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At least 1,027 records · Page 57Linked to original sources
PubMed2000

Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat.

BACKGROUND & AIMS: Abnormal presentation of luminal constituents to the mucosal immune system, caused by dysfunction of the intestinal epithelial barrier, is a candidate theory for the cause of Crohn's disease. Increased epithelial permeability is found in subgroups of patients at high risk for the development of Crohn's disease and has been found to precede disease recurrence. Clinical observations have suggested that disease recurrence can follow times of increased psychological stress, although the underlying mechanism remains obscure. We hypothesized that environmental stress increases gastrointestinal permeability. METHODS: We evaluated site-specific gastrointestinal permeability after application of graded levels of stress in rats. RESULTS: Increased epithelial permeability after stress was shown in all regions of the gastrointestinal tract and seemed to be mediated by adrenal corticosteroids. Stress-induced increases in epithelial permeability disappeared after adrenalectomy or pharmacologic blockade of glucocorticoid receptors. Dexamethasone treatment of control animals increased gastrointestinal permeability and mimicked the effects of stress. CONCLUSIONS: Psychological stress may increase gastrointestinal permeability, allowing luminal constituents access to the mucosal immune system. This provides a potential mechanism for the observation of stress-induced disease recurrence in Crohn's disease.

Adrenal Cortex Hormones↗
PubMed1996

Response of germfree rat colonic mucous cells to peroral endotoxin application.

During microbial colonization, mucin-releasing goblet cells of germ-free (GF) rats proliferate and upregulate their mucin synthesis, thus improving the intestinal mucus barrier. The present study determined the significance of bacterial membrane constituents for this development. A single dose of lipopolysaccharide (LPS) (35 micrograms/100 g body weight) and lipid A (3.5 micrograms/100 g body weight, respectively), was perorally administered to GF AS/Ztm rats. One, 3 and 5 days later, sections of the proximal and distal colon served for characterization of mucin-secreting goblet cells, released mucins were isolated in parallel. Maximal goblet cell diameters were evidenced at day 3. LPS generated a maximal goblet cell hyperplasia one day after challenge, lipid A stimulated the goblet cell proliferation continuously up to day 5. Three days after challenge with one of the stimuli, either, intracellular mucins had shifted significantly to neutral constituents. In addition, mucins, adherent to the colon mucosa and submerged to the luminal content, respectively, then were augmented. At day 5, adherent mucins were similar to the controls, while luminal, soluble constituents had further increased. Histometrical and biochemical methods evidenced a transient, inflammatory response of mucin-secreting cells, followed by an upregulated release of immature mucins.

Administration, Oral↗
PubMed1997

Sympathetic and renin-angiotensin activation during graded hypovolemia in pigs: impact on mesenteric perfusion and duodenal mucosal function.

Sympathetic and angiotensinergic activation reduce splanchnic oxygen delivery during hypovolemia, which may lead to failure of the intestinal mucosal barrier and eventually multiple organ dysfunction. This study integrates sympathetic and angiotensinergic responses with splanchnic hemodynamics and duodenal mucosal function during hypovolemia and evaluates pharmacologic blockade of either system to ameliorate the impact of acute hypovolemia. Chloralose-anesthetized pigs subjected to 20 and 40% blood volume reductions were randomized to controls or administered guanethidine or enalaprilate to block sympathetic and angiotensinergic activation, as assessed by plasma norepinephrine spillover and angiotensin II levels, respectively. Mesenteric and hepatic oxygen delivery/consumption as well as duodenal mucosal alkaline secretion and potential difference were determined. Hypovolemia preferentially increased mesenteric sympathetic outflow and caused a vigorous angiotensinergic activation. Guanethidine and enalaprilate blocked effectively the sympathetic and angiotensinergic responses. Treatment with enalaprilate, but not guanethidine, prevented the reduction of mesenteric oxygenation and duodenal mucosal alkaline secretion and potential difference observed in control animals. The down-regulation of mesenteric oxygenation and duodenal mucosal function during hypovolemia can be prevented by administration of enalaprilate, whereas guanethidine is uneffective in this respect. Interference with the reninangiotensin system might be of clinical interest to support mesenteric perfusion and organ function in hypovolemia.

Angiotensin II↗
PubMed2001

Inflammatory bowel disease is associated with changes of enterocytic junctions.

Changes of the intestinal mucosal barrier are considered to play a role in the pathogenesis of inflammatory bowel disease (IBD). Our experiments were designed to identify dysregulation of epithelial junctional molecules in the IBD intestinum and to address whether altered expression of these molecules is a primary event in IBD or a phenomenon secondary to the inflammatory process. Noninflamed and inactively and actively inflamed mucosal tissues from patients with ulcerative colitis or Crohn's disease as well as tissues from control subjects were analyzed for the expression of junctional molecules by different methods. Marked downregulation of junctional proteins and their respective mRNAs was observed in actively inflamed IBD tissues. In IBD tissues with inactive inflammation, only a few junctional molecules such as E-cadherin and alpha-catenin were affected, whereas expression of desmosomal or tight junction-associated proteins appeared almost unchanged. In noninflamed IBD tissues, junctional protein expression was not different from that seen in normal control subjects. In IBD, downregulation of junctional molecule expression is apparently associated with the inflammatory process and does not likely represent a primary phenomenon.

Adult↗
PubMed1996

Epidermal growth factor promotes rapid response to epithelial injury in rabbit duodenum in vitro.

BACKGROUND & AIMS: Growth factors are mainly involved in the regulation of intestinal epithelial barrier function. This study investigated the effect of epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) on epithelial restitution of rabbit duodenum in vitro. METHODS: Rabbit duodenal mucosal strips mounted in an Ussing chamber were luminally exposed to 10 mmol/L HCl for 10 minutes and then incubated with buffer alone or luminal buffer containing various concentrations of EGF and IGF-1 for 3 hours. Resistance was calculated from potential difference and short-circuit current. Damage was assessed by morphometry on H&E-stained sections. RESULTS: HCl caused resistance to decrease from 112 +/- 2 to 51 +/- 4 ohms x cm2 10 minutes after injury (n = 6; P < 0.05). Postinjury treatment with 25 or 50 ng/mL luminal EGF for 3 hours stimulated resistance to recover to 94 +/- 3 and 104 +/- 3 ohms x cm2, respectively, vs. 81 +/- 3 omega x cm2 in controls (P < 0.05). Ten minutes after injury, 62% of the mucosa was damaged; 3 hours after injury, damage was reduced to 24% +/- 1.09% and 10% +/- 1.42% in the 25 and 50 ng/mL EGF group, respectively, vs. 38% +/- 0.93% in controls (n = 6 per group). EGF stimulated enterocyte migration. IGF-1 did not impair epithelial restitution. CONCLUSIONS: EGF, but not IGF-1, promoted epithelial restitution of rabbit duodenum in vitro.

Animals↗
PubMed1983

Serum acute phase reactants in pediatric patients; especially in neonates.

We studied serum acute phase reactant (APR) levels in 45 pediatric surgical patients. Alpha 1-acid glycoprotein (alpha 1-AG) showed a peak value on day 3 postoperatively (P.O.) and alpha 1-antitrypsin (alpha 1-AT) showed a high value on days 3-5 P.O. These glycoproteins returned to normal levels by day 21 P.O., but the level of haptoglobin (Hp) remained high until day 21 P.O. The postoperative changes of alpha 1-AG and alpha 1-AT correlated with the process of recovery from inflammatory conditions, but C-reactive protein (CRP) reached a peak on days 1-2 P.O. and returned to normal limits by day 14 P.O. In patients with infection, CRP returned to the normal level rapidly before recovery from infection. Of the 3 glycoproteins, alpha 1-AG seemed to be a valuable indicator of the pathological conditions. Postoperative changes in APR levels should be useful for early detection of postoperative complications. Persistent ileus led to an increase in APR levels, as a consequence of an inflammatory reaction due to breakdown of the intestinal mucosal barrier.

Abdomen↗
PubMed2004

Gut barrier dysfunction as detected by intestinal luminal microdialysis.

OBJECTIVE: To evaluate the use of gut luminal microdialysis as a tool for monitoring ischaemic metabolites, particularly glycerol, as markers of intestinal dysfunction during and after intestinal ischaemia. DESIGN: A randomised, controlled animal experiment. SETTING: National laboratory animal centre. INTERVENTIONS: In seven pigs the thoracic aorta was cross-clamped for 60 min followed by 2 h of reperfusion, while five pigs served as controls. MEASUREMENTS AND RESULTS: Glycerol, lactate and glucose in the intestinal lumen and mucosa were measured by microdialysis. Intestinal tissue blood flow was determined by means of colour-labelled microspheres. To assess intestinal permeability, (14)C-polyethylene glycol 4000 (PEG-4000) was instilled in a jejunal segment and then measured in venous blood. Intestinal blood flow was reduced to 10% of baseline by aortic cross-clamping ( p=0.001) and returned to baseline during reperfusion. Intestinal luminal lactate increased during ischaemia and further increased during reperfusion. The increase was paralleled by augmented intestinal permeability; there was a significant correlation between luminal lactate and venous PEG-4000 ( r=0.89, p<0.01). Aortic cross-clamping caused a marked increase in intestinal mucosal glycerol concentrations, which correlated with luminal glycerol during both ischaemia and reperfusion ( r=0.85, p<0.01). CONCLUSION: Microdialysis of lactate may be useful for monitoring intestinal ischaemia and reperfusion. Release of lactate into the intestinal lumen appears to be related to increased permeability. Intestinal luminal glycerol closely mirrored glycerol concentrations in the intestinal wall.

Analysis of Variance↗
PubMed1990

Poliovirus type 1 enters the human host through intestinal M cells.

It was demonstrated by electron microscopy that after in vitro incubation of human Peyer's patches with poliovirus type 1, either Sabin or Mahoney strain, poliovirus particles adhere specifically to and are endocytosed by intestinal epithelial M cells. These findings suggest that M cells in humans are the site of poliovirus penetration of the intestinal epithelial barrier.

Adult↗
PubMed1994

Preferential interaction of Salmonella typhimurium with mouse Peyer's patch M cells.

We have used a mouse Peyer's patch gut loop model to investigate the role of the intestinal membranous epithelial (M) cells in the pathogenesis of Salmonella typhimurium. These specialized antigen sampling cells are located in the follicle-associated epithelium (FAE) overlying the isolated and aggregated lymphoid follicles in the small and large intestines. Our studies have demonstrated that S. typhimurium adheres more frequently to the Peyer's patch FAE cells than to the villous enterocytes and that, within the FAE, this bacterium preferentially interacts with the M cells. Quantitative light microscopic studies, using the lectin Ulex europaeus 1 (UEA1) to identify M cells, revealed that 34-fold more bacteria bound per unit area of M cells than per unit area of enterocyte. Within a 30-min incubation period, some M cells had clearly been invaded by the Salmonella. We therefore propose that M cells are a major route by which S. typhimurium penetrates the intestinal epithelial barrier. Bacterial adhesion to M cells occurred in a non-uniform pattern, suggesting the existence of M-cell subtypes. The interaction of S. typhimurium with mouse Peyer's patch M cells was accompanied by membrane ruffle formation and polymerized actin redistribution similar to that observed in cultured cell lines infected by this bacterium. This study emphasizes the suitability of Salmonella as an oral vaccine delivery system since, by preferentially interacting with the M cells, these bacteria are targeted to sites where cells of the immune system are concentrated.

Animals↗
PubMed2004

Nanomedicines for overcoming biological barriers.

Drug delivery is an interdisciplinary area of research that aims at making the administration of complex new drugs feasible, as well as adding critical value to the drugs that are currently in the market. At present, one of the most attractive areas of research in drug delivery is the design of nanomedicines consisting of nanosystems that are able to deliver drugs to the right place, at appropriate times. The goal of the present article is to review the advances we have made in the development and characterization of nanosystems intended to be used as drug carriers for mucosal administration. These nanocarriers are able to protect the associated drug against degradation and facilitate its transport across critical and specific barriers. Some of them, are further able to release the associated drug to the target tissue in a controlled manner. These nanocarriers have been made of safe materials, including synthetic biodegradable polymers, lipids and polysaccharides. A number of nanotechnologies have been developed that enable the association of a variety of drugs to these nanocarriers, ranging from classical small drug to large DNA fragments. The in vitro cell culture studies and the in vivo experiments have evidenced the potential of these nanocarriers for overcoming important mucosal barriers, such as the intestinal, nasal and ocular barriers. Hopefully, this will soon represent a strategy for making cheaper and faster, more efficacious medicines.

Administration, Oral↗
PubMed2005

Micromachined devices: the impact of controlled geometry from cell-targeting to bioavailability.

Advances in microelectomechanical systems (MEMS) have allowed the microfabrication of polymeric substrates and the development of a novel class of controlled delivery devices. These vehicles have specifically tailored three-dimensional physical and chemical features which, together, provide the capacity to target cells, promote unidirectional controlled release, and enhance permeation across the intestinal epithelial barrier. Examining the biological response at the microdevice biointerface may provide insight into the benefits of customized surface chemistry and structure in terms of complex drug delivery vehicle design. Therefore, the aim of this work was to determine the interfacial effects of selective surface chemistry and architecture of tomato lectin (TL)-modified poly(methyl methacrylate) (PMMA) drug delivery microdevices on the Caco-2 cell line, a model of the gastrointestinal tract.

Biological Availability↗
PubMed2004

Binding of the insecticidal lectin Concanavalin A in pea aphid, Acyrthosiphon pisum (Harris) and induced effects on the structure of midgut epithelial cells.

Concanavalin A (lectin from Canavalia ensiformis L., ConA) has previously been shown to act as a feeding inhibitor for Acyrthosiphon pisum, the pea aphid. In the present study a range of histochemical and biochemical techniques were used to elucidate the target tissues and binding sites of the lectin in the aphid. Diet uptake was evaluated using a radioactive tracer (14C-methylated inulin) and demonstrated that adults were capable of ingesting high quantities of the toxin (approx. 1 microg over a 48 h period). Electophoretic analysis and enzyme-linked immuno-sorbent assay of honeydew samples confirmed these results and further demonstrated that only small levels of ConA were excreted. Histofluorescence and immunolocalisation studies on nymphs revealed that the stomach was the primary target for ConA. At concentrations up to 400 microg ml(-1), lectin binding only occurred in the stomach region, however, at high concentrations (800 microg ml(-1)) the whole digestive tract was stained, although there was no evidence of binding in either the oesophagus or rectum. In addition to binding, there was evidence to suggest that ConA was also causing systemic effects in that the lectin appeared to cross the intestinal epithelial barrier. Immunohistochemical and electron microscopy studies revealed that ConA induced severe cellular swelling of the epithelial cells, accompanied by hypersecretion and a progressive detachment of the apical membrane; however, the striated border itself did not appear to be directly affected. Furthermore, there was no lysis of the epithelium, nor loss of integrity of the epithelial cells themselves. Our results suggest that ConA interacts with glycosylated receptors at the surface of the stomach epithelial cells, interfering with normal metabolism and cell function, resulting in a rapid feedback response on feeding behaviour. Whilst our results provide a much greater understanding regarding the modes of action of ConA in insects, they suggest that different lectins, including other mannose binding lectins, have different modes of action at the cellular levels, and thus generalizations should be treated with caution.

Animals↗
PubMed2004

Lactobacillus casei DN-114 001 inhibits the increase in paracellular permeability of enteropathogenic Escherichia coli-infected T84 cells.

Probiotics are living microorganisms which, when ingested in adequate amounts, exert health benefits toward the host. For instance, probiotics might act through reinforcement of the intestinal epithelial barrier function. The goal of the present study was to determine whether Lactobacillus casei DN-114 001 could abrogate the increase in paracellular permeability induced by enteropathogenic Escherichia coli. We used the human colon T84 cell line infected with a wild-type enteropathogenic E. coli (strain E2348/69). Paracellular permeability was followed by monitoring transepithelial electrical resistance variations and by observing zonula occludens-1 distribution. Two infection procedures were used: co-incubation (the pathogenic and probiotic strains were simultaneously incubated with T84 cells) and post-infection (the probiotic was added in the presence of pathogenic bacteria 3 h after the beginning of the infection). We also investigated the effect of L. casei on enteropathogenic E. coli adhesion. L. casei DN-114 001 inhibited, in a dose-dependent-manner, the decrease in enteropathogenic E. coli-induced transepithelial electrical resistance and zonula occludens-1 redistribution using two different infection procedures. However, L. casei did not inhibit pathogenic strain adhesion. L. casei DN-114 001 inhibited the increase in EPEC-induced paracellular permeability. This property could partially explain the previously observed health benefits of this probiotic for human natural defenses, such as those associated with prevention of diarrhea.

Bacterial Adhesion↗
PubMed1999

Optimizing oral absorption of peptides using prodrug strategies.

Prodrug strategies applied to peptides have tended to focus on modification of a single functional group (e.g., N-terminal end). Recently, our laboratory introduced the concept of making cyclic prodrugs of peptides as a way to modify their physicochemical properties sufficiently to allow them to permeate biological barriers (i.e., intestinal mucosa). This cyclization strategy required the development of new 'chemical linkers,' including an acyloxyalkoxy linker, a phenylpropionic acid linker, and a coumarinic acid linker. All three chemical linkers were designed to be susceptible to esterase metabolism (slow step), leading to a cascade of chemical reactions (fast steps) that result in release of the peptide. These cyclic prodrug strategies have been applied to opioid peptides in an attempt to stabilize them to metabolism and/or improve their intestinal mucosal permeation. Specifically, we prepared acyloxyalkoxy-, phenylpropionic acid- and coumarinic acid-based cyclic prodrugs of [Leu(5)]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and its metabolically stable analog DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) and determined their metabolic and biopharmaceutical properties. The cyclic prodrugs of these opioid peptides were shown to have: (i) favorable physicochemical properties (e.g., increased lipophilicity) for membrane permeation; (ii) unique solution structures (e.g., beta-turns) that reduce their hydrogen bonding potential; and (iii) metabolic stability to exo- and endopeptidases. The cell membrane permeation characteristics of [Leu(5)]-enkephalin, DADLE and the cyclic peptide prodrugs were evaluated using Caco-2 cell monolayers, a cell culture model of the intestinal mucosa. The phenylpropionic acid- and coumarinic acid-based cyclic prodrugs of [Leu(5)]-enkephalin and DADLE were shown to have significantly better cell permeation characteristics than the parent opioid peptides. Furthermore, these cyclic prodrugs were shown to be transcellular permeants (in contrast to the opioid peptides, which are paracellular permeants), and were not substrates for polarized efflux systems. Surprisingly, the acyloxyalkoxy-based prodrugs of [Leu(5)]-enkephalin and DADLE were shown to exhibit very low permeation through Caco-2 cell monolayers, which could be attributed to their substrate activity for efflux systems.

Administration, Oral↗
PubMed2000

A coumarin-based prodrug strategy to improve the oral absorption of RGD peptidomimetics.

In recent years, major progress has been made in the design and synthesis of fibrinogen antagonists, which are peptidomimetic Arg-Gly-Asp (RGD) analogs. These RGD analogs are very promising antiplatelet agents. However, the clinical development of orally active RGD analogs has been hindered by the low oral bioavailability of many such RGD analogs. Aimed at enhancing their oral bioavailability, we have synthesized several coumarin-based cyclic prodrugs of RGD analogs, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. As expected, these cyclic prodrugs have higher membrane interaction potentials as estimated by determining their partitioning between aqueous buffer and an immobilized artificial membrane than the corresponding RGD analogs. Consequently, these cyclic prodrugs are 5-6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier. Preliminary studies using dog also indicate the promising potential of using this coumarin-based prodrug strategy to improve the oral bioavailability of such RGD analogs.

Animals↗
PubMed1998

Characterization of P-glycoprotein mediated transport of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor, across MDR1-MDCK and Caco-2 cell monolayers.

PURPOSE: Here we characterized the transport properties of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a newly developed peptidomimetic cysteine protease inhibitor, across monolayers of P-gp-expressed MDRI transfected MDCK cells (MDR1-MDCK) and Caco-2 cells. METHODS: MDR1-MDCK, MDCK and Caco-2 cells, grown to confluence on Transwell insert membranes, were used to investigate transcellular transport of [14C]-K02. RESULTS: The basolateral to apical (B-A) flux of 10 microM [14C]-K02 across MDR1-MDCK cells was markedly greater than its apical to basolateral (A-B) flux (ratio = 39). This specific B-A transport was temperature dependent and saturable, with an apparent Michaelis-Menten constant and maximum velocity of 69.1 +/- 19.5 microM and 148.9 +/- 16.3 pmol/min/cm2, respectively. This B-A flux was significantly inhibited by cyclosporine (IC50 = 17.1 +/- 0.7 microM), vinblastine (IC50 = 75.9 +/- 13.0 microM) and verapamil (IC50 = 236 +/- 63 microM). In Caco-2 cell monolayers, the B-A flux was reduced about 50% compared to that in MDR1-MDCK and the A-B flux was increased about 8-fold. The apparent Michaelis-Menten constant and maximum velocity values for the B-A transport were 71.8 +/- 45.9 microM and 35.3 +/- 9.0 pmol/min/ cm2. This B-A flux was also significantly inhibited by P-gp substrates/ inhibitors. Western blots showed that the P-gp expression in MDR1-MDCK cells was about 10-fold that in Caco-2 cells. CONCLUSIONS: K02 is transported by P-gp in both MDR1-MDCK and Caco-2 cells, and the in vitro interactions between K02 and various P-gp substrates may provide strategies to overcome the bioavailability barrier by intestinal P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Extraction and purification of biologically active intestinal trefoil factor from human meconium.

Intestinal trefoil factor (TFF3/ITF), a member of trefoil factor family (TFF) domain peptides, is normally expressed by goblet cells and secreted into the lumen of the intestinal tract, and plays an important role in the maintenance and repair of the intestinal mucosal barrier. Significant amounts of TFF3/ITF are present in the meconium of human infants. Here, we describe a relatively simple method for extraction and purification of natural human TFF3/ITF from meconium. The purification methods include acid treatment, ammonium sulfate precipitation, isoelectric precipitation, and iron exchange chromatography. A relatively large amount of natural TFF3/ITF can be purified from meconium of full-term infants and this purified, natural TFF3/ITF is biologically active in an ethanol-induced rat gastric mucosal injury model.

Animals↗