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At least 343 records · Page 19Linked to original sources
PubMed2003

Bronchoscopy induces intestinal mucosal barrier dysfunction: a possible role for nitric oxide.

OBJECTIVE: This study investigates the effect of bronchoscopy on intestinal mucosal barrier function and its association with intestinal nitric oxide production. METHODS: 30 rats were used. The study group (n=15) underwent rigid bronchoscopy. At 24 h following bronchoscopy, ileal nitrite/nitrate levels were evaluated. The ileum was also examined for mucosal damage, and graded according Chiu's histologic injury scale. RESULTS: In the bronchoscopy group, the ileal nitrite/nitrate levels were significantly higher than those of controls (398.5 +/- 85.1 and 44.5 +/- 6.6 nmol/g tissue, respectively, P=0.001). In the bronchoscopy group, the mucosal damage was significant, compared with those of controls (mean ranks, 22.8 and 8.2, P<0.0001). The changes varied from denuded villi and dilated capillaries to significant architectural distortion, lamina propria disintegration, ulceration and hemorrhage. Significant correlation was found between ileal nitrite/nitrate levels and mucosal damage in the bronchoscopy group (rs=0.56, P=0.03). CONCLUSION: This study suggests that bronchoscopy induces intestinal mucosal barrier dysfunction in association with excess intestinal nitric oxide production. These events may be involved in mechanisms responsible for bacterial translocation after bronchoscopy.

Animals↗
PubMed2006

Mechanism of glucocorticoid regulation of the intestinal tight junction barrier.

A defective intestinal epithelial tight junction (TJ) barrier has been proposed as an important pathogenic factor contributing to the intestinal inflammation of Crohn's disease. Glucocorticoids are first-line therapeutic agents for the treatment of moderate to severe Crohn's disease. Glucocorticoid treatment has been shown to induce retightening of the intestinal TJ barrier defect in Crohn's disease patients. However, the mechanisms that mediate the glucocorticoid therapeutic action on intestinal TJ barrier function remain unknown. The aim of this study was to elucidate the mechanism of glucocorticoid modulation of the intestinal epithelial TJ barrier using an in vitro model system. Filter-grown Caco-2 intestinal epithelial cells were used as an in vitro model to examine the effects of glucocorticoids on basal intestinal epithelial TJ barrier function and on TNF-alpha-induced disruption of the TJ barrier. Glucocorticoids (prednisolone and dexamethasone) did not have a significant effect on baseline Caco-2 TJ barrier function but prevented the TNF-alpha-induced increase in Caco-2 TJ permeability. The glucocorticoid protective effect against the TNF-alpha-induced increase in Caco-2 TJ permeability required activation of the glucocorticoid receptor (GR) complex. The activation of the GR complex resulted in GR complex binding to the glucocorticoid response element (GRE) site on DNA and activation of a GR-responsive promoter. Glucocorticoids inhibited the TNF-alpha-induced increase in myosin light chain kinase (MLCK) protein expression, a key process mediating the TNF-alpha increase in intestinal TJ permeability. The glucocorticoid inhibition of the TNF-alpha-induced increase in MLCK protein expression was due to the binding of the GR complex to a GRE binding site on the MLCK promoter region suppressing the TNF-alpha-induced activation. Glucocorticoids inhibit the TNF-alpha-induced increase in Caco-2 TJ permeability. The prednisolone protective action was mediated by binding of activated GR complex to the GRE site on the MLCK promoter, suppressing the TNF-alpha-induced increase in MLCK gene activity, protein expression, and subsequent opening of the intestinal TJ barrier.

Active Transport, Cell Nucleus↗
PubMed2006

Prostaglandin-mediated inhibition of Na+/H+ exchanger isoform 2 stimulates recovery of barrier function in ischemia-injured intestine.

Prostaglandins stimulate repair of the ischemia-injured intestinal barrier in the porcine ileum through a mechanism involving cAMP-dependent Cl- secretion and inhibition of electroneutral Na+/H+ exchanger (NHE) activity. In the present study, we focused on the role of individual NHE isoforms in the recovery of barrier function. Ischemia-injured porcine ileal mucosa was mounted on Ussing chambers. Short-circuit current (I(sc)), transepithelial electrical resistance (TER), and isotopic fluxes of 22Na were measured in response to PGE2 and selective inhibitors of epithelial NHE isoforms. Immunoassays were used to assess the expression of NHE isoforms. Forty-five minutes of intestinal ischemia resulted in a 45% reduction in TER (P < 0.01). Near-complete restitution occurred within 60 min. Inhibition of NHE2 with HOE-694 (25 microM) added to the mucosal surface of the injured ileum stimulated significant elevations in TER, independent of changes in I(sc) and histological evidence of restitution. Pharmacological inhibition of NHE3 or NHE1 with mucosal S-3226 (20 microM) or serosal cariporide (25 microM), respectively, had no effect. Ischemia-injured tissues treated with mucosal S-3226 or HOE-694 exhibited equivalent reductions in mucosal-to-serosal fluxes of 22Na+ (by approximately 35%) compared with nontreated ischemia-injured control tissues (P < 0.05). Intestinal ischemia resulted in increased expression of the cytoplasmic NHE regulatory factor EBP50 in NHE2 but not in NHE3 immunoprecipitates. Selective inhibition of NHE2, and not NHE3, induces recovery of barrier function in the ischemia-injured intestine.

Animals↗
PubMed2006

Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection.

BACKGROUND & AIMS: Intestinal epithelial integrity and permeability is dependent on intercellular tight junction (TJ) complexes. How TJ integrity is regulated remains unclear, although phosphorylation and dephosphorylation of the integral membrane protein occludin is an important determinant of TJ formation and epithelial permeability. We have investigated the role intestinal intraepithelial lymphocytes (iIELs) play in regulating epithelial permeability in response to infection. METHODS: Recombinant strains of Toxoplasma gondii were used to assess intestinal epithelial barrier function and TJ integrity in mice with intact or depleted populations of iIELs. Alterations in epithelial permeability were correlated with TJ structure and the state of phosphorylation of occludin. iIEL in vivo reconstitution experiments were used to identify the iIELs required to maintain epithelial permeability and TJ integrity. RESULTS: In the absence of gammadelta+ iIELs, intestinal epithelial barrier function and the ability to restrict epithelial transmigration of Toxoplasma and the unrelated intracellular bacterial pathogen Salmonella typhimurium was severely compromised. Leaky epithelium in gammadelta+ iIEL-deficient mice was associated with the absence of phosphorylation of serine residues of occludin and lack of claudin 3 and zona occludens-1 proteins in TJ complexes. These deficiencies were attributable to the absence of a single subset of gammadelta T-cell receptor (TCR-Vgamma7+) iIELs that, after reconstituting gammadelta iIEL-deficient mice, restored epithelial barrier function and TJ complexes, resulting in increased resistance to infection. CONCLUSIONS: These findings identify a novel role for gammadelta+ iIELs in maintaining TJ integrity and epithelial barrier function that have implications for understanding the pathogenesis of intestinal inflammatory diseases associated with disruption of TJ complexes.

Animals↗
PubMed2000

Enhanced expression of iNOS in inflamed colons of IL-2-deficient mice does not impair colonic epithelial barrier function.

On the basis of recently observed high levels of iNOS expression that correlated with intestinal inflammation in interleukin-2-deficient [IL-2(-/-)] mice, it was postulated that nitric oxide may damage colonic epithelial cells or impair intestinal epithelial barrier function. This damage may result in an increased permeability of the colonic epithelium leading to high antigenic exposure of the intestinal immune system, which may perpetuate chronic inflammation. Our data demonstrate that high expression of iNOS in IL-2(-/-) mice is correlated with the length/weight ratio (L/W ratio), a widely accepted marker for intestinal inflammation. However, no reduction of epithelial resistance was observed, as would be expected in case of a damaged, leaky epithelium. Our results suggest that enhanced formation of NO in IL-2(-/-) mice does not cause impairment of epithelial barrier function.

Animals↗
PubMed2003

Intestinal adherent bacteria and bacterial translocation in breast-fed and formula-fed rats in relation to susceptibility to infection.

The barrier function of the intestinal mucosa is immature in the newborn mammal, and is strengthened by breast milk. We investigated this effect of breast milk by comparing the susceptibility to infection assessed in terms of adherent bacterial colonization of the intestinal tissue (AdC) and bacterial translocation (BT) between breast-fed and formula-fed newborn rats. Three-day-old rat pups were assigned to one of three groups: mother-reared (MR), pseudo-cannulated (sham), and artificially reared (AR). AR rats were infused with formula through an intragastric cannula, under the control of a computer-regulated pumping machine. MR and sham rat pups were reared with their respective dams and received breast milk until weaning in a specially designed cage. In 10-d-old rats, there was no significant difference in the fecal or cecal flora between the AR and MR groups, whereas the AdC and the BT to the liver were greater in the AR than MR group. Enterobacteriaceae, Streptococcus and/or Enterococcus, and Staphylococcus were dominantly detected as microorganisms in AdC flora and BT. The AdC flora did not directly reflect the bacterial colonization flora. These findings suggest that AR rat pups mature normally, although there is a greater colonization of Enterobacteriaceae and BT in AR than MR pups. Consequently, the intestinal barrier function of the pups reared by artificial feeding may become susceptible to BT, and AdC may be more indicative than bacterial colonization of the susceptibility to BT.

Animals↗
PubMed2004

Relationship between protein deficiency in the ration of rats during early ontogeny and function of enzyme systems of digestive and non-digestive organs in adult life.

Low protein content in the ration of rat pups during transfer from mixed to definitive nutrition (days 21-30 of life) has a negative impact on digestive function of the small intestine and trophic and barrier functions of the large intestine, liver, and kidneys and increases (sucrase, glycyl-L-leucin dipeptidase) or decreases (alkaline phosphatase, aminopeptidase M, glycyl-L-leucine dipeptidase) enzyme activities in these organs in 6-month-old rats. Protein deficiency during the early ontogeny modulates functioning of the enzyme systems in digestive and non-digestive organs in adult life, which can lead to the development of not only gastrointestinal, but other visceral diseases.

Alkaline Phosphatase↗
PubMedDate not supplied

Impact of caloric intake on parenteral nutrition-associated intestinal morphology and mucosal barrier function.

BACKGROUND: Parenteral nutrition (PN) is known to induce villus atrophy, epithelial cell (EC) apoptosis, and increase mucosal permeability. The study hypothesized that increasing amounts of energy delivery to mice would result in the best outcome, with the least effects on the mucosa. METHODS: Mice were randomized to enteral controls (saline infusion with ad libitum enteral food) or to 1 of 3 PN groups (with no enteral nutrition): full (100% of daily average energy intake for the mouse), reduced (75% of energy intake) or very low (50% of energy intake). Mice received PN for 7 days. Mucosal morphology, EC apoptosis, and bacterial translocation were assessed. RESULTS: Villus height decreased significantly with decreasing levels of caloric intake and was significantly lower in all PN groups compared with controls. Body weight loss was significantly greater in PN groups vs controls and was greatest in mice with the lowest caloric delivery. A consistent trend toward a higher EC apoptotic index with decreasing caloric intake was observed, and apoptosis in all PN groups exceeded controls (2-fold). All PN groups demonstrated greater bacterial translocation than controls. CONCLUSIONS: PN induces intestinal EC apoptosis and villus and crypt atrophy, even at 100% of predicted energy needs, and such changes increased with greater reduction of energy intake. This study supports a concept that lack of enteral nutrition, rather than absolute caloric levels, is responsible for many of the adverse effects of PN. The study also allows the investigators to better optimize a mouse model of PN delivery.

Animals↗
PubMed1994

Clinical significance of translocation.

The gastrointestinal tract, besides being the organ responsible for nutrient absorption, is also a metabolic and immunological system, functioning as an effective barrier against endotoxin and bacteria in the intestinal lumen. The passage of viable bacteria from the gastrointestinal tract through the epithelial mucosa is called bacterial translocation. Equally important may be the passage of bacterial endotoxin through the mucosal barrier. This article reviews the evidence that translocation of both endotoxin and bacteria is of clinical significance. It summarises recent published works indicating that translocation of endotoxin in minute amounts is a physiological important phenomenon to boost the reticuloendothelial system (RES), especially the Kupffer cells, in the liver. Breakdown of both the mucosal barrier and the RES capacity results in systemic endotoxaemia. Systemic endotoxaemia results in organ dysfunction, impairs the mucosal barrier, the clotting system, the immune system, and depresses Kupffer cell function. If natural defence mechanisms such as lipopolysaccharide binding protein, high density lipoprotein, in combination with the RES, do not respond properly, dysfunction of the gut barrier results in bacterial translocation. Extensive work on bacterial translocation has been performed in animal models and occurs notably in haemorrhagic shock, thermal injury, protein malnutrition, endotoxaemia, trauma, and intestinal obstruction. It is difficult to extrapolate these results to humans and its clinical significance is not clear. The available data show that the resultant infection remains important in the development of sepsis, especially in the critically ill patient. Uncontrolled infection is, however, neither necessary nor sufficient to account for the development of multiple organ failure. A more plausible sequelae is that bacterial translocation is a later phenomenon of multiple organ failure, and not its initiator. It is hypothesized that multiple organ failure is more probably triggered by the combination of tissue damage and systemic endotoxaemia. Endotoxaemia, as seen in trauma patients especially during the first 24 hours, in combination with tissue elicits a systemic inflammation, called Schwartzmann reaction. Interferon gamma, a T cell produced cytokine, is thought to play a pivotal part in the pathogenesis of this reaction. This reaction might occur only if the endotoxin induced cytokines like tumour necrosis factor and interleukin 1, act on target cells prepared by interferon gamma. After exposure to interferon gamma target cells become more sensitive to stimuli like endotoxin, thus boosting the inflammatory cycle. Clearly, following this line of reasoning, minor tissue damage or retroperitoneal haematoma combined with systemic endotoxaemia could elicit this reaction. The clinically observed failure of multiple organ systems might thus be explained by the interaction of tissue necrosis and high concentrations of endotoxin because of translocation. Future therapeutic strategies could therefore focus more on binding endotoxin in the gut before the triggering event, for example before major surgery. Such a strategy could be combined with the start of early enteral feeding, which has been shown in animal studies to have a beneficial effect on intestinal mucosal barrier function and in traumatized patients to reduce the incidence of septic complications.

Animals↗
PubMed1976

[Epithelial barriers of the intestine. Significance and function in defense against infection].

The epithelial surface of the intestinal tract provides for an important barrier between the organism and its environment. However, it permits the passage into the tissues of limited amounts of macromolecules and/or particles, especially bacteria. These functions are age- and species-dependent, and they are closely related to nonspecific and specific immune reactions. Continuous and intimate contact between antigenic material from the gut lumen and immunocompetent cells takes place in gut-associated lymphoid tissues.

Bacterial Infections↗
PubMed2004

Epidermal growth factor prevents acetaldehyde-induced paracellular permeability in Caco-2 cell monolayer.

BACKGROUND: Intestinal permeability and endotoxemia play a crucial role in the pathogenesis of alcoholic liver disease. Previous studies showed that acetaldehyde disrupts intestinal epithelial barrier function and increases paracellular permeability by a tyrosine kinase-dependent mechanism. In the present study, the role of epidermal growth factor (EGF) in protection of epithelial barrier function from acetaldehyde was evaluated in Caco-2 intestinal epithelial cell monolayer. METHODS: Caco-2 cells on Transwell inserts were exposed to acetaldehyde in the absence or presence of EGF, and the paracellular permeability was evaluated by measuring transepithelial electrical resistance and unidirectional flux of inulin. Integrity of epithelial tight junctions and adherens junctions was analyzed by confocal immunofluorescence microscopy and immunoblot analysis of occludin, zonula occludens (ZO)-1, E-cadherin, and beta-catenin in the actin cytoskeleton. Reorganization of actin cytoskeletal architecture was examined by confocal microscopy. RESULTS: Acetaldehyde increased paracellular permeability to inulin and lipopolysaccharide, and EGF significantly reduced these effects of acetaldehyde in a time- and dose-dependent manner. EGF prevented acetaldehyde-induced reorganization of occludin, ZO-1, E-cadherin, and beta-catenin from the cellular junctions to the intracellular compartments. Acetaldehyde treatment induced a reorganization of actin cytoskeletal network and reduced the levels of occludin, ZO-1, E-cadherin, and beta-catenin associated with the actin cytoskeleton. EGF effectively prevented acetaldehyde-induced reorganization of actin cytoskeleton and the interaction of occludin, ZO-1, E-cadherin, and beta-catenin with the actin cytoskeleton. CONCLUSION: These results indicate that EGF attenuates acetaldehyde-induced disruption of tight junctions and adherens junctions and prevents acetaldehyde-induced reorganization of actin cytoskeleton and its interaction with occludin, ZO-1, E-cadherin, and beta-catenin.

Acetaldehyde↗
PubMed1990

Structure and function of the intestinal epithelial barrier in health and disease.

The major and rate-limiting barrier to transepithelial permeation in the intestine is the intercellular tight junction. Tight junction structure is often cell type specific and general but imperfect correlates between tight junction structure and permeability exist. The structure and permeability of this key barrier is not static and can be regulated physiologically. The means of regulation appears to involve the cytoskeleton of neighboring epithelial cells (particularly absorptive cells). Meal-related solutes--nutrients such as glucose--can reversibly enhance the permeability of absorptive cell tight junctions. Although this may substantially enhance the ability of the small intestine to harvest meal-related nutrients, it is conceivable that this may also result in transient exposure of the subepithelial compartment to potentially noxious lumenal compounds. Some features found in many intestinal disease states such as PMN migration across the epithelium may also result in transient barrier defects. With PMN transmigration it is clear that even macromolecules may permeate junctions being impaled by PMNs. When disease processes finally result in focal epithelial denudation, the epithelium has the potential of resealing such defects with remarkable efficiency. The preceding discussion highlights how dynamic the tight junction is and sets the stage for future work aimed at understanding the initial signaling events and intracellular cascade(s) that allow this major barrier to demonstrate such plasticity.

Epithelial Cells↗
PubMed1979

Intestinal structure and function related to toxicology.

The study of toxic effects on small intestinal function is complicated by the integration of the activity of the small intestine with the activities of other regions of the GI tract. Also, the barrier and portal functions of the intestine are not as clearly defined as sometimes assumed. The intestinal surface functions as a barrier to the ingress of large quantities of large water soluble molecules. Lipidic substances enter the body quite readily as do small water-soluble molecules. The small intestinal surface is more a portal than a barrier, with its portal functions divided between nonspecific diffusional entry, which depends on physical properties and electric charge, and entry by specific membrane transport, which depends upon chemical structure. The implications of these properties of the small intestine for toxicological studies are stressed.

Animals↗
PubMed2005

[Influence of hyperoxic fluid on the down-regulated proteins of intestinal mucosa in scalded rats].

OBJECTIVE: To investigate the influence of hyperoxic fluid on the down-regulated proteins of intestinal mucosa in scalded rats, so as to provide a theoretical basis for the clinical use of hyperoxic fluid. METHODS: Sprague-Dawley (SD) rats with 35% TBSA full-thickness scald were randomly divided into scald control (S, n = 6,with intraperitoneal fluid infusion after scalding), hyperoxic (H, n = 6, with hyperoxic fluid infusion after scalding) groups. Six rats without scald injury served as normal group. The proteins in the intestinal mucosa were separated with the two-dimensional electrophoresis (2-DE), and were analyzed with ImageMaster 2D Elite. The influence of hyperoxic fluid on the down-regulated proteins of intestinal mucosa in scalded rats was studied with bio-spectrum, protein bank and document analysis. RESULTS: (1) Among the 34 down-regulated protein spots in S group, 9 of them definitely exhibited up-regulation compared with those in H group. (2) The expression of mitochondrial aconitase, alpha-propionyl-CoA carboxylase, short chain of hydroxyacyl-Coenzyme A dehydrogenase, transcription factor EB (estradiol benzoate), triosephosphate isomerase 1, T cell receptor V delta 6, and dynein-like protein-5 in H group were significantly up-regulated. CONCLUSION: The hyperoxic fluid could up-regulate the down-regulated proteins in rat intestinal mucosa at early postburn stage, so that the barrier function of intestinal mucosa of rats with severe burns could be partially recovered.

Animals↗
PubMed2006

[Influence of carbachol on intestinal dysfunction after traumatic or burn injury].

OBJECTIVE: To investigate the influence of enteral administration of carbachol on the intestinal dysfunction of both severely burn patients and rabbits with partial intestinal ischemia/reperfusion (I/R) injury. METHODS: Seventy-five white rabbits were inflicted with I/R injury and randomized into intestinal I/R (I, n=25), carbachol [C, n=25, with 3g/L carbachol (3 mg/kg) injection into duodenum 1 h after SMA occlusion] and sham operation (SO, n=25, with SMA isolation but no occlusion) groups, and 5 other as normal controls. The blood flow of intestinal mucosa was detected before and after SMA occlusion or admission of carbachol. Changes in diamine oxidase (DAO), D-lactate, xylopyranose absorption, blue dextran discharging time were measured at 2, 4, 6, 8, 24, 48, 72 h after SMA occlusion. In addition, eight severe burn patients with TBSA of 84 +/- 12% were enrolled in the study, and carbachol (15 microg/kg) was administered to patients when abdominal distension or bowel sound was lower than 2 times/min, then the number of abdominal distension and bowel sounds per minute were observed. RESULTS: The blood flow in intestinal mucosa of rabbits without SMA occlusion was (102 +/- 5) PU, reduced to (48 +/- 6) PU after SMA occlusion, and increased to (77 +/- 3) PU after injection of carbachol. The plasma DAO activity and D-lactic acid content in I group began to increase 4 hours after SMA occlusion, and they reached the peak 24 hours after SMA occlusion (4.63 +/- 0.27 U/ml, 7.9 +/- 2.4 mg/L) , after that they decreased gradually, but still higher than the normal value (0.89 +/- 0.14 U/ml, 2.0 +/- 1.1 mg/L, P < 0.05). In carbachol group, data showed the same trends as that in intestine I/R group with lower values, while no obvious changes were in sham operation group (P > 0.05). The content of D-lactic decreased dramatically 2 hours after D-lactic administration in both I and C groups, increased 6 hours after SMA occlusion, then decreased gradually, but it in C group was always higher than normal values, and little fluctuation was in sham operation group. There was no blue dextran discharge 2 hours after SMA occlusion. The discharging distance increased 6 hours later, but it was obviously shorter than the normal value 24 hrs after operation (P < 0.05) , then it returned to normal 48 to 72 hrs after operation. In the C group, blue dextran discharge was found immediately after its injection, with obvious increase in the discharging distance to peak value (43 +/- 6 cm) 6 hours after injury, and returning to normal (28 +/- 3 cm) gradually. In severe burned patients, the bowel sounds was (1.6 +/- 1.1) per minutes before carbachol administration, then increased dramatically to (6.9 +/- 1.7) per minutes 10 mins after administration, reached to a higher level 30 minutes after administration (8.3 +/- 2.4 ) times/min, and it maintained to (6.1 +/- 1.3) times/min 1 hour after administration. Abdominal distension was ameliorated 2 hours after carbachol administration, six patients were able to defecate. CONCLUSION: Enteral administration of Carbachol can increase the blood flow of intestine mucosa, help to improve the movement, absorption and barrier functions of intestine, and ameliorate intestinal dysfunction in patients with severe burns.

Adolescent↗