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PubMed2006

Thalidomide treatment reduces the alteration of paracellular barrier function in mice ileum during experimental colitis.

Small intestine permeability is frequently altered in inflammatory bowel diseases and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJs) and adherence. Thus, the aim of the present study was to examine the effects of thalidomide treatment on the permeability and structure of small intestine TJs in an animal model of experimental colitis induced by dinitrobenzene sulfonic acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin and zonula occludens 1. When compared with DNBS-treated mice, thalidomide-treated (200 mg/kg orally starting 30 min after the administration of DNBS) mice subjected to DNBS-induced colitis experienced a significantly reduced rate of the extent and severity of the histological signs of colon injury associated with a significant reduction of plasma and colon tumor necrosis factor alpha levels. After administration of DNBS to the mice induced a significant increase of ileal permeability was observed. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. In particular, we have observed that thalidomide treatment resulted in a significant reduction of the following: (1) the degree of colon injury, (2) the alteration of zonula occludens 1 and occludin localization (immunohistochemistry), and (3) intestinal permeability caused by DNBS in the colon. Taken together, our results clearly show that thalidomide treatment reduced small intestinal permeability in experimental colitis through the regulation of TJ protein.

Animals↗

PubMed2000

[The prevention of infection complicating acute necrotizing pancreatitis:an experimental study].

OBJECTIVE: To observe the effects of 5 intervention measures on infection complicating acute necrotizing pancreatitis (ANP) in dogs and rats. METHODS: A lethal model of ANP was reproduced by infusion of artificial bile into the biliopancreatic duct. Animals were divided randomly into: ANP group (no treatment); Chinese medicine group ("Qing Yi Tang"); Bifidobacterium mixture group; purgation group (MgSO(4)); selective decontamination of the digestive tract (SDD) group; and somatostatin group. The pancreas and intestine were observed morphologically and tight junction on ileum epithelia was assessed on cryofracture replicas. Blood and/or tissue levels of DAO and D-lactic acid and uric contents of lactulose/mannitol (L/M), served as indicators of gut barrier function, were measured at various time points. Intestinal flora and incidence of bacterial translocation (BT) to organs were examined. RESULTS: In early stage of ANP, mucosal and epithelial tight junction damage and flora disturbance occurred in the gut. In addition, the gut barrier function indicators deteriorated. The BT rates were as high as 78.6% (canine) and 59.5% (rat). Treatment with Chinese medicine markedly improved gut barrier function and reduced BT rate (32.1% - 37.0%). Having similar purgative response as Chinese medicine, MgSO4 did not show any beneficial effect on gut barrier protection and the incidence of BT was not reduced. In bifidobacterium mixture and SDD group, flora balance was preserved well and similar results as Chinese medicine were obtained. The BT rates of these two groups decreased to 33.9% and 33.3%, respectively. Somatostatin markedly blunted pancreatic tissue injury and ameliorated gut barrier damage during early phase of ANP. All intervention measures except for purgation also decreased mortalities (14.3% - 35.3%, compared with 58.8% of the no treatment group). CONCLUSIONS: Treatment with Chinese medicine, bifidobacterium mixture, SDD and somatostatin attenuated gut barrier damage and BT after ANP, and could be used to prevent secondary infection after ANP, but purgation alone is not effective.

Animals↗

PubMed2006

Alcohol intoxication and post-burn complications.

Results from the studies discussed in this article suggest that alcohol (EtOH) intoxication is a major public health problem. While the effects of injury and EtOH intoxication independent of each other have been studied in detail, only few studies have evaluated the effect of a combined insult of EtOH intoxication and burn injury on host defense. An analysis of the studies conducted in the clinical setting suggests that intoxicated patients require frequent intubations, experience delayed wound healing and longer hospital stay. Furthermore, there is a greater risk of mortality in these patients compared to those who sustained injuries in the absence of EtOH intoxication. On the other hand, there are a few studies that do not support this notion. The results obtained in experimental models clearly suggest that acute EtOH intoxication before burn injury impairs host defense and increases susceptibility to infection. Additionally, experimental data from our laboratory also indicate that EtOH intoxication before burn injury suppresses intestinal immune defense, impairs gut barrier functions and increases bacterial growth. This results in increased bacterial translocation in EtOH and burn injury. In addition, a decrease in cardiac function is also reported following a combined insult of EtOH intoxication and burn injury. Altogether, these findings suggest that EtOH intoxication before burn injury diminishes host resistance resulting in increased susceptibility to infection. Moreover, the findings of a higher incidence of infectious complications in burn and trauma patients who sustained injury in the presence of EtOH compared to those in its absence suggest that EtOH intoxication at the time of injury is a risk factor. Therefore blood EtOH should be monitored in burn/trauma patients at the time of admission in the emergency room.

Accidents↗

PubMed1995

Mice lacking glial fibrillary acidic protein display astrocytes devoid of intermediate filaments but develop and reproduce normally.

Glial fibrillary acidic protein (GFAP) is the main component of the intermediate filaments in cells of astroglial lineage, including astrocytes in the CNS, nonmyelin forming Schwann cells and enteric glia. To address the function of GFAP in vivo, we have disrupted the GFAP gene in mice via targeted mutation in embryonic stem cells. Mice lacking GFAP developed normally, reached adulthood and reproduced. We did not find any abnormalities in the histological architecture of the CNS, in their behavior, motility, memory, blood-brain barrier function, myenteric plexi histology or intestinal peristaltic movement. Comparisons between GFAP and S-100 immunohistochemical staining patterns in the hippocampus of wild-type and mutant mice suggested a normal abundance of astrocytes in GFAP-negative mice, however, in contrast to wild-types, GFAP-negative astrocytes of the hippocampus and in the white matter of the spinal cord were completely lacking intermediate filaments. This shows that the loss of GFAP intermediate filaments is not compensated for by the up-regulation of other intermediate filament proteins, such as vimentin. The GFAP-negative mice displayed post-traumatic reactive gliosis, which suggests that GFAP up-regulation, a hallmark of reactive gliosis, is not an obligatory requirement for this process.

Animals↗

PubMed2000

Regulation of bacterial translocation by nitric oxide.

Nitric oxide (NO) appears to play a paradoxical role in intestinal physiology. Although NO has potent bactericidal effects, a growing body of evidence suggests that it mediates intestinal injury and breakdown of gut barrier function. Data from our lab and others show an increased incidence of bacterial translocation following endotoxin challenge, and upregulation of inducible NO synthase (iNOS) mRNA and protein in the intestine. These phenomena co-localize with enterocyte apoptosis at the tips of the intestinal villi and immunoreactivity to nitrotyrosine. Electron microscopy reveals swollen mitochondria, implicating these organelles as putative targets for NO or its reactive nitrogen intermediates. We review some of the literature and discuss our current work in trying to define this mechanism.

Animals↗

PubMed1999

The effect of phospholipids and mucin on bacterial internalization in an enterocyte-cell culture model.

A primary component of the intestinal mucous layer that functions as a barrier to luminal bacteria is mucin, a high-molecular-weight glucoprotein. In addition, the mucous layer also contains other important elements such as phospholipids (PLs), which may effect bacterial translocation (BTL). It has been reported that mucin inhibits Escherichia coli translocation; however, the effect of PLs on intestinal permeability is still controversial. We have recently reported that the concentration of mucous PLs is higher in neonatal as compared to adult rabbits. The functional significance of these biochemical differences on BTL remains to be determined. The aim of this study was to evaluate the effect of PL and mucin composition on BTL in a human enterocyte-cell culture model. Human enterocyte Caco-2 cells were seeded in 24-well tissue-culture plates and grown for 14 days to confluence. The monolayers were pretreated with phosphate buffered saline as control, 10 mg/ml or 20 mg/ml mucin, 0. 5 mM or 1.0 mM PL mixture based on neonatal (NPL) and adult (APL) composition, and 10 mg/ml mucin with 0.5 mM either APL or NPL mixtures 30 min before a 120-min incubation period at 37 degrees C with 10(8) colony forming units (CFU) of E. coli C25. Non-internalized bacteria were killed by the addition of gentamicin. Internalized bacteria were quantified by counting CFU from enterocyte-cell lysates grown on MacConkey's agar. Mucin inhibited bacterial internalization, while both compositions of PLs promoted it. Mucin added to the PL solution also diminished the stimulatory effect of PLs on bacterial internalization. These results indicate that the increased concentration of PLs found in the intestinal mucous layer of neonates, and/or the alteration in the balance between PLs and mucin, may play a role in the increased BTL seen in neonates.

Animals↗

PubMed2003

Glycyl-glutamine-supplemented long-term total parenteral nutrition selectively improves structure and function in heterotopic small-bowel autotransplantation in the pig.

Marked atrophy and impaired absorptive and barrier function occur in transplanted small intestinal graft during total parenteral nutrition (TPN), TPN is required by all the patients after small bowel transplantation (SBT). Glutamine (Gln) is a conditional indispensable amino acid that is not included in regimens for parenteral nutrition because of its chemical instability in aqueous solution. Glutamine-containing dipeptide, however, is heat-stable. With this study, we determine whether the glycyl-glutamine-supplemented long-term TPN improves mucosal structure and function in heterotopic transplanted small intestinal graft in the pig. Ten outbred pigs, randomly divided into two groups, underwent heterotopic small bowel autotransplantation. In the STPN group, the animals received standard TPN without glycyl-glutamine (Gly-Gln) and in the GTPN group, the animals received isonitrogenous (0.3g kg day(-1)) and isocalories (nonprotein calories, 30 kcal kg day(-1)) TPN with Gly-Gln (3% Gln) for 28 days. At the end of TPN, there was no significant difference in the body weight loss between two groups ( P>0.05). The mucosal contents of Gln and protein were significantly higher in the GTPN group than in the STPN group ( P<0.05). The mucosal disaccharidase activities in the homogenate of the graft mucosa of the GTPN group were significantly higher than that of the STPN group ( P<0.05). The villous height, surface area, mucosal thickness were significantly higher in the GTPN group than in the STPN group ( P<0.05). There was no significant difference in crypt depth between the two groups ( P>0.05). These results suggest that glycyl-glutamine-supplemented long-term TPN improves graft mucosal structure in heterotopic autotransplanted small bowel grafts in the pig. Long-term (4 weeks) TPN supplemented with Gln could alleviate small intestinal graft atrophy, but could not completely eliminate atrophy.

Animals↗

PubMed1994

Role of mucin, mannose, and beta-1 integrin receptors in Escherichia coli translocation across Caco-2 cell monolayers.

Our previous work suggests that Caco-2 cells play an active role in bacterial translocation (BT). Since bacterial enterocyte interactions may be receptor-mediated, the current study was performed to investigate the role of beta 1 integrin and mannose receptors as well as the general protective effect of the mucous layer in this process. Caco-2 cells grown to confluence on semipermeable membranes contained in the upper compartment of a two compartment system were utilized. BT was assessed by quantitating the number of Escherichia coli crossing the monolayers after challenge with 10(8) E. coli C25. Pretreatment of the Caco-2 cells with the beta 1 integrin receptor competitive inhibitors fibronectin or RGD did not inhibit BT; while pretreatment of Caco-2 cells with the LFA-1 (lectin) receptor competitive inhibitor mannose (12 mg/ml) or purified mucin (8 mg/ml) decreased BT compared to control membranes (p < .001). Transepithelial resistance was similar among all the groups indicating maintenance of tight junction integrity. These studies suggest that E. coli BT in the Caco-2 system can be reduced by mannose and that intestinal mucin contributes to the barrier function of the monolayer.

Amino Acid Sequence↗

PubMed2005

Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion.

The functional integrity of the intestinal epithelial barrier forms a major defense against invading pathogens, including gastrointestinal-dwelling nematodes, which are ubiquitous in their distribution worldwide. Here, we show that an increase in the rate of epithelial cell turnover in the large intestine acts like an "epithelial escalator" to expel Trichuris and that the rate of epithelial cell movement is under immune control by the cytokine interleukin-13 and the chemokine CXCL10. This host protective mechanism against intestinal pathogens has implications for our wider understanding of the multifunctional role played by intestinal epithelium in mucosal defense.

Animals↗

PubMed2004

Aeromonas hydrophila beta-hemolysin induces active chloride secretion in colon epithelial cells (HT-29/B6).

The diarrheal mechanisms in Aeromonas enteritis are not completely understood. In this study we investigated the effect of aeromonads and of their secretory products on ion secretion and barrier function of monolayers of human intestinal cells (HT-29/B6). Ion secretion was determined as a short-circuit current (I(SC)) of HT-29/B6 monolayers mounted in Ussing-type chambers. Transepithelial resistance (R(t)) served as a measure of permeability. A diarrheal strain of Aeromonas hydrophila (strain Sb) added to the mucosal side of HT-29/B6 monolayers induced a significant I(SC) (39 +/- 3 microA/cm(2)) and decreased the R(t) to approximately 10% of the initial value. A qualitatively identical response was obtained with sterile supernatant of strain Sb, and Aeromonas supernatant also induced a significant I(SC) in totally stripped human colon. Tracer flux and ion replacement studies revealed the I(SC) to be mainly accounted for by electrogenic Cl(-) secretion. Supernatant applied serosally completely abolished basal I(SC). The supernatant-induced I(SC) was inhibited by the protein kinase C inhibitor chelerythrine, whereas a protein kinase A inhibitor (H8) and a Ca(2+) chelator (BAPTA-AM) had no effect. Physicochemical properties indicated that the supernatant's active compound was an aerolysin-related Aeromonas beta-hemolysin. Accordingly, identical I(SC) and R(t) responses were obtained with Escherichia coli lysates harboring the cloned beta-hemolysin gene from strain SB or the aerA gene encoding for aerolysin. Sequence comparison revealed a 64% homology between aerolysin and the beta-hemolysin cloned from Aeromonas sp. strain Sb. In conclusion, beta-hemolysin secreted by pathogenic aeromonads induces active Cl(-) secretion in the intestinal epithelium, possibly by channel insertion into the apical membrane and by activation of protein kinase C.

Aeromonas hydrophila↗

PubMed1999

[Effect of catecholamines on splanchnic perfusion in sepsis].

Splanchnic ischemia is frequent in sepsis and septic shock and is related to impairment in intestinal permeability, derangement in mucosal barrier functions and translocation of proinflammatory mediators. These changes can contribute to the pathogenesis of multiple organ failure. Vasoactive drugs such as dobutamine and dopexamine can improve splanchnic perfusion and gastric intramucosal pH during sepsis. However, contradictory results have been obtained with dopamine and norepinephrine. On the other hand, epinephrine further impairs splanchnic perfusion. In view of the contradictory effects of different vasoactive drugs, gastric tonometry must be measured during their use, to find the optimal drug combination that optimizes splanchnic blood flow.

Dopamine↗

PubMed1990

[The mucosa of the small intestine: development of the cellular lipid composition during enterocyte differentiation and postnatal maturation].

Alterations in lipids linked to intestinal maturation and enterocyte differentiation were reviewed. The 3 main lipid components of cell membranes, ie cholesterol, phospholipids and glycolipids, were examined. Cell phospholipid content increases from the crypts to the mid-villus, which accounts for membrane development and organelle growth in differentiating cells. Changes in the proportion of phospholipid polar head groups occur in brush border membrane during postnatal maturation of the small intestine. The possibility that phospholipid fatty acid composition in differentiating cells might be altered by dietary lipids is discussed. Cholesterol biosynthesis mainly occurs in crypt and lower villus cells whereas its absorption from luminal content and esterification into lipoproteins occur in upper villus mature cells. Cholesterol cell content increases in mature cells in comparison to immature cells on the one hand, and in the distal by comparison with proximal parts of the intestine on the other. Increasing cholesterol content is generally correlated with decreasing membrane fluidity, which in turn could modulate functional properties of the mucosa. Glycosphingolipids are mainly found in the brush border membrane, which contains 20-30% glycolipids by weight of total lipids. These components tend to reinforce the membrane stability and significantly contribute to the surface properties of epithelial cells. The latter undergo noticeable changes during cell differentiation and postnatal maturation. Significant changes in both the glycosidic and lipophilic parts of glycosphingolipid molecules occur in differentiating cells and are of possible importance in the process of mucosal maturation. It is possible that the addition of a terminal sialic acid (sialyltransferase activity) instead of a terminal galactose (galactosyltransferase) to an endogenous acceptor (lactosylceramide) could constitute an important event in the differentiation process, and may account for the increasing content of hematosides along the intestinal villus of rat. Alterations in lipid counterpart mainly consist of hydroxylation of fatty acids in hematosides during postnatal maturation or in glucosylceramides during cell differentiation. Collectively these intestinal lipid changes may contribute in part to the development of mucosal barrier, selective permeability and functional properties of the mature intestinal mucosa.

Animals↗

PubMed1998

Derangement of mucosal barrier function by bacteria colonizing the rat colonic mucosa.

BACKGROUND: Interaction between gut flora and the intestinal barrier may involve changes in permeability. METHODS: Rats with a colonic segment excluded from faecal transit were surgically prepared. Matched groups were either kept on luminal antibiotics to prevent colonization of the segment or recolonized with mixed rat flora. Permeability to low-dose trinitrobenzenesulphonic acid (TNBS) or trinitrophenol (TNP), and mucosal injury by the compounds at a high dose were tested in antibiotic and recolonized rats (the compounds differ in water solubility but share a common antigenic domain). RESULTS: Lumen to blood clearance of the hydrophilic probe (TNBS) was faster in recolonized than in antibiotic rats. The hydrophobic compound TNP was absorbed at faster rates than TNBS, but there was no difference between antibiotic and recolonized rats. Instillation of TNBS at a high dose induced mucosal release of inflammatory mediators and tissue myeloperoxidase accumulation in recolonized rats but not in antibiotic rats. Large necrotic lesions with submucosal involvement after TNBS were only observed in recolonized rats. In contrast, TNP induced mucosal inflammation and large lesions with submucosal necrosis both in recolonized and in antibiotic rats. CONCLUSION: Colonizing bacteria may increase intestinal permeability to hydrophilic compounds and render the mucosa susceptible to injury.

Animals↗

PubMed2003

Passage of Salmonella through the crop and gizzard of broiler chickens fed with fermented liquid feed.

In vivo experiments were conducted in order to investigate the passage and bacterial reduction of Salmonella in the crop and gizzard of chickens when fed two different feeds. The chickens were fed dry conventional feed and fermented liquid feed. The fermented feed contains a relatively high concentration of lactic and acetic acid and lactobacilli. One and three week old broiler chickens were necropsied at short intervals after inoculation with Salmonella Enteritidis. Counts of Salmonella from the crop, gizzard, duodenum, caecum and colon/rectum were obtained. This revealed a sharper decrease of Salmonella in the anterior parts of the gastro-intestinal tract in chickens fed with fermented feed than in chickens fed dry feed. It is therefore concluded that fermented feed improves the barrier formed by the crop and gizzard. The reduction of Salmonella is fully realised in the crop and gizzard. The lower intestinal compartment did not show a substantial effect on the reduction of Salmonella. The performed in vivo method appeared to be an appropriate way to study intervention strategies that aim to control Salmonella by improving the barrier function of the upper gastro-intestinal tract.

Animal Feed↗

PubMed2002

[The phospholipase A2 inhibitor, aristolochic acid, inhibits chloride secretion without altering barrier function].

AIM: To study the effect of aristolochic acid (AA) and the effect of phospholipase A2 (PLA2) on barrier function and electrogenic chloride secretion in intestinal epithelium. MATERIAL AND METHODS: Electrophysiological studies were performed in the T84 cell line and rat distal colon. Ionic secretion and transepithelial resistance were determined. RESULTS: Exogenous AA increased calcium-stimulated secretion in the T84 cell line. Incubation of rat distal colon in the presence of AA, a PLA2 inhibitor, reduced basal ionic secretion without affecting transepithelial resistance and inhibited ionic secretion stimulated by a cyclic adenosine monophosphate (AMPc) agonist, forskolin. In T84 cells, AA inhibited both carbachol- and forskolin-stimulated secretion. CONCLUSION: PLA2 modulates electrogenic chloride secretion but has no effect on barrier function in the T84 cell line or in rat distal colon.

Animals↗

PubMedDate not supplied

Intestinal amino acid absorption during sepsis.

Sepsis has been shown to cause a decrease in mesenteric blood flow in association with ultrastructural changes in the small intestine and impaired immune, barrier, and metabolic functions of the gut. These impairments in the structure and function of the gastrointestinal tract may have a detrimental effect on the morbidity and mortality of sepsis. Two recent studies have shown that the ability of the small intestine to absorb amino acids is also impaired during sepsis, but the systemic and cellular mechanisms of this impairment are not known. Release of cytokines induced by systemic bacteria or endotoxin may lead to a reduction in the synthesis of transporter proteins by the enterocyte at a time when there is reduced availability of both luminal (because of anorexia) and circulating (because of reduced mesenteric blood flow) substrates. Future research needs to investigate the systemic and local mediation of the sepsis-induced reduction in intestinal amino acid absorption and the possibility of correcting the defect by the administration of enteral nutrients, hormones, or drugs.

Amino Acids↗

PubMed1992

Clostridium difficile toxin B disrupts the barrier function of T84 monolayers.

The contribution of toxin B to Clostridium difficile-associated infection is undefined. Toxin B induces dramatic phenotypic alterations (cytotoxic effects) in cultured mesenchymal and nonintestinal epithelial cells, yet its effects on intestinal epithelial cells are not clearly understood. The alterations induced by toxin B in nonintestinal cells appear to be secondary to toxin-induced redistribution of filamentous actin. It has not been determined whether toxin B exerts similar effects on cultured intestinal epithelial cells or whether such phenotypic alterations are of any physiological consequence. To address these questions, we examined the effect of C. difficile toxin B on the phenotype and barrier function of T84 cell monolayers. Our studies show that the cytotoxic effects of toxin B, i.e., cell rounding, do extend to cultured intestinal epithelial cells (T84). In addition, toxin B dramatically reduces the barrier function of T84 monolayers grown on collagen-coated filters. Toxin B-induced redistribution of filamentous actin appears to be responsible for the alterations in both intestinal epithelial cell phenotype and barrier function. Specifically, filamentous actin comprising the perijunctional actomyosin ring, known to be important in regulating tight junction permeability, is condensed into discrete plaques. Flux studies confirm that the permeability defect is at the level of the tight junction. We conclude that toxin-induced changes in actin distribution perturb intercellular junctional contacts and thereby ablate epithelial barrier function. There was no evidence of cell death as determined by lactate dehydrogenase release assays.

Actins↗

PubMed2000

Prostanoid receptors in intestinal epithelium: selective expression, function, and change with inflammation.

The tissue concentration of PGE(2)is heightened during mucosal inflammation. Nevertheless, the cellular targets of this prostanoid and its effects on epithelial cell physiology are incompletely understood. We used a panel of specific immunoglobulin and mRNA probes in order to localize and quantitate the four member EP family of prostanoid receptors for binding PGE(2)on cells of histologically normal and inflamed human colonic mucosa, and then examined the physiological consequences for the epithelial component of intestine, with special attention to its barrier function. Prostanoid receptors were selectively expressed on a limited number of human colonic mucosal cells, and differed markedly between normal and inflamed tissue. In non-inflamed mucosa, EP(2)and EP(3)were expressed on epithelia at the apex of crypts; while EP(4)was expressed on surface and lateral crypt epithelia. Dual immunostaining and in situ hybridization with digoxygenin-labelled RNA probes largely confirmed the epithelial localization of EP(4). On the other hand, during inflammation, lateral crypt (non-surface) epithelial cells newly and significantly expressed prostanoid receptors EP(2)and EP(3)(p<0.05, by computer-assisted densitometry). Functionally, exogenous E series prostanoids applied to epithelial monolayers in nM concentrations brought about a 24% increase in the level of barrier function; an associated rise in intracellular cAMP (EC(50)of 281); and protection of epithelium from the effects of T cell cytokines. A major perturbation in the number and distribution of functional eicosonoid receptors on epithelia occurs in chronic inflammation of human colonic mucosa.

Alprostadil↗