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PubMed1996

Effects of hyperoxia on bacterial translocation and mortality during gut-derived sepsis.

BACKGROUND: While hyperoxia is commonly used for treating carbon monoxide poisoning, chronic nonhealing ulcers, acute traumatic and chronically ischemic wounds, and refractory osteomyelitis, its efficacy is unproven in numerous clinical situations, including treatment during severe sepsis. OBJECTIVE: To test the effects of hyperoxia on bacterial translocation and mortality during gut-derived sepsis in a clinically relevant model of infection. METHODS: Balb/c mice were gavaged with 10(9) Escherichia coli and subjected to a 20% burn injury. Then, the animals were randomized to receive hyperoxia for different periods of time. Survival and the extent of translocation were determined, as well as intestinal histologic features. RESULTS: Hyperoxia treatment preserved gut morphology and improved gut barrier function, decreasing the amount of bacterial translocation. Short-term (4- or 8-hour) hyperoxia (100% oxygen) treatment improved survival only on day 1 after injury but did not affect the final outcome. Short-term (8-hour) hyperoxia (100% oxygen) plus 5-day 40% oxygen environment significantly improved long-term survival. CONCLUSION: Tissue pO2 may be an important regulator of gut barrier function. Hyperoxia treatment appears to play a major role in preserving gut barrier function.

Animals↗
PubMed2004

Internal biliary drainage improves decreased number of gut mucosal T lymphocytes and MAdCAM-1 expression in jaundiced rats.

BACKGROUND: Although the effect of preoperative biliary drainage in patients with obstructive jaundice is controversial, bacterial or endotoxin translocation is one of the main postoperative problem in jaundiced patients. Failure in gut barrier functions causes bacterial translocation; homing and distribution of T lymphocytes in the intestinal lamina propria are important for gut mucosal immune defense. This study was performed to examine whether bile regulates the numbers of T lymphocyte subsets or the expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in experimental jaundice in rats with and without external and internal biliary drainage. METHODS: Four groups of Wistar rats were used: those that received a sham operation (SHAM), common bile duct ligation (CBDL), CBDL followed by external drainage (ED), and CBDL followed by internal drainage (ID). Numbers of CD4(+) and CD8(+) T lymphocytes and MAdCAM-1-positive cells in the lamina propria were counted immunohistochemically in the specimens of jejunum and ileum of each group. Bacterial translocation was examined by culturing from the mesenteric lymph node complex isolated from rats in each group. RESULTS: A significant decrease in numbers of CD4(+) and CD8(+) T lymphocytes and MAdCAM-1-positive cells in the lamina propria was seen in obstructive jaundice, although numbers of peripheral blood lymphocytes increased in comparison with the sham-operated control. The numbers of CD4(+) and CD8(+) T lymphocytes and MAdCAM-1 expression in the lamina propria did not recover to a normal level after external drainage, but did so after internal drainage. Frequencies of bacterial translocation were high in the CBDL and ED group. In contrast, bacterial translocation was not present in any animals in the SHAM group and was at a low percentage in the ID group. CONCLUSIONS: Changes in the number of T lymphocytes and MAdCAM-1 expression are associated with the presence of bile in the gastrointestinal tract and are inversely correlated with the frequency of bacterial translocation induced by CBD ligation. MAdCAM-1 expression maintained by the presence of bile may regulate T-lymphocyte homing to the lamina propria in obstructive jaundice.

Animals↗
PubMed1999

Effect of chitosan on epithelial permeability and structure.

Numerous studies have shown that chitosan, a mucoadhesive polymer, is a potential enhancer for transmucosal drug delivery. To further understand the mechanisms involved in chitosan action on the mucosal barrier, the activity of chitosan on the function and structure of monolayers of intestinal epithelial cells was investigated. In Caco-2 cells, chitosan caused a reversible, time and dose-dependent decrease in transepithelial electrical resistance. The effect of chitosan on tight junctions was confirmed by an increased permeability coefficient for mannitol transport when cells were treated with 0.1-0.5% w/v chitosan solution for 60 min compared to control cells. Involvement of tight junctions was visualized by confocal scanning microscopy using occludin and ZO-1, tight junctional proteins. Following an incubation with 0.01 or 0.1% w/v chitosan, labeling of both proteins varied in localization and decreased in fluorescent intensity at the cell periphery. In addition, a focal condensation of actin was observed preferentially at areas of cell-to-cell contacts. However, after 24-h recovery, the cell structure resembled untreated control cells. Simultaneous addition of cycloheximide, a protein synthesis inhibitor, prevented full recovery. This implied that protein synthesis was required for the cells to return to baseline levels. Chitosan treatment appeared to slightly perturb the plasma membrane as assessed by an increased release of lactate dehydrogenase. However, addition of 0.5% chitosan for 60 min did not affect cell viability as shown by Trypan blue dye exclusion. These data suggest that chitosan increases cell permeability by affecting paracellular and intracellular pathways of epithelial cells, in a reversible manner.

Animals↗
PubMed2004

Effect of a pore-forming protein derived from Flammulina velutipes on the Caco-2 intestinal epithelial cell monolayer.

We have previously found a transepithelial electrical resistance (TEER)-decreasing protein derived from Flammulina velutipes, which was revealed to be identical to flammutoxin (FTX) that is known as a hemolytic pore-forming protein. This protein induced a rapid decrease in TEER and parallel increase in paracellular permeability in the intestinal epithelial Caco-2 cell monolayer without any cytotoxicity. An immunoblotting analysis revealed that the FTX-induced decrease in TEER was accompanied by the formation of a high-molecular-weight complex on the surface of Caco-2 cells. Intracellular Ca(2+) imaging showed that exposure to FTX caused a rapid Ca(2+) influx. It was observed by electron microscopy that FTX induced swelling of microvilli and expansion of the cellular surface. Staining with fluorescent phalloidin showed a marked change to filamentous actin in the FTX-treated cells. These results suggest that TEER reduction could sensitively detect small membrane pore formation by FTX in the intestinal epithelium which causes a morphological alteration and disruption of the paracellular barrier function.

Actins↗
PubMed2002

Clarification of the mechanism of structural change induced by reoxygenation following the induction of lipid peroxidation in Caco-2 cell monolayers.

Recently, we established a system for assessing ischemia/reperfusion injury, specifically the opening of tight junctions (TJ), caused by reoxygenation following the induction of lipid peroxidation by tertiary-butylhydroperoxide (t-BuOOH), using the human intestinal epithelial cell line Caco-2 in order to focus on the barrier function of the epithelium independent of the vascular compartment. In the present study, we attempted to identify factors involved in the structural changes induced by reoxygenation using 0.5 mM t-BuOOH in Caco-2 cell monolayers. Glutathione (GSH) and N-acetylcystein, a precursor of GSH, inhibited the opening of TJ evoked by reoxygenation following the induction of lipid peroxidation by 0.5 mM of t-BuOOH. Tiron, as a cell permeable superoxide anion scavenger and deferoxamine, an iron-chelating agent ameliorated the opening in a dose-dependent manner. Also, Tiron suppressed the apical-to-basal and basal-to-apical permeability of the increased Rhodamine123 by reoxygenation in a concentration-dependent manner. These results collectively suggest that superoxide anion and iron ions play an important role or contribute to structural changes such as the opening of TJ induced by reoxygenation following the induction of lipid peroxidation by 0.5 mM t-BuOOH.

Journal Article↗
PubMed1993

Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interaction with modulators.

The functional expression of P-glycoprotein has been studied in confluent epithelial layers of human Caco-2 cells, a polarized, highly differentiated cell line demonstrating an intestinal absorptive cell phenotype. Expression of P-glycoprotein was localized, by indirect immunofluorescence with monoclonal antibody MRK16, to the apical brush-border, approximately 20 microns above the base of the cells. Functional, high capacity expression of P-glycoprotein in Caco-2 cell layers was demonstrated by the saturable secretion of vinblastine, a typical substrate, from basolateral to apical surfaces: Km 18.99 +/- 5.55 microM, Vmax 1285.9 +/- 281.2 pmol.cm-2 h-1. The direct correlation of apical P-glycoprotein expression with vinblastine net secretory flux was demonstrated by the reduction of this flux after treatment with MRK16 antibodies. Vinblastine secretory flux was also reduced by treatment with verapamil (R- and S-isomers with equal affinity), nifedipine, taxotere, and 1,9-dideoxyforskolin. Kinetic analyses suggest that the inhibition of vinblastine secretory flux by verapamil and nifedipine was competitive, while that by dideoxyforskolin was non-competitive, in nature. The polarized expression and activity of P-glycoprotein in Caco-2 cells is direct evidence for its secretory detoxifying function in the intestine, subserving at least one role of the gastrointestinal epithelial barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Isolation and characterization of the viscous, high-molecular-mass microbial carbohydrate fraction from faeces of healthy subjects and patients with Crohn's disease and the consequences for a therapeutic approach.

1. An earlier study by our group revealed that the viscosity of faeces from patients with Crohn's disease is significantly lower than that of healthy subjects. This is due to low concentrations of a high-molecular-mass carbohydrate, probably of bacterial origin. The cause of this phenomenon might be the impaired barrier function of the gut mucosa. Low viscosity may allow close contact of intestinal contents (bacterial products and toxins) with the intestinal wall. This could play a role in the maintenance of the disease.2. The first aim of this study was to investigate the high-molecular-mass carbohydrate fraction, responsible for viscosity, in detail. We also tried (in a pilot study) to raise the intestinal viscosity of patients with Crohn's disease with the undegradable food additive hydroxypropylcellulose (E463), in an attempt to alleviate clinical symptoms.3. The high-molecular-mass fraction (>300 kDa) responsible for faecal viscosity was sensitive to lysozyme and contained high levels of muramic acid. It was concluded that this material consisted mainly of peptidoglycan polysaccharides and was consequently of bacterial origin. The muramic acid in material from patients with Crohn's disease was 7.5 (1.5-13.9)%, which was less than in healthy subjects [11.4 (8.5-24.1)%; P=0.0004]. Furthermore, viscosity in material from patients with Crohn's disease was found to be half [14.9 (1.0-33.6) cP] of that found in healthy subjects [35.0 (2.7-90.7) cP; P=0.004].4.A daily dose of 1 g of hydroxypropylcellulose caused an increase in faecal viscosity in patients with Crohn's disease (from 1.4 to 2.3 cP) and in healthy subjects (from 4.9 to 7.5 cP). Faecal consistency improved in patients with Crohn's disease (from watery and loose to formed) and the defecation frequency decreased from 3-4 to about 2 times a day. No changes in defecation patterns were found in healthy subjects.5. These data indicate that the high-molecular-mass fraction that is responsible for faecal viscosity is peptidoglycan. Furthermore, a daily dose of a hydroxypropylcellulose solution to increase the viscosity of the intestinal contents of patients with Crohn's disease might be beneficial. This approach merits further study.

Adult↗
PubMed2002

PKC-zeta prevents oxidant-induced iNOS upregulation and protects the microtubules and gut barrier integrity.

Using intestinal (Caco-2) monolayers, we reported that inducible nitric oxide synthase (iNOS) activation is key to oxidant-induced barrier disruption and that EGF protects against this injury. PKC-zeta was required for protection. We thus hypothesized that PKC-zeta activation and iNOS inactivation are key in EGF protection. Wild-type (WT) Caco-2 cells were exposed to H(2)O(2) (0.5 mM) +/- EGF or PKC modulators. Other cells were transfected to overexpress PKC-zeta or to inhibit it and then pretreated with EGF or a PKC activator (OAG) before oxidant. Relative to WT cells exposed to oxidant, pretreatment with EGF protected monolayers by 1) increasing PKC-zeta activity; 2) decreasing iNOS activity and protein, NO levels, oxidative stress, tubulin oxidation, and nitration); 3) increasing polymerized tubulin; 4) maintaining the cytoarchitecture of microtubules; and 5) enhancing barrier integrity. Relative to WT cells exposed to oxidant, transfected cells overexpressing PKC-zeta (+2.9-fold) were protected as indicated by decreases in all measures of iNOS-driven pathways and enhanced stability of microtubules and barrier function. Overexpression-induced inhibition of iNOS was OAG independent, but EGF potentiated this protection. Antisense inhibition of PKC-zeta (-95%) prevented all measures of EGF protection against iNOS upregulation. Thus EGF protects against oxidative disruption of the intestinal barrier by stabilizing the cytoskeleton in large part through the activation of PKC-zeta and downregulation of iNOS. Activation of PKC-zeta is by itself required for cellular protection against oxidative stress of iNOS. We have thus discovered novel biologic functions, suppression of the iNOS-driven reactions and cytoskeletal oxidation, among the atypical PKC isoforms.

Caco-2 Cells↗
PubMed2005

[Effect of oxygen therapy for injury of intestinal mucosal barrier of rabbits in high altitude hemorrhagic shock].

OBJECTIVE: To investigate the protective effects of oxygen therapy on gut barrier function of rabbits after hemorrhagic shock at high altitude. METHODS: Fifteen rabbits were exposed to a simulated 4000 m high altitude in a hypobaric chamber, and they were randomly divided into two groups of treatment and control. Then hemorrhagic shock was induced through bleeding to mean artery pressure 40 mmHg (1 mmHg=0.133 kPa). After 1 hour, the rabbits were resuscitated with infusion of total volume of shed blood and balanced saline equivalent to 1.5 times of the shed blood. In addition, the animals of the treatment group were given oxygen therapy. RESULTS: After 4 hours treatment, the mean arterial pressure of the treatment group was increased significantly in comparison with the control group, and the concentrations of plasma lactate in the former were significantly decreased after treatment for 4 hours and 8 hours. The plasma lipopolysaccharide levels in the treatment group were significantly lower than those in the control after treatment, and the histologic evidence of damage to the intestinal mucosa of the rabbits in the treatment group was less marked than that in the control group (P<0.05 or P<0.01). CONCLUSION: Hemorrhagic shock at high altitude may cause disruption of the intestinal mucosa barrier and oxygen therapy could afford protection to the intestinal mucosa barrier in such circumstance.

Altitude Sickness↗
PubMed2001

Pathologic and physiologic interactions of bacteria with the gastrointestinal epithelium.

Communication between microorganisms and the gastrointestinal epithelium, ie, bacterial-epithelial "crosstalk," is examined. Because most basic research on the molecular interaction of bacteria with the gut epithelium relates to pathogen-enterocyte interaction, crosstalk with pathologic bacterial is considered in detail. Through their interactions with the intestinal epithelium, pathogens can modify epithelium function to enhance their penetration across the epithelial barrier and to exploit mucosal host defenses for their own benefit. Three representative pathogens are used to illustrate the various adaptive techniques used to colonize and penetrate the mucosal barrier. Salmonella enterica typhimurium interacts with the physiologic receptor for epidermal growth factor to co-opt the receptor's signal transduction mechanisms. Enteropathic Escherichia coli secretes a receptor (type III secretion) into the microvillus surface of enterocytes that disrupts the microvillus and alters its actin structure to form a dome-like anchoring site. Shigella flexneri is used to illustrate how pathogens use the follicular epithelial cell (M cell), the physiologic conduit for antigens to reach gut associated-lymphoid tissues, for penetration of the epithelial barrier. Shigella organisms attached to M cells use their endocytotic properties to enter the cell. Once inside the cell, the organism lyses the endocytic vacuole and co-opts actin and myosin to form a propelling tail for further penetration of the epithelium through the basolateral surface. Probiotics can protect the intestine by competing with pathogens for attachment, strengthening tight junctions between enterocytes, and enhancing the mucosal immune response to pathogens. However, additional molecular studies are needed to define more precisely the mechanism of probiotic-epithelial crosstalk.

Escherichia coli↗
PubMedDate not supplied

Attenuation of Helicobacter pylori endotoxin-provoked rat intestinal inflammation by selective inhibition of the inducible nitric oxide synthase.

We studied the actions of purified Helicobacter pylori endotoxin (3 mg kg(-1), i.v.) on rat intestinal vascular permeability (assessed by the radiolabelled human serum albumin leakage technique) and on nitric oxide synthase induction (assessed by the citrulline assay) 4 h later. We found increased albumin leakage and expression of the inducible nitric oxide synthase in jejunum and colon, effects reversed by a selective inducible nitric oxide synthase inhibitor N-(8-(aminomethyl)benzyl)-acetamidine (1400W; 0.2-1 mg kg(-1), s.c., concurrently with endotoxin). Thus, H. pylori endotoxin seems to be capable of provoking an inflammatory response in the rat intestinal tissue. Systemic liberation of H. pylori endotoxin might possibly attenuate jejunal and colonic mucosal barrier function, a process mediated by the expression of the inducible nitric oxide synthase.

Amidines↗
PubMed1998

Ischaemia-reperfusion injury to the intestine.

Ischaemia-reperfusion injury (IRI) is of obvious relevance in situations where there is an interruption of blood supply to the gut, as in vascular surgery, or in the construction of free intestinal grafts. It is now appreciated that IRI also underlies the guy dysfunction that occurs in early shock, sepsis, and trauma. The events that occur during IRI are complex. However, recent advances in cellular biology have started to unravel these underlying processes. The aim of this review is to provide an outline of current knowledge on the mechanisms and consequences of IRI. Initially, IRI appears to be mediated by reactive oxygen metabolites and, at a later stage, by the priming and activation of polymorphonuclear neutrophils (PMN). Ischaemia-reperfusion injury can diminish the barrier function of the gut, and can promote an increase in the leakage of molecules (intestinal permeability) or the passage of microbes across the wall of the bowel (bacterial translocation). Ischaemia-reperfusion injury to the gut can result in the generation of molecules that may also harm distant tissues.

Bacterial Translocation↗
PubMed1978

GI absorption of beta-lactam antibiotics II: deviation from pH--partition hypothesis in penicillin absorption through in situ and in vitro lipoidal barriers.

The absorption of propicillin from the rat stomach and small intestine in situ was examined as a function of recirculating solution pH. The in vitro interphase transport from an aqueous buffer of various pH values to the octanol phase was also studied for several penicillins by the use of a two-phase rolling cell. The rate--pH profiles obtained from both in situ and in vitro experiments deviated significantly from the dissociation curves. The degrees of the shifts were approximately 2 pH units for the in situ intestinal absorption of propicillin and in vitro transport of propicillin and cloxacillin, approximately 1.5 pH units for the in vitro transport of penicillin V, and 0.8 pH unit for the in situ stomach absorption of propicillin. These discrepancies from the classical pH--partition hypothesis can be interpreted by the permeation through the lipoidal barrier of the undissociated species of penicillins transported through the aqueous diffusion layer adjacent to the lipoidal surface. All in situ and in vitro experiments tend to support this theory.

Animals↗
PubMed1988

Increased intestinal permeability associated with infection in burn patients.

Thermal injury may be associated with disruption of normal gut barrier integrity. To test this hypothesis, we assessed intestinal permeability with the nonmetabolizable, poorly absorbed disaccharide lactulose, which is efficiently excluded by the normal intestinal mucosa. Permeability studies were performed in 15 burned patients (aged 18 to 67 years; mean burn size, 40%) and 11 healthy controls. Lactulose, 10 g, was administered enterally, together with 5 g of mannitol as a control, and urinary excretion rates were determined. Lactulose excretion and the lactulose/mannitol excretion ratio increased threefold (160 +/- 30 vs 57 +/- 7 mumol and 0.113 +/- 0.033 vs 0.035 +/- 0.005) in the infected patients (sepsis score, 10 +/- 2; burn size, 38% +/- 6%). In contrast, noninfected burn patients (sepsis score, 0) had permeability values similar to those of controls (66 +/- 10 mumol and 0.036 +/- 0.007). Permeability increased as the severity of infection increased. Infection in burn patients is associated with increased bowel permeability. The intestine may be a primary source of sepsis. Alternatively, the systemic response to infection may alter gut barrier function, which could facilitate translocation of bacteria and absorption of endotoxin.

Adolescent↗
PubMedDate not supplied

[Epithelial barrier of mucous membranes in the course of chronic inflammation].

The barrier function of the epithelium was studied immunohistochemically, electron microscopically and autoradiographically in 105 bronchial biopsies and 1140 biopsies of the stomach and intestinal mucosa in the course of chronic inflammation. The role of the transitory and local deficiency of SIgA and immunocomplex reactions in the morphogenesis of the permeability increase of the epithelial barrier in inflammation was established. Structural equivalents of the plastic deficiency appearing in the chronization of the inflammation and reflecting the distortion and exhaustion of the regeneration and immunity reaction as a basis of atrophy were demonstrated in the epitheliocytes and immunocompetent cells. The atrophy is defined as a reestablishment of the mucous epithelial barrier at the expense of other functions of mucous membranes, namely immune and mucous forming ones.

Bronchitis↗
PubMed2000

Surgical stress induces phospholipid degradation in the intestinal brush border membrane.

BACKGROUND: Surgical stress can lead to translocation of bacteria from the intestine into the systemic circulation. The intestinal brush border membrane (BBM) plays an important role in defense against such invasion by luminal bacteria and endotoxin. Our earlier work has shown the development of oxidative stress in the intestine after surgical stress and since the BBM is sensitive to free radical attack, this study examined the effect of surgical stress on the structure and function of intestinal BBM. METHODS: Intestinal BBM were isolated from control and after surgical stress and compared for structural and functional alterations. Surgical stress was also carried out following pretreatment with the xanthine oxidase inhibitor allopurinol or the nitric oxide donor l-arginine, to study the protection offered by these compounds. RESULTS: Surgical stress affected intestinal BBM structure as well as function. A decrease in alkaline phosphatase activity and alpha-tocopherol content, accompanied by an increase in lipid peroxidation, was seen. Surgical stress induced phospholipid degradation with generation of arachidonic acid. Functional impairment with a decrease in glucose transport ability was also seen. These changes are prevented by inhibition of xanthine oxidase by allopurinol pretreatment but not by NO. CONCLUSION: Surgical stress in the small intestine causes structural and functional alterations in the BBM through oxidative stress. This damage could affect gut barrier integrity and generation of arachidonic acid might mediate distal organ dysfunction.

Abdomen↗