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PubMed2005

[Dynamic observation of pathological changes and expression of nuclear factor-kappaB in the intestinal mucosa of rats after diffuse brain injury].

OBJECTIVE: To investigate the dynamic pathological changes in the intestinal mucosa of rats and the role of activation of nuclear factor-kappaB (NF-kappaB) in the alteration in intestinal mucosal barrier dysfunction after diffuse brain injury. METHODS: The animal model established by Marmarou was used to produce diffuse brain injury. One hundred and fifty male Wistar rats were randomly divided into nine groups in terms of postinjury time: 1, 2, 4, 8, 12, 24, 48, 72, 168 hours after injury, and control group. Mucosal thickness, villous height and width were estimated under light microscope, and expression of NF-kappaB was assessed with immunohistochemical staining in control group to compare with those in injury groups. RESULTS: Mucosal thickness, villous height and width were diminished and the optical density of expression of NF-kappaB was much higher in the injury groups than those of control group. CONCLUSION: The structure of intestinal mucosa is damaged in the earlier stages after diffuse brain injury. NF-kappaB is activated by cellular stress, which may be involved in the pathogenesis of secondary intestinal lesion.

Animals↗
PubMed2006

Spontaneous bacterial peritonitis: pathogenesis, diagnosis, treatment.

Due to inadequate defence mechanisms, cirrhotic patients with ascites have an increased susceptibility to infections, the most frequent and the most severe one being spontaneous bacterial peritonitis (SBP). SBP diagnosis is based on testing of the ascitic fluid obtained by paracentesis. A polymorphonuclear cell count of more than 250 cells/mm3 of ascitic fluid is considered diagnostic and from cultures of ascitic fluid only one germ should be isolated. 60% of the SBP episodes are produced by gram negative enteric bacilli - E. coli and Klebsiella spp. being the most frequent isolated microorganisms. The most important pathogenic mechanism for SBP is bacterial translocation. In liver cirrhosis, three mechanisms are proposed for the pathogenesis of SBP: intestinal bacterial overgrowth, the alterations (structural and functional) of the intestinal mucosal barrier and the deficiencies of the local immune response. The most appropriate antibiotic treatment is a third generation cephalosporin (Cefotaxim or Ceftriaxon) which should be administrated for 5 days. With early start of the antibiotic treatment, the short-term prognosis of cirrhotic patients with SBP has improved significantly. Unfortunately, the long term prognosis remains extremely poor due to the severity of subjacent liver disease.

Anti-Bacterial Agents↗
PubMed2006

Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application.

The intestinal epithelium is faced with the complex task of providing a barrier while also allowing nutrient and water absorption. The frequency with which these processes are disrupted in disease can be taken as evidence of their importance. It is therefore of interest to define the mechanisms of altered intestinal barrier and transport function and develop means to correct disease-associated defects. Over the past 10 years, some of the molecular events underlying physiological epithelial barrier regulation have been described. Remarkably, recent advances have shown that activation of the same mechanisms is central to barrier dysfunction in both in vitro and in vivo models of disease. Although the contribution of barrier dysfunction to pathogenesis of chronic disease remains incompletely understood, it is now clear that cytoskeletal regulation of barrier function is both an important pathogenic process and that targeted inhibition of myosin light chain kinase, which affects this cytoskeleton-dependent tight junction dysfunction, is an attractive candidate for therapeutic intervention.

Actins↗
PubMed1988

Morphological aspects of gastrointestinal tract invasion by Candida albicans in the infant mouse.

The infant mouse has proved to be a useful model for examination of various aspects of gastrointestinal and systemic candidosis. Oral-intragastric inoculation of 5-6-day-old mice with yeast of a virulent strain of Candida albicans (CA30) resulted in systemic spread within 30 min after challenge. Histological examinations of the gastrointestinal (GI) tract have shown that the highest frequency of invasion of the mucosa by yeast cells occurred in the region of the jejunum 1-3 h after inoculation. Results of ultrastructural examinations of sites where the fungus invaded the bowel wall suggested that C. albicans yeast cells are capable of progressive extracellular digestion of the intestinal mucus barrier and microvillus layer, followed by intracellular invasion of columnar epithelial cells. Minimal disruption of cytoplasmic contents of the host epithelial cells appears to result from invasion and transmigration of the pathogen. The infant mouse model is suggested to be well suited for localization of extracellular products of C. albicans yeast in vivo which may play pivotal roles in the invasion of host tissue during GI candidosis.

Animals↗
PubMed2003

Induction of proinflammatory responses in the human monocytic cell line THP-1 by Campylobacter jejuni.

Campylobacter jejuni can cause an enteritis that is associated with an acute inflammatory response at the gut epithelial surface. The signals inducing inflammation are unknown. C. jejuni can penetrate the intestinal epithelial barrier and may then interact with leucocytes, potentially inducing proinflammatory responses. To investigate this, we studied the interaction of C. jejuni with the human monocytic cell line THP-1 and show that a range of proinflammatory cytokines and chemokines is induced. These include interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-8, and tumor necrosis factor alpha. Responses can be induced by killed Campylobacter as well as live bacteria and do not depend on the cytolethal distending toxin. C. jejuni infection of THP-1 cells triggers both nuclear translocation of functional NF-kappa B and stimulation of IL-1 alpha, indicating that NF-kappa B-dependent and -independent stimulation is occurring. The extent of proinflammatory cytokine stimulation suggests that monocytes might significantly contribute to intestinal inflammation and disease pathology.

Bacterial Toxins↗
PubMed2003

Transport of parthenolide across human intestinal cells (Caco-2).

This study examined the intestinal epithelial membrane transport of the sesquiterpene lactone parthenolide, a bioactive compound present in the migraine prophylactic herb feverfew. The Caco-2 human colonic cell line was used as an in vitro model of the human intestinal mucosal barrier. The bidirectional transport (apical to basolateral and basolateral to apical) of parthenolide was investigated using Caco-2 monolayers grown on Transwell inserts. Quantitation of parthenolide was performed using high performance liquid chromatography (HPLC). Apical to basolateral and basolateral to apical permeability coefficients and percent transport were calculated and a potential bioavailability of parthenolide was determined. Sodium fluorescein was used as a marker for paracellular leakage. Parthenolide, at a concentration of 250 microM, demonstrated substantial linear transport across the monolayer. The transport parameters were not affected by the presence of MK-571, an inhibitor of multidrug resistance transporter P-glycoprotein (MRP). Upon comparison of the transport parameters of parthenolide with atenolol under identical conditions and the reported values for model compounds like mannitol and propranolol, it is concluded that parthenolide is effectively absorbed through the intestinal mucosa via a passive diffusion mechanism.

Biological Transport, Active↗
PubMed1992

[An animal model of posttraumatic multiple system organ failure (MSOF)].

Hemorrhagic shock, sepsis, excessive systemic inflammatory reactions, and failure of intestinal mucosal barrier function are known to be major predisposing factors in the development of MSOF in patients after severe trauma or burns. We investigated the possibility of complicating clinically simulating MSOF in animals. Our results showed that, with compounded traumatic factors, including damages to the bowel, and proper circulatory and respiratory support, an animal model which simulated the pathophysiology and histopathology of MSOF could be reproduced to offer opportunity for the study of mechanisms and therapy. Markers of MSOF were also described for reference.

Animals↗
PubMed2005

Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption.

Oxidants such as monochloramine (NH(2)Cl) decrease epithelial barrier function by disrupting perijunctional actin and possibly affecting the distribution of tight junctional proteins. These effects can, in theory, disturb cell polarization and affect critical membrane proteins by compromising molecular fence function of the tight junctions. To examine these possibilities, we investigated the actions of NH(2)Cl on the distribution, function, and integrity of barrier-associated membrane, cytoskeletal, and adaptor proteins in human colonic Caco-2 epithelial monolayers. NH(2)Cl causes a time-dependent decrease in both detergent-insoluble and -soluble zonula occludens (ZO)-1 abundance, more rapidly in the former. Decreases in occludin levels in the detergent-insoluble fraction were observed soon after the fall of ZO-1 levels. The actin depolymerizer cytochalasin D resulted in a decreased transepithelial resistance (TER) more quickly than NH(2)Cl but caused a more modest and slower reduction in ZO-1 levels and in occludin redistribution. No changes in the cellular distribution of claudin-1, claudin-5, or ZO-2 were observed after NH(2)Cl. However, in subsequent studies, the immunofluorescent cellular staining pattern of all these proteins was altered by NH(2)Cl. The actin-stabilizing agent phalloidin did not prevent NH(2)Cl-induced decreases in TER or increases of apical to basolateral flux of the paracellular permeability marker mannitol. However, it partially blocked changes in ZO-1 and occludin distribution. Tight junctional fence function was also compromised by NH(2)Cl, observed as a redistribution of the alpha-subunit of basolateral Na(+)-K(+)-ATPase to the apical membrane, an effect not found with the apical membrane protein Na(+)/H(+) exchanger isoform 3. In conclusion, oxidants not only disrupt perijunctional actin but also cause redistribution of tight junctional proteins, resulting in compromised intestinal epithelial barrier and fence function. These effects are likely to contribute to the development of malabsorption and dysfunction associated with mucosal inflammation of the digestive tract.

Actins↗
PubMed1998

The electroanalysis of mannitol, xylose and lactulose at copper electrodes: voltammetric studies and bioanalysis in human urine by means of HPLC with electrochemical detection.

The electrochemical behavior of mannitol, xylose and lactulose has been investigated at a copper working electrode. A sensitive, accurate and precise method employing HPLC with electrochemical detection in the d.c. amperometric mode, has been developed and validated for the determination of mannitol and lactulose in human urine. The ratio of these probe carbohydrates is altered in conditions that cause damage to the intestinal mucosal barrier. Systematic studies employing cyclic voltammetry indicate that the electrode reaction involves an electrocatalytic oxidation of each carbohydrate in a process yielding a single irreversible anodic wave that is dependent on the ionic strength of the sodium hydroxide supporting electrolyte solution. High performance liquid chromatography with electrochemical detection was performed using a thin-layer cell housing a custom manufactured copper working electrode. The optimized HPLC method can detect 72, 57 and 419 pg of mannitol, xylose and lactulose injected on column, respectively. The corresponding linear calibration ranges are 359 pg-2.24 microgram, 57.4 pg-896 ng and 419 pg-262 ng, respectively. Solid-phase extraction of human urine on polar sorbents, and direct injection after simple 1 + 99 dilution in 0.025 M NaOH were compared for bioanalysis. Direct injection was selected for further method developed as the technique proved robust and simple. The optimized method was validated for the determination of mannitol and lactulose in human urine over the concentration ranges predicted when assessing intestinal permeability (0.25-2.5 mg ml-1 mannitol and 0.05-1.0 mg ml-1 lactulose). Over these ranges intra- and inter-assay bias is < +/- 6.5%, and imprecision (coefficient of variation) is < 9% for each carbohydrate. The validated method provides a useful alternative to HPLC with pulsed-amperometric detection at gold electrodes.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Development of a method to detect secretory mucinolytic activity from Candida albicans.

Ultrastructural examinations of sites where Candida albicans invaded the bowel wall after oral intragastric inoculation of infant mice suggested that blastoconidia are capable of progressive extracellular digestion of the intestinal mucus barrier. Microplate assay methods, based on biotin or digoxigenin-labelling systems, were therefore devised for quantitation of protease and glycosidase activities against the glycoprotein mucin. Labelled mucin was adsorbed on microplate wells, incubated with sample to be assayed for enzyme activity, and the remaining labelled mucin was quantitated by spectrophotometry. Proteolytic activity against mucin was demonstrated using concentrated culture filtrate of C. albicans strain LAM-1, grown in yeast nitrogen base medium containing mucin as sole nitrogen source. The activity was inhibited by boiling for 10 min or by incubation with the aspartyl proteinase inhibitor pepstatin A.

Animals↗
PubMed1999

Midazolam metabolism by modified Caco-2 monolayers: effects of extracellular protein binding.

It has been suggested that the binding of a drug to plasma proteins will influence the intestinal extraction efficiency when drug is delivered to the mucosal epithelium via either the gut lumen or vasculature. We evaluated this hypothesis using cytochrome P-450 (CYP)3A4-expressing Caco-2 monolayers as a model for the intestinal epithelial barrier and midazolam as a CYP3A-specific enzyme probe. The rate of 1'-hydroxylation was measured following apical or basolateral midazolam administration to monolayers incubated in the presence or absence of 4 g/dl of human serum albumin (HSA) in the basolateral compartment medium. The midazolam-free fraction in culture medium containing HSA was 3.3%. Inclusion of HSA in the basolateral medium decreased peak intracellular midazolam accumulation after an apical midazolam dose (3 microM) by 35% and reduced the 1'-hydroxymidazolam formation rate by approximately 20%. Because of the accelerated diffusion of midazolam through the cell monolayer and into the basolateral compartment, there was a 61% reduction in the first-pass metabolic extraction ratio: 13.3 +/- 0. 12% for control versus 5.2 +/- 1% with HSA. Compared with control, addition of HSA resulted in a 91% decrease in the peak intracellular midazolam level and a 86% decrease in the rate of 1'-hydroxylation after the administration of midazolam into basolateral medium. These findings suggest that, in vivo, binding of a drug to plasma proteins will impact both first-pass and systemic intestinal midazolam extraction efficiency. Furthermore, the effect will be more pronounced for a drug that is delivered to mucosal enterocytes by way of arterial blood, compared with oral drug delivery.

Algorithms↗
PubMed2005

Short-chain fatty acid induces intestinal mucosal injury in newborn rats and down-regulates intestinal trefoil factor gene expression in vivo and in vitro.

BACKGROUND: Luminal administration of short-chain fatty acids (SCFAs) induces dose-dependent intestinal mucosal injury in newborn rats. However, the mechanism underlying the injurious effects of SCFAs on intestinal mucosa in neonates is unclear. Intestinal trefoil factor (ITF) is a factor important for the maintenance and repair of the intestinal mucosal barrier. Regulation of ITF gene expression by SCFAs may be involved as one of the mechanisms. OBJECTIVES: To examine the effect of butyrate-induced colonic injury on ITF gene expression in vivo and to determine the molecular mechanisms underlying the butyrate regulation of ITF gene expression in vitro. METHODS: Whole-section colonic tissues from 9- to 10-day-old Sprague-Dawley rats that have received butyric acid at two different concentrations (150 mmol/L and 300 mmol/L) and for different time periods were processed for total RNA extraction and Northern blot analysis. Littermates that received normal saline or lactic acid at 300 mmol/L served as controls. The effect of butyrate on ITF gene expression was also examined in vitro with human colonic epithelial LS 174T cells. To further define ITF gene regulation by butyrate, transient transfection assays were performed on a 930 bp human ITF promoter-luciferase reporter gene plasmid in LS174T cells with or without the presence of butyrate. RESULTS: Concurrent with mucosal injury, butyric acid inhibited ITF gene expression in colonic tissues of newborn rats as well as in intestinal epithelial cells in a dose- and time-dependent manner. Furthermore, butyrate reduced ITF promoter report gene activity in transfected LS174T cell, suggesting that butyric acid regulation of ITF gene is by way of a specific ITF promoter. CONCLUSIONS: Butyric acid induced-intestinal mucosal injury in newborn rats is associated with down-regulation of ITF gene expression. The changes in ITF gene expression in vivo may play a role in the pathogenesis of SCFA-induced intestinal mucosal injury.

Animals↗
PubMed2003

Shigellosis: innate mechanisms of inflammatory destruction of the intestinal epithelium, adaptive immune response, and vaccine development.

Acute infectious colitis remains a major pediatric issue of worldwide impact because it still represents a significant public health burden among the larger group of diarrheal diseases with the highest mortality rate. It is also a relevant model of inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis. Among cases of acute colitis of infectious origin, shigellosis is certainly the one that has benefited the most from a significant research effort. Shigella, the causative agent, is a Gram-negative bacterium that has the capacity to invade, disrupt, and cause inflammatory destruction of the intestinal epithelial barrier. The molecular and cellular bases of this invasive phenotype essentially encompass crossing of the epithelial lining, apoptotic killing of macrophages, entry into epithelial cells, and escape into the cytoplasm, followed by cell-to-cell spread. Intracellular colonization is likely to protect the micro-organisms from killing by humoral and cellular effectors of the innate immune response. Concurrently, the capacity of Shigella to reprogram invaded epithelial cells to produce proinflammatory mediators plays a major role in the strong inflammatory profile of the disease. This profile is likely to impact on the nature and quality of the adaptive response, which is dominated by humoral protection at the mucosal level.

Adaptation, Physiological↗
PubMed2004

Paneth cell granule depletion in the human small intestine under infective and nutritional stress.

Paneth cells are important contributors to the intestinal antimicrobial barrier through synthesis and release of antimicrobial peptides and proteins. Animal studies indicate that Paneth cell numbers, location and granule morphology are altered by infection and zinc status. We examined human tissue to determine whether Paneth cell numbers, distribution or granule morphology are altered in infective, inflammatory and nutritional disorders. Archival sections from infective disorders (giardiasis, cryptosporidiosis, HIV, helminth infection) were compared with active inflammatory conditions (coeliac, Crohn's and graft-versus-host diseases) and histologically normal tissues. A subset of tissues was studied by electron microscopy and TUNEL staining for apoptosis. Human defensin-5 (HD5) peptide and mRNA was analysed by immunohistochemistry, in situ hybridization and quantitative reverse transcription polymerase chain reaction. Sections from a tropical population cohort study were then analysed to determine the relationship of granule depletion to infection, nutritional status and plasma zinc concentration. In HIV-related cryptosporidiosis, but not other disorders, Paneth cells were reduced in number and markedly depleted of granules. Paneth cell granule depletion was associated with reduced HD5 immunoreactivity, but this was not due to apoptosis and there was no reduction in mRNA transcripts. In the tropical population studied, depletion of granules was associated with reduced body mass index, reduced plasma zinc levels and HIV infection. Paneth cell granules in human small intestine may be depleted in response to infective and nutritional stress. We postulate that this is one mechanism through which zinc status influences host susceptibility to intestinal infection.

AIDS-Related Opportunistic Infections↗
PubMed2000

Polarized transport of hydrophilic compounds across rat colonic mucosa from serosa to mucosa is temperature dependent.

BACKGROUND & AIMS: In both clinical and experimental studies, intestinal epithelial barrier function is routinely assessed by measuring mucosal permeability to various hydrophilic compounds. We performed experiments to determine whether permeation of several hydrophilic compounds across rat colonic mucosa is polarized. METHODS: Sheets of colonic mucosa, stripped of the underlying seromuscular coats, were mounted in Ussing chambers. RESULTS: The rates of permeation across colonic mucosa by numerous hydrophilic compounds (fluorescein isothiocyanate [FITC]-dextrans with molecular weights of 4000 [FD4] and 70,000 [FD70] daltons, fluorescein disulfonic acid [FS], lucifer yellow [LY], lactulose, and mannitol) were several times greater in the serosal-to-mucosal (S-->M) direction than in the opposite direction. Increased S-->M permeation by FD4, lactulose, and mannitol was evident at 37 degrees C, but not at 4 degrees C. Efflux of FD4 and FS in the S-->M direction was dose-dependently inhibited by verapamil, an inhibitor of the P-glycoprotein efflux system. Indomethacin, an anion transporter inhibitor, showed no effect on the S-->M permeation of FD4, FD70, FS, or LY. Adding an excess of unlabeled dextran (mol wt, 10,000 daltons) dose-dependently decreased the S-->M efflux of FD4, but not FS or LY. CONCLUSIONS: The transport across rat colonic mucosa of a number of hydrophilic substances, including some compounds that are commonly used to measure intestinal permeability in clinical practice, is greater in the S-->M than in the M-->S direction. S-->M transport of these hydrophilic solutes is temperature dependent, suggesting that the process is an active one. S-->M transport of FD4 may occur via a process that manifests some degree of substrate specificity for polysaccharides.

Animals↗
PubMed1999

Absorption prediction from physicochemical parameters.

Modern drug design not only focuses on the pharmacological activity of a compound but also considers its ability to be absorbed and to reach its site of action. The prediction of in vivo barrier permeabilities, particularly intestinal absorption and blood-brain barrier passage, are substantial concerns in the development of new drug compounds. For several decades, n-octanol-water partition coefficients dominated absorption prediction. In recent years, the basic physicochemical parameters describing both membrane permeability and lipophilicity have been established. This review provides an outline of some selected absorption-prediction models with emphasis on intestinal absorption.

Journal Article↗
PubMed1991

[ The intestine-liver-lung axis in septic syndrome].

Abacteremic sepsis is frequent in intensive care units, and is closely associated with the development of adult respiratory distress syndrome (ARDS) and multiple systems organ failure (MSOF). It carries a high mortality. The gut is thought to be the "motor" of such septic states and the first step of a "gut-liver-lung axis". Shock of any type or sepsis can by themselves lead to increased permeability of the intestinal mucosal barrier. This, in turn, may promote bacterial translocation, i.e. the passage of bacteria or bacterial products such as endotoxin from the lumen of the gut into the portal bloodstream. When such products reach the liver, activation of Küpffer cells occurs, resulting in the secretion of pro-inflammatory and hypotensive mediators. The latter are mainly the tumor necrosis factor-alpha and interleukins-1 and -6. These substances trigger many biologic cascades, and may explain the development of abacteremic septic states and MSOF. The mediators cause binding of polymorphonuclear neutrophils to pulmonary endothelial cells, and their degranulation. In addition, they activate local and systemic coagulation mechanisms. This explains the morphological changes observed in early sepsis-induced ARDS, i.e. pulmonary edema, vascular thrombosis and hemorrhages. Studies are currently in progress in an attempt to limit bacterial and endotoxin translocation and the action of the mediators.

Bacterial Physiological Phenomena↗
PubMed2006

Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease.

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappaB (NFkappaB) binding sites in each promoter. Furthermore, NFkappaB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-alpha and transforming growth factor-beta, which could be blocked by NFkappaB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P = 0.003) polymorphism with CD and for MUC4-A585S (P = 0.025), as well as MUC13-R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFkappaB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

Adult↗