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PubMed2001

Peritoneal lavage with oxygenated perfluorochemical preserves intestinal mucosal barrier function after ischemia-reperfusion and ameliorates lung injury.

OBJECTIVE: To evaluate the effect of peritoneal lavage with an oxygenated perfluorochemical (PFC) on intestinal ischemia-reperfusion injury (IIR), we assessed intestinal barrier function in terms of bacterial translocation and endotoxemia, morphologic changes, and changes of intestinal luminal pH in rats subjected to IIR. We also examined lung injury after IIR to test the effect of oxygenated PFC lavage on remote organ failure. DESIGN: Prospective, randomized, and controlled animal study. SETTING: Laboratory of a university hospital. SUBJECT: Male Sprague-Dawley rats. INTERVENTIONS: Rats were subjected to ischemia by clipping the superior mesenteric artery. Reperfusion was achieved by release of the clip. Lavage of the abdominal cavity was performed by inflow and outflow of oxygenated PFC solution during ischemia. RESULTS: Rats undergoing peritoneal lavage with oxygenated PFC (PFC group) showed significantly better survival after IIR. The frequency of bacterial translocation and the endotoxin concentration in superior mesenteric venous blood were significantly lower in the PFC group. Luminal acidosis also was alleviated in the PFC group. Furthermore, PFC lavage preserved the intestinal mucosal architecture and inhibited interstitial edema and infiltration of inflammatory cells in the lungs. CONCLUSION: We conclude that peritoneal lavage with oxygenated PFC protects the intestinal mucosa and maintains mucosal barrier function after IIR. Preservation of the intestinal mucosa ameliorates lung injury after IIR.

Animals↗
PubMed1999

Transcellular uptake mechanisms of the intestinal epithelial barrier Part one.

Part one of this two-part review addresses the transport of therapeutics across the intestinal barrier, and focuses on transcellular transport through the intestinal epithelia. The anatomical, biochemical and physiological parameters impacting transcellular uptake of orally administered drugs are described, and methods for overcoming obstacles limiting successful transcellular oral drug delivery are discussed. Part two will cover paracellular transport.

Journal Article↗
PubMed2026

Eagle-Derived Weissella confusa EG05 Prevents LPS-Induced Enteritis Through Modulation of Inflammation, Gut Barrier, And Microbiota.

Intestinal enteric inflammation can seriously harm animal health and lead to massive economic losses in livestock production. Probiotics have become a promising alternative to antibiotics for preventing and controlling enteritis. In this study, a novel lactic acid bacterium (LAB) was isolated from eagle feces and identified as Weissella confusa EG05 (W. confusa EG05), and its probiotic characteristics and protective effects on lipopolysaccharide (LPS)-induced enteritis in mice were evaluated. In vitro experiments showed that W. confusa EG05 has strong antimicrobial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), good tolerance to acidic and bile salt conditions, high auto-aggregation ability and surface hydrophobicity, and no hemolytic activity. Whole-genome analysis further confirmed its safety and probiotic potential by revealing genes involved in adhesion, immune regulation, and stress tolerance. In mouse experiments, pretreatment with W. confusa EG05 alleviated LPS-induced intestinal pathological damage, inhibited the secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6), promoted the expression of anti-inflammatory cytokine IL-10, enhanced the activities of antioxidant enzymes, and up-regulated the expression of tight junction proteins (Occludin, ZO-1). In addition, W. confusa EG05 restored gut microbiota homeostasis disturbed by LPS, increasing the abundance of beneficial genera and decreasing harmful bacteria. Taken together, these results suggest that W. confusa EG05 can effectively prevent LPS-induced enteritis in mice by modulating the inflammatory response, enhancing antioxidant capacity, protecting the intestinal barrier and the reshaping gut microbiota. These results indicate that W. confusa EG05 exhibits prominent probiotic potential in mouse models, providing a strain resource for the future development of microecological preparations.

Weissella confusa EG05↗
PubMed1999

Lisofylline ameliorates intestinal mucosal barrier dysfunction caused by ischemia and ischemia/reperfusion.

In an effort to determine whether treatment with lisofylline (LSF) ameliorates intestinal barrier dysfunction in rats subjected to mesenteric ischemia and reperfusion (I/R), regional mesenteric vessels were occluded for 60 min and then unclamped for 60 min more. In Protocol 1, intravenous LSF (15 mg/kg bolus then 10 mg/kg/h) was administered 5 min before ischemia. In Protocol 2, LSF (same dose) was given 1 min before reperfusion. Controls received an equivalent volume of Ringer's lactate solution. Permeability was assessed by determining the mucosal-to-serosal clearance of fluorescein isothiocyanate-conjugated dextran (4 kDa) in everted ileal gut sacs incubated ex vivo. In Protocol 1, LSF treatment during ischemia ameliorated mucosal barrier dysfunction; mean +/- SEM clearances for the LSF and Ringer's lactate solution groups after 60 min of ischemia were 34.4+/-6.1 and 64+/-7.1 nL/min/cm2, respectively; p = .007. Clearances after reperfusion were the same in the two groups. In Protocol 2, LSF treatment just before reperfusion ameliorated barrier dysfunction measured 60 min after the restoration of blood flow; clearances for the LSF and Ringer's lactate solution groups were 23.1+/-3.8 and 40.2+/-4.5 nL/min/cm2, respectively; p = .012. Treatment with LSF did not affect intestinal levels of reduced glutathione or adenosine triphosphate or the extent of histological damage to the mucosa after I/R. Nevertheless, villus height was greater in animals treated with LSF than RLS prior to ischemia in Protocol 1 (250+/-37 and 160+/-15 microm, respectively; p = .04) and during reperfusion in Protocol 2 (170+/-21 and 82+/-7 microm, respectively; p = .002). We conclude that LSF is effective in reducing both ischemia- and I/R-induced gut barrier dysfunction, possibly due to a mechanism related to preservation of villus height.

Adenosine Triphosphate↗
PubMed2005

Current concepts in the evaluation, diagnosis and management of acute infectious diarrhea.

Despite recent advances in our understanding of the pathogenesis of enteric diseases, acute infectious diarrhea remains a major cause of morbidity and mortality worldwide. Infection is the most common cause of acute diarrhea. Some causes of infectious diarrhea also result in serious long-term sequelae such as hemolytic uremic syndrome, Guillain-Barré syndrome and malnutrition. A better understanding of bacterial pathogenesis has grown increasingly important because of the emergence of new pathogens and the growing problems of resistance among enteric pathogens and other enteric flora. Non-antimicrobial approaches to therapy have become increasingly important with the emergence of serious antimicrobial resistance, such as vancomycin-resistant enterococcal colonization of the gastrointestinal tract. Finally, new understanding of how intestinal bacteria cause disease is revealing that enteric infections might trigger damage to epithelial cells or the intestinal barrier, or disrupt intestinal barrier and absorptive function (without necessarily causing overt diarrhea); thus, enteric infections might be far more important as emerging causes of malnutrition than has been previously appreciated. Therefore, diarrhea is both a cause and an effect of malnutrition. Treatment in most cases of bacterial and viral diseases consists of correcting fluid loss and electrolyte imbalance by oral or parenteral rehydration. Prevention of enteric illness by virtue of improved hygiene and provision of sanitation and water treatment is impractical in most developing countries, where morbidity and mortality rates are highest. For this reason, development of vaccines against the most important gastrointestinal infections remains a high priority.

Acute Disease↗
PubMed2002

[A preliminary study of the postburn intestinal biological barrier injury in severely burned rats].

OBJECTIVE: To investigate the postburn change in the intestinal biological barrier in severely burned rats. METHODS: Wistar rats inflicted by 30% TBSA III degree scalding on the back were employed as the model. The samples were harvested at 24, 48, 72 and 96 postburn hours (PBHs), respectively with the employment of microorganism analysis, biochemical and radio-immune methods for the study. The membranous flora in cecum, the mucin and sIgA in intestinal content, the intestinal endotoxin and bacterial translocation rate and quantification analysis and the endotoxin content in cava vein were observed. RESULTS: The total intestinal membranous flora amount decreased, especially and obviously did the anaerobic bacteria such as bifidobacteria. But aerobic ones increased. In addition, The fungus and enterobacteria exhibited rapid overgrowth. This lead to evident imbalance between anaerobic and aerobic bacteria and to the destruction of intestinal biological barrier and the decrease of colonization resistance. As a result, the intestinal bacterial translocation rate increased markedly. The endotoxin content in the cava and intestinal containing increased, while the mucin and sIgA contents decreased. CONCLUSION: Intestinal biological barrier could be severely damaged after major burn, which might be one of the causes of postburn intestinal infection.

Animals↗
PubMed2003

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

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

Animals↗
PubMedDate not supplied

Total parenteral nutrition increases uptake of latex beads by Peyer's patches.

BACKGROUND: Dysfunction of the intestinal barrier, as evidenced by increased intestinal permeability and bacterial translocation, has been reported under total parenteral nutrition (TPN). However, the role of Peyer's patches on the intestinal barrier in TPN is not well understood. We investigated whether TPN alters the uptake of microparticles by the follicle-associated epithelium of Peyer's patches. METHODS: Twenty rats were divided into two groups, a control group and a TPN group. Fluorescent polystyrene latex beads, 3.2 +/- 0.2 microns in diameter, were used as a probe for measuring the uptake by Peyer's patches. After 1 week of consuming either the control or TPN diet, rats were killed. On the day of killing, 0.1 mL of latex beads solution was injected into a 1-cm length of ileal loop, within 10 cm of the ileocecal valve. Samples were taken after 30 minutes of injection, sectioned by cryostat, and then viewed under a fluorescent microscope. Follicle-associated epithelial length and particles were counted using a confocal laser scanning microscope. The number of particles within each compartment was standardized per unit length of epithelium of Peyer's patches. RESULTS: Particle numbers within Peyer's patch dome of the TPN group were significantly increased compared with those of the control group (p < .01). CONCLUSIONS: These data suggest that dysfunction of the intestinal barrier in TPN might be associated with a change of uptake by Peyer's patches.

Animals↗
PubMed2006

[Studies of the possible mechanisms for protective effects of recombinant human growth hormone on intestinal mucosa barrier in rat sepsis].

OBJECTIVE: To investigate the protective effects of recombinant human growth hormone (rhGH) on intestinal mucosal barrier in rat sepsis and explore its possible mechanisms. METHODS: E. coli was injected intraperitoneally to produce rats sepsis models. Forty-two female SD rats were randomly divided into the control group (group C), sepsis group (group S) and treatment group (group T). Group S and group T were further divided into 1 d and 3 d subgroups (T1d,T3d, Sld, S3d), respectively. The expression of IGF-1 mRNA in liver, expression of Bcl-2 protein in intestine, bacteria translocation, the levels of growth hormone(GH) and insulin-like growth factor-1 (IGF-1) in plasma, and the histological appearance of intestine were determined dynamically by means of RT-PCR, radioimmunoassay, immunohistochemical staining and other corresponding methods, respectively. RESULTS: (1) rhGH could significantly attenuate intestinal mucosal injuries and ameliorate bacteria translocation on sepsis rats. (2) The levels of Bcl-2 protein expression in intestine in group T (T1d:2441 +/- 117; T3d: 3628 +/- 235) were obviously higher than those of group S (S1d: 321 +/- 36; S3d: 1873 +/- 57) (P < 0.01). (3) The plasma levels of GH in group T (T1d: 1.28 +/- 0.24 microg/L; T3d: 2.14 +/- 0.48 microg/L) increased markedly than those of group S (S1d: 0.74 -/+ 0.12 microg/L; S3d: 0.60 +/- 0.18 microg/L) (P < 0.01). (4) The plasma levels of IGF-1 in group T (Tld: 168.94 +/- 65.67 microg/L; T3d: 201.56 +/- 64.98 microg/L) elevated significantly than those of group S (Sld: 116.72 +/- 13.96 microg/L; S3d:107.50 +/- 23.53 microg/L) (P < 0.05). (5) The levels of liver IGF-1 mRNA in group T (Tld: 0.98 +/- 0.20; T3d: 1.76 +/- 0.17) were significantly higher than those in group S (S1d: 0.38 +/- 0.09; S3d: 0.46 +/- 0.10) (P < 0.01). CONCLUSION: rhGH conferred protective efficacy in maintaining the integrity of intestinal mucosal barrier against sepsis in rat. The possible mechanisms might involve the rhGH-diminished apoptosis of intestinal mucosa cells and the rhGH-maintained intestinal mucosa barrier via the roles of GH and IGF-1.

Animals↗
PubMed2004

Identification of peptide sequences that induce the transport of phage across the gastrointestinal mucosal barrier.

To investigate whether specific peptide sequences could induce virion transport across the intestinal barrier, we used phage display to both identify signalling peptides capable of inducing trans-intestinal transport and also provide a suitable model of virion translocation. We utilised simple, single-round high input in vivo biopanning protocol using a 7-mer random amino acid phage display library. Phage were applied by gavage and translocation across the intestinal barrier assessed by phage recovery from the spleen 2h later. Following isolation, a number of phage were sequenced and several homologies with HIV gp120 were identified. Immunocytochemical analysis of phage translocation across the intestinal barrier by a phage bearing the peptide YPRLLTP demonstrated that phage were actively transported along specific channels. It is concluded that utilisation of in vivo phage display (IVPD) has provided evidence for a specific peptide-guided transport of undegraded cargo across the intestinal barrier, modelled by M13 phage.

Animals↗
PubMed2006

The probiotic bacterium Lactobacillus plantarum species 299 reduces intestinal permeability in experimental biliary obstruction.

AIMS: Extrahepatic biliary obstruction is associated with the failure of intestinal barrier function, allowing bacteria and other substances from the intestine to enter the circulation and initiate a systemic inflammatory response, causing impairment of organ function. Probiotic bacteria have been shown to have beneficial effects on intestinal barrier function in other conditions, but their effects have never been studied in biliary obstruction. METHODS AND RESULTS: This study examined the effects of enteral administration of Lactobacillus plantarum species 299 (LP299) in oatmeal fibre compared with sterile oatmeal fibre in water or water alone in an animal model of biliary obstruction. Administration of LP299 was associated with reduced intestinal permeability compared with sterile oatmeal alone (0.262 +/- 0.105%vs 0.537 +/- 0.037%, P=0.019, percentage excretion of (14)Carbon), but there was no evidence of reduced endotoxin exposure or blunting of the systemic inflammatory response. Animals receiving sterile oatmeal fibre alone also failed to develop the hyperpermeability after biliary obstruction seen in animals receiving water only (0.512+/- 0.05%vs 0.788 +/- 0.18%), suggesting that oatmeal itself may have some beneficial effects on intestinal barrier function. CONCLUSION: Enteral administration of the probiotic bacterium LP299 reduces intestinal hyperpermeability associated with experimental biliary obstruction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides insight to direct further work into the modulation of intestinal barrier function by probiotic bacteria.

Animals↗
PubMed1994

Neonatal necrotizing enterocolitis, a disease of the immature intestinal mucosal barrier.

Necrotizing enterocolitis (NEC) is an enigmatic process in that one single etiologic factor has been sought and not found. Epidemiologic studies suggest that immaturity of the host plays a very important role. This article reviews the intestinal host defense system and its immature nature early in life in animal models and humans and suggests that it is this immaturity, along with other factors, which allows for the proliferation and invasion of antigens and organism, and the subsequent development of NEC. Data are presented which support the efficacy of pharmacologic maturation of the intestinal barrier with growth factors, either prenatally or postnatally, to decrease the incidence of NEC or, potentially, to provide a more benign course for the disease.

Animals↗
PubMed2001

iNOS upregulation mediates oxidant-induced disruption of F-actin and barrier of intestinal monolayers.

Using oxidant-induced hyperpermeability of monolayers of intestinal (Caco-2) cells as a model for the pathophysiology of inflammatory bowel disease (IBD), we previously showed that oxidative injury to the F-actin cytoskeleton is necessary for the disruption of monolayer barrier integrity. We hypothesized that this cytoskeletal damage is caused by upregulation of an inducible nitric oxide (NO) synthase (iNOS)-driven pathway that overproduces reactive nitrogen metabolites (RNMs) such as NO and peroxynitrite (OONO(-)), which cause actin nitration and disassembly. Monolayers were exposed to H(2)O(2) or to RNMs with and without pretreatment with antioxidants or iNOS inhibitors. H(2)O(2) concentrations that disassembled and/or disrupted the F-actin cytoskeleton and barrier integrity also caused rapid iNOS activation, NO overproduction, and actin nitration. Added OONO(-) mimicked H(2)O(2); iNOS inhibitors and RNM scavengers were protective. Our results show that oxidant-induced F-actin and intestinal barrier disruption are caused by rapid iNOS upregulation that further increases oxidant levels; a similar positive feedback mechanism may underlie the episodic recurrence of the acute IBD attack. Confirming these mechanisms in vivo would provide a rationale for developing novel anti-RNM therapies for IBD.

Actins↗
PubMed2004

[Bowel preparation before colorectal surgery: from intestinal mucosal barrier].

The routine bowel preparation before colorectal surgery usually includes mechanical and medicine preparations, with the original purpose of reducing complications such as anastomosis leakage, wound, and abdominal infections. Many domestic hospitals are still employing the methods of three-day bowel preparation, while in the West, the way of this preparation has dramatically changed. In last decade, one-day preparation has been widely accepted internationally, with two major medications of sodium phosphate and polyethylene glycol frequently used in the clinic. It has also been indicated that excessive mechanical and medicinal bowel preparations exert harmful effects on the combined intestinal barrier, and may result in various complications. A few reports have suggested to omit the mechanical bowel preparation before surgery, which is still under controversy, however, well-designed clinical trials are needed to readjust and regulate the duration and intensity of bowel preparation before colorectal surgery in China.

Colorectal Surgery↗
PubMed2006

Mechanism of glucocorticoid regulation of the intestinal tight junction barrier.

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

Active Transport, Cell Nucleus↗
PubMed2006

IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction.

BACKGROUND & AIMS: Tumor necrosis factor (TNF) plays a critical role in intestinal disease. In intestinal epithelia, TNF causes tight junction disruption and epithelial barrier loss by up-regulating myosin light chain kinase (MLCK) activity and expression. The aim of this study was to determine the signaling pathways by which TNF causes intestinal epithelial barrier loss. METHODS: Caco-2 cells that were either nontransfected or stably transfected with human TNF receptor 1 (TNFR1) or TNFR2 and mouse colonocytes were used for physiologic, morphologic, and biochemical analyses. RESULTS: Colitis induced in vivo by adoptive transfer of CD4(+)CD45RB(hi) T cells was associated with increased epithelial MLCK expression and myosin II regulatory light chain (MLC) phosphorylation as well as morphologic tight junction disruption. In vitro studies showed that TNF caused similar increases in MLCK expression and MLC phosphorylation, as well as barrier dysfunction, in Caco-2 monolayers only after interferon (IFN)-gamma pretreatment. This reductionist model was therefore used to determine the molecular mechanism by which IFN-gamma and TNF synergize to cause intestinal epithelial barrier loss. IFN-gamma priming increased TNFR1 and TNFR2 expression, and blocking antibody studies showed that TNFR2, but not TNFR1, was required for TNF-induced barrier dysfunction. Transgenic TNFR2, but not TNFR1, expression allowed IFN-gamma-independent TNF responses. CONCLUSIONS: IFN-gamma primes intestinal epithelia to respond to TNF by inducing TNFR2 expression, which in turn mediates TNF-induced MLCK-dependent barrier dysfunction. The data further suggest that epithelial TNFR2 blockade may be a novel approach to restore barrier function in intestinal disease.

Animals↗
PubMed2003

The invasive phenotype of Shigella flexneri directs a distinct gene expression pattern in the human intestinal epithelial cell line Caco-2.

Invasion of the human colonic epithelium by Shigella flexneri causes inflammation that disrupts the intestinal barrier. Invaded intestinal epithelial cells are the major source of mediators recruiting the inflammatory infiltrate. To better characterize the global response of intestinal epithelial cells to Shigella invasion, Caco-2 cells were infected by an invasive isolate of S. flexneri 5a, and their transcriptome was analyzed by Affymetrix (Santa Clara, CA) microarrays (12,000 genes) and compared with these elicited by a non-invasive Shigella mutant and tumor necrosis factor (TNF)-alpha. The invasive and non-invasive strains enhanced transcription of a common pattern of 240 genes, among which genes encoding isoforms of cytochrome P-450 were induced. These genes were not induced by TNF-alpha. Conversely, both the invasive strain and TNF-alpha induced a common set of 18 genes, mainly encoding proinflammatory molecules. They also induced specific sets of genes. The transcriptome induced by the invasive strain was characterized by the induction of early genes (i.e. expressed within the first 45 min of invasion) and late genes (i.e. after 60 min of invasion) whose pattern was strongly biased toward stimulation of granulopoiesis, chemoattraction, activation, and adherence of polymorphonuclear leukocytes. When compared with a non-invasive Shigella and TNF-alpha, invasive Shigella induced a narrow transcriptome that seems to program infected epithelial cells to recruit a mucosal polymorphonuclear leukocyte to infiltrate. Dramatic increase in IL-8 gene transcription points to this chemokine as the major molecule orchestrating mucosal inflammation in shigellosis.

Cytochrome P-450 Enzyme System↗
PubMed2001

Effect of chronic renal failure on the expression and function of rat intestinal P-glycoprotein in drug excretion.

BACKGROUND: In chronic renal failure, the renal excretion of certain drugs is dramatically reduced. To determine whether other routes of drug elimination, such as secretion through the intestinal barrier by intestinal P-glycoprotein can be altered, we compared P-glycoprotein activity, P-glycoprotein protein content, and P-glycoprotein mRNA levels in intestine of control and chronic renal failure rats. METHODS: Chronic renal failure was surgically induced in rats by partial (7/8) nephrectomy. After 5 weeks, intestinal transport of rhodamine 123, a P-glycoprotein substrate, was carried out using an in vitro model of everted gut sacs. P-glycoprotein protein content was quantified by enzyme-linked immunosorbent assay and P-glycoprotein mRNA expression was evaluated by semi-quantitative reverse transcriptase polymerase chain reaction. RESULTS: A decrease of intestinal rhodamine 123 transport was observed in chronic renal failure rats, pointing to an inhibition of P-glycoprotein activity. Transport was inhibited in both sham-operated rats and rats with chronic renal failure by verapamil and cyclosporin A, but relative inhibition vs baseline was less marked in chronic renal failure than in sham-operated rats. In contrast, no significant differences in levels of P-glycoprotein protein or mRNA were observed between the two groups. CONCLUSIONS: Intestinal secretion of rhodamine 123 is mainly mediated by P-glycoprotein. It was reduced in rats with chronic renal failure, reflecting reduced intestinal drug elimination via a decrease in P-glycoprotein transport activity rather than via protein underexpression.

ATP Binding Cassette Transporter, Subfamily B↗