development of multiple organ failure. The intestinal endothelial and epithelial layers play a major role preventing the entry of toxic substances from the gut, but the influence of protease-antiprotease systemic balance on these barrier functions and the relationship between epithelial DNA synthesis, apoptosis, and endothelial and epithelial barrier macromolecule permeability are not fully investigated. Endothelial and epithelial barrier macromolecular permeability, epithelial DNA synthesis, the endothelial and epithelial plasma membrane system, apoptosis and oncosis, plasma levels of proteinase inhibitors, and proenzymes were measured in rats subjected to 20 and 40 min intestinal ischemia and 1, 3, 6, or 12 h reperfusion. Endothelial permeability increased after both 20 and 40 min intestinal ischemia. Epithelial permeability significantly increased during 1-6 h reperfusion after 20 min ischemia and during 1-12 h reperfusion after 40 min ischemia. Epithelial DNA synthesis increased in animals with 20 min ischemia followed by 12 h reperfusion. Plasma levels of prekallikrein, C1-esterase inhibitor, and alpha1-macroglobulin were significantly lower following both 20 and 40 min ischemia from 3 h reperfusion and on. Apoptotic epithelial cells significantly increased in animals subjected to 20 min ischemia followed by 12 h reperfusion. The severity of reperfusion injury in the intestinal endothelial and epithelial barrier seems to correlate with the period of ischemia and the pathway of cell damage and death, together with proteinase-antiproteinase imbalance.

Albumins↗