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PubMed2005

Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins.

Tight junctions between intestinal epithelial cells prevent ingress of luminal macromolecules and bacteria and protect against inflammation and infection. During stress and inflammation, mast cells mediate increased mucosal permeability by unknown mechanisms. We hypothesized that mast cell tryptase cleaves protease-activated receptor 2 (PAR2) on colonocytes to increase paracellular permeability. Colonocytes expressed PAR2 mRNA and responded to PAR2 agonists with increased [Ca2+]i. Supernatant from degranulated mast cells increased [Ca2+]i in colonocytes, which was prevented by a tryptase inhibitor, and desensitized responses to PAR2 agonist, suggesting PAR2 cleavage. When applied to the basolateral surface of colonocytes, PAR2 agonists and mast cell supernatant decreased transepithelial resistance, increased transepithelial flux of macromolecules, and induced redistribution of tight junction ZO-1 and occludin and perijunctional F-actin. When mast cells were co-cultured with colonocytes, mast cell degranulation increased paracellular permeability of colonocytes. This was prevented by a tryptase inhibitor. We determined the role of ERK1/2 and of beta-arrestins, which recruit ERK1/2 to PAR2 in endosomes and retain ERK1/2 in the cytosol, on PAR2-mediated alterations in permeability. An ERK1/2 inhibitor abolished the effects of PAR2 agonist on permeability and redistribution of F-actin. Down-regulation of beta-arrestins with small interfering RNA inhibited PAR2-induced activation of ERK1/2 and suppressed PAR2-induced changes in permeability. Thus, mast cells signal to colonocytes in a paracrine manner by release of tryptase and activation of PAR2. PAR2 couples to beta-arrestin-dependent activation of ERK1/2, which regulates reorganization of perijunctional F-actin to increase epithelial permeability. These mechanisms may explain the increased epithelial permeability of the intestine during stress and inflammation.

Actins↗
PubMed2000

Mucosal in vitro permeability in the intestinal tract of the pig, the rat, and man: species- and region-related differences.

BACKGROUND: The barrier properties of the gastrointestinal mucosa may be studied by measuring its permeability to different-sized marker molecules. Owing to difficulties in obtaining human tissue it is, however, often necessary to extrapolate findings from experimental animals to man. The aim of the present study was to compare regional intestinal mucosal permeability in man, the rat, and the pig, using the same marker molecules and in vitro technique. METHODS: Segments from jejunum, ileum, colon, and rectum were mounted in Ussing diffusion chambers, and the mucosa-to-serosa passage of 14C-mannitol, fluorescein isothiocyanate (FITC)-dextran 4,400, alpha-lactalbumin, ovalbumin, and FITC-dextran 70,000 was studied. RESULTS: Irrespective of species or intestinal region an inverse relationship between the molecular weight of the markers and the permeability was seen. The mannitol permeability was higher in the small intestine than in the colon in man, whereas the rat showed a higher permeability in the ileum than in the jejunum and colon. The FITC-dextran 4,400 permeability was higher in all intestinal regions in the rat than in man and the pig. The macromolecules showed low permeability with no regional differences. CONCLUSIONS: The results showed differences between intestinal regions and between species. Permeability data from the pig correlated fairly well with those of man, whereas the rat differed, making it difficult to extrapolate from the rat to man.

Adult↗
PubMed2005

Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon.

OBJECTIVE: Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine. MATERIAL AND METHODS: Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions. RESULTS: In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP. CONCLUSIONS: Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.

Adenosine Triphosphate↗
PubMed1994

Intracarotid histamine infusion increases blood tumour permeability in RG2 glioma.

Histamine will alter blood flow and permeability in systemic and cerebral vessels. We reported that intracarotid infusion of histamine selectively increased the blood flow in experimental brain tumours and caused extravassation of Evans blue within tumours. In this study, the effects of histamine on tumour and brain capillary permeability were quantified using autoradiography. RG2 glioma cells were implanted in female Wistar rats. Seven days after implantation, either low doses of histamine (1 or 10 micrograms kg-1 min-1) or saline as a control was infused through the carotid artery of rats. Regional permeability was measured by autoradiography using [14C] aminoisobutyric acid, and the unidirectional transfer constant, Ki (microliters g-1 min-1), was calculated. Intracarotid infusion of 10 micrograms kg-1 min-1 histamine resulted in significant increase in brain tumour permeability, compared to controls. The permeability, Ki, for the 10 micrograms kg-1 min-1 histamine group, the 1 micrograms kg-1 min-1 histamine group, and the control group was 18.8 +/- 4.6 (p < 0.05), 14.9 +/- 5.2, 13.9 +/- 3.7 microliters g-1 min-1, respectively. There was no significant change in blood brain permeability in other brain regions. The effect of increased permeability by 10 micrograms kg-1 min-1 histamine was suppressed by the H2-blocker, cimetidine. This suggests that the effect of histamine on tumour capillaries is mediated by H2-receptors. Intracarotid histamine infusion selectively increases permeability in brain tumours.

Animals↗
PubMed2005

Prediction of permeability coefficients of compounds through caco-2 cell monolayer using artificial neural network analysis.

Artificial neural network (ANN) analysis was used to predict the permeability of selected compounds through Caco-2 cell monolayers. Previously reported models, which were shown to be useful in the prediction of permeability values, use many structural parameters. More complex equations have also been proposed using both linear and non-linear relationships, including ANN analysis and various structural parameters. But proposed models still need to be developed using different neuron patterns for more precise predictions and a better understanding of which factors affect the permeation. To develop a simple and useful model or method for easy prediction is also a general need. Permeability coefficients (log kp) were obtained from various literature sources. Some structural parameters were calculated using computer programs. Multiple linear regression analysis (MLRA) was used to predict Caco-2 cell permeability for the set of 50 compounds (r2=0.403). A successful ANN model was developed, and the ANN produced log kp values that correlated well with the experimental ones (r2=0.952). The permeability of a compound, famotidine, which has not previously been studied, through the Caco-2 cell monolayer was investigated, and its permeability coefficient determined. It was then possible to compare the experimental data with that predicted using the trained ANN with previously determined Caco-2 cell permeability values and structural parameters of compounds. The model was also tested using literature values. The developed and described ANN model in this publication does not require any experimental parameters; it could potentially provide useful and precise prediction of permeability for new drugs or other penetrants.

Algorithms↗
PubMed1998

Intestinal permeability and contractility in murine colitis.

We developed an in vitro organ bath method to measure permeability and contractility simultaneously in murine intestinal segments. To investigate whether permeability and contractility are correlated and influenced by mucosal damage owing to inflammation, BALB/c mice were exposed to a 10% dextran sulphate sodium (DSS) solution for 8 days to induce colitis. The effect of pharmacologically induced smooth muscle relaxation and contraction on permeability was tested in vitro. Regional permeability differences were observed in both control and 10% DSS-treated mice. Distal colon segments were less permeable to 3H-mannitol and 14C-PEG 400 molecules compared with proximal colon and ileum. Intestinal permeability in control vs. 10% DSS mice was not altered, although histologic inflammation score and IFN-gamma pro-inflammatory cytokine levels were significantly increased in proximal and distal colon. IL-1beta levels were enhanced in these proximal and distal segments, but not significantly different from controls. Any effect of pharmacologically induced contractility on intestinal permeability could not be observed. In conclusion, intestinal permeability and contractility are not correlated in this model of experimentally induced colitis in mice. Although simultaneous measurement in a physiological set-up is possible, this method has to be further validated.

Animals↗
PubMed2001

Water permeability of asymmetric planar lipid bilayers: leaflets of different composition offer independent and additive resistances to permeation.

To understand how plasma membranes may limit water flux, we have modeled the apical membrane of MDCK type 1 cells. Previous experiments demonstrated that liposomes designed to mimic the inner and outer leaflet of this membrane exhibited 18-fold lower water permeation for outer leaflet lipids than inner leaflet lipids (Hill, W.G., and M.L. Zeidel. 2000. J. Biol. Chem. 275:30176-30185), confirming that the outer leaflet is the primary barrier to permeation. If leaflets in a bilayer resist permeation independently, the following equation estimates single leaflet permeabilities: 1/P(AB) = 1/P(A) + 1/P(B) (Eq. l), where P(AB) is the permeability of a bilayer composed of leaflets A and B, P(A) is the permeability of leaflet A, and P(B) is the permeability of leaflet B. Using for the MDCK leaflet-specific liposomes gives an estimated value for the osmotic water permeability (P(f)) of 4.6 x 10(-4) cm/s (at 25 degrees C) that correlated well with experimentally measured values in intact cells. We have now constructed both symmetric and asymmetric planar lipid bilayers that model the MDCK apical membrane. Water permeability across these bilayers was monitored in the immediate membrane vicinity using a Na+-sensitive scanning microelectrode and an osmotic gradient induced by addition of urea. The near-membrane concentration distribution of solute was used to calculate the velocity of water flow (Pohl, P., S.M. Saparov, and Y.N. Antonenko. 1997. Biophys. J. 72:1711-1718). At 36 degrees C, P(f) was 3.44 +/- 0.35 x 10(-3) cm/s for symmetrical inner leaflet membranes and 3.40 +/- 0.34 x 10(-4) cm/s for symmetrical exofacial membranes. From, the estimated permeability of an asymmetric membrane is 6.2 x 10(-4) cm/s. Water permeability measured for the asymmetric planar bilayer was 6.7 +/- 0.7 x 10(-4) cm/s, which is within 10% of the calculated value. Direct experimental measurement of P(f) for an asymmetric planar membrane confirms that leaflets in a bilayer offer independent and additive resistances to water permeation and validates the use of.

Animals↗
PubMed1983

Permeability of human red cells to a homologous series of aliphatic alcohols. Limitations of the continuous flow-tube method.

Human red cell permeability to the homologous series of methanol, ethanol, n-propanol, n-butanol, and n-hexanol was determined in tracer efflux experiments by the continuous flow tube method, whose time resolution is 2-3 ms. Control experiments showed that unstirred layers in the cell suspension were less than 2 X 10(-4) cm, and that permeabilities less than or equal to 10(-2) cm s-1 can be determined with the method. Alcohol permeability varied with the chain length (25 degrees C): Pmeth 3.7 X 10(-3) cm s-1, Peth 2.1 X 10(-3) cm s-1, Pprop 6.5 X 10(-3) cm s-1, Pbut less than or equal to 61 X 10(-3) cm s-1, Phex 8.7 X 10(-3) cm s-1. The permeability for methanol, ethanol, and n-propanol was concentration independent (1-500 mM). The permeability to n-butanol and n-hexanol, however, increased above the upper limit of determination at alcohol concentrations of 100 and 25 mM, respectively. The activation energies for the permeability to methanol, n-propanol, and n-hexanol were similar, 50-63 kJ mol-1. Methanol permeability was not reduced by p-chloromercuribenzene sulfonate (PCMBS), thiourea, or phloretin, which inhibit transport of water or hydrophilic nonelectrolytes. It is concluded (a) that all the alcohols predominantly permeate the membrane lipid bilayer structure; (b) that both the distribution coefficient and the diffusion coefficient of the alcohols within the membrane determine the permeability, and (c) that the relative importance of the two factors varies with changes in the chain length.

1-Propanol↗
PubMed1999

Neutrophils do not mediate blood-brain barrier permeability early after controlled cortical impact in rats.

Controlled cortical impact (CCI) produces blood-brain barrier (BBB) permeability and an acute inflammatory response in injured brain, associated with upregulation of cell adhesion molecules and accumulation of neutrophils. Nevertheless, the role of acute inflammation in the pathogenesis of BBB permeability after traumatic brain injury (TBI) is undefined. The purpose of this study was to examine the time course of acute inflammation and BBB permeability after CCI in rats and to determine the effect of neutrophil depletion on BBB permeability early after CCI. In the first protocol, four groups of rats (n = 4-7/group) were subjected to CCI. Expression of endothelial (E)-selectin on cerebrovascular endothelium, accumulation of neutrophils, and BBB permeability were measured in brain at 1, 4, 8, and 24 hours after injury by immunohistochemistry or spectrophotometric quantification of Evans blue. E-selectin upregulation and neutrophil accumulation in injured brain occurred at later times than maximal BBB permeability. In a second protocol, rats made neutropenic with a murine monoclonal IgM antibody (RP-3) specific for rat neutrophils were subjected to CCI, given Evans blue at 3.5 hours, and sacrificed at 4 hours after injury. Neutrophil depletion did not affect BBB permeability at 4 hours after CCI. We conclude that events other than those mediated by neutrophils initiate BBB permeability early after CCI.

Animals↗
PubMed1995

Thy-1 induced on rat endothelium regulates vascular permeability at sites of inflammation.

We investigated the role of surface adhesion molecules on endothelial cells in regulating vascular permeability, in vitro and in vivo. Cultured rat endothelial cells (REC) express Thy-1, intercellular adhesion molecule-1 (ICAM-1), CD44 and RT1A. Permeability of albumin across the REC monolayer increased through the interaction of Thy-1 and anti-Thy-1 mAb, but not through ICAM-1 and anti-ICAM-1, CD44 and anti-CD44, and RT1A and anti-RT1A mAb. This anti-Thy-1-effect was completely inhibited when the calmodulin antagonist W-7 and the protein kinase inhibitor H-7 was combined, while the IL-6-mediated increase in REC permeability was blocked by either W-7 or H-7, independently. The anti-Thy-1-mediated permeability increase was additively augmented when IL-6 was admixed. These data suggest that intracellular signaling pathways of anti-Thy-1- and IL-6-mediated permeability regulation may be overlapping to some extent but are largely independent. As anti-Thy-1-treatment generated rearrangement of vimentin filaments within REC, alteration of the cytoskeleton distribution may possibly correlate with the regulation of permeability. Although Thy-1-expression on rat vascular endothelium in vivo was not evident, it was induced at sites of Freund's complete adjuvant-induced dermatitis. The administered anti-Thy-1 mAb exclusively located on vascular endothelial surface at the sites of inflammation. Vascular permeability in inflamed skin tissues was significantly augmented when anti-Thy-1 but not anti-ICAM-1, anti-CD44 or anti-RT1A mAb was administered i.v., without affecting populations of inflammatory cells. The collective evidence suggests that Thy-1 induced on rat endothelium is one important regulatory event in vascular permeability at sites of inflammation.

Animals↗
PubMed1996

Lectins binding on human sperm surface increase membrane permeability and stimulate acrosomal exocytosis.

Cross-linked complexes formed between certain lectins and their specific multivalent carbohydrates and glycoconjugates on the sperm surface were studied for their ability to modify sperm membrane permeability and to induce the acrosome reaction. Wheat germ agglutinin (WGA), concanavalin A (Con A) and peanut agglutinin (PNA) increased the proportions of human spermatozoa permeable to the impermeable propidium iodide (31.9 compared with 13.8%, 38.4 compared with 18.4% and 72.7 compared with 18.9% respectively). Removal of sperm surface sialic acid by neuraminidase treatment was a prerequisite for Con A and PNA binding to the sperm surface. The percentage of permeable and acrosome-reacted spermatozoa was not affected by sperm treatment with 500 mIU/ml Arthrobacter ureafaciens neuraminidase. WGA did not induce the acrosome reaction, whereas PNA induced the acrosome reaction regardless of the sperm capacitation status, allowing the proportion of acrosome-reacted spermatozoa to reach 27.7% of capacitated spermatozoa. However, the ability of Con A to induce the acrosome reaction was limited to uncapacitated spermatozoa. To test the physiological relevance of this study, uncapacitated human spermatozoa were incubated with human zonae pellucidae and the permeability of spermatozoa bound to the zona surface was analysed according to the time post-insemination. Two-thirds of spermatozoa bound to zona pellucida became permeable to propidium iodide in the first 30 min post-insemination and almost all bound spermatozoa became permeable to the impermeable dye after 60 min. Our results show that molecular interactions between human zona pellucida and sperm surface increase the permeability of sperm membranes; the cross-linked complexes formed by PNA lectin and its specific multivalent carbohydrates and glycoconjugates on the sperm surface were also able to increase sperm membrane permeability and to induce the acrosome reaction. These results suggest a role for the saccharide moieties of sperm surface glycoconjugates in the induction of the acrosome reaction.

Acrosome↗
PubMed1992

Modulation of venular microvessel permeability by calcium influx into endothelial cells.

It has been proposed that calcium ion influx into endothelial cells modulates the permeability of venular microvessels via a calcium-dependent contractile process. The results of recent investigations using permeabilized endothelial cell monolayers conform to this hypothesis by demonstrating a calcium-dependent interaction of endothelial actin and myosin during the retraction of adjacent endothelial cells exposed to inflammatory agents. Little is known about the pathway for calcium influx into endothelial cells after exposure to mediators of inflammation, but evidence suggests that the properties of the calcium entry pathways are similar to the calcium entry pathways that regulate the release of endothelium-derived relaxing factor (EDRF). Substances that stimulate EDRF release from arterial endothelium also increase venular microvessel permeability. Recently developed methods to measure cytoplasmic calcium concentration in the endothelial cells forming the walls of individually perfused microvessels enable a direct investigation of the modulation of the permeability of venular microvessels by calcium influx. These experiments demonstrate that the magnitude of the initial increase in the permeability of microvessels after exposure to an agent that increases permeability, such as a calcium ionophore, is determined by the magnitude of calcium ion influx into the endothelial cells. Furthermore, the magnitude of the calcium influx into endothelial cells is modulated by the membrane potential of the endothelial cells. Depolarization of the endothelial cell membrane reduces calcium influx and attenuates increases in permeability whereas hyperpolarization of the endothelial membrane increases calcium influx and potentiates increases in permeability. These data conform to the hypothesis that a passive conductance channel for calcium is a major pathway for calcium ion flux responsible to eliciting an increase in the permeability of the endothelial barrier in microvessels.

Animals↗
PubMed1990

Morphine and alfentanil permeability through the spinal dura, arachnoid, and pia mater of dogs and monkeys.

Little information exists about which spinal meninx is the principal permeability barrier between the epidural space and the spinal cord or about what physicochemical properties of drug molecules govern their meningeal permeability. To better understand these aspects of epidural pharmacokinetics, the authors measured the permeability of morphine and alfentanil through the different components of the spinal meninges-dura mater, arachnoid mater, and pia mater-of dogs and monkeys in vitro. Live meningeal tissue from either species (dura mater alone, pia mater alone, or intact dura-arachnoid-pia) was placed between two fluid reservoirs of a temperature-controlled diffusion cell. The permeability of the tissues to each opioid was determined by placing the opioid in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and appeared in the second reservoir. The arachnoid mater was found to be the major meningeal diffusion barrier between the epidural space and the spinal cord. Alfentanil was 3.7 times more permeable than morphine through all three meninges, suggesting that increased lipid solubility increases meningeal permeability. However, neither lipid solubility nor molecular weight adequately explained the difference in permeability between morphine and alfentanil. The authors conclude that this in vitro model has significant utility for studies aimed at predicting in vivo meningeal permeability and hence the potency and rapidity of action of any opioid administered by the epidural route.

Alfentanil↗
PubMed1993

Alterations in feline tracheal permeability after mechanical ventilation.

OBJECTIVES: Previous investigations of ventilator-induced airway injury focused on histopathologic changes associated with various ventilators and strategies for their use. We hypothesized that mechanical ventilation is associated with alterations in tracheal epithelial permeability, and designed a study using an animal model to evaluate changes in tracheal epithelial permeability after administering different types of mechanical ventilation to test this hypothesis. DESIGN: Prospective, multiple-group, controlled trial. Five groups of animals were studied and compared. Eight animals were studied without intubation or mechanical ventilation. A total of 28 animals (seven in each group) were studied after conventional mechanical ventilation, high-frequency positive-pressure ventilation, high-frequency jet ventilation, or high-frequency flow interruption at respiratory rates of 20, 150, 400, and 900 breaths/min, respectively. Comparison of data for each group was done using the Kruskall-Wallis analysis of variance. Between-group comparisons were made using standard error of the mean comparisons. For airway pressures and other physiologic data, one-way analysis of variance was performed. Between-group comparisons were made using the Student-Newman-Keuls' test. SETTING: Small animal physiology laboratory. SUBJECTS: Thirty-six adult cats. INTERVENTIONS: Mechanically ventilated animals were treated for 8 hrs and then killed. Inspired oxygen concentration, BP, and mean airway pressures were comparable in mechanically ventilated animals. Spontaneously breathing control animals were killed without endotracheal intubation or exposure to mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Permeability values in isolated tracheal segments were calculated for 14C-sucrose, 3H-inulin, and fluorescein isothiocyanate-dextran-20. Tracheal epithelial permeability to all studied molecules increased after exposure to mechanical ventilators. These different mechanical ventilators increased epithelial permeability in a progressive manner that paralleled ventilatory frequency. The changes were greatest after ventilation at the highest frequency. These observed changes in tracheal permeability are consistent with previously observed alterations in tracheal histopathology after exposure to mechanical ventilation. CONCLUSIONS: Mechanical ventilation was associated with increases in tracheal permeability to large and small nonionic molecules. These changes occurred with all studied ventilators, used as they are clinically. Permeability changes paralleled ventilatory rate changes.

Animals↗
PubMed1995

Increased intestinal permeability following blunt and penetrating trauma.

OBJECTIVES: To determine changes in the absorption of lactulose and mannitol in patients undergoing laparotomy following blunt or penetrating trauma and to correlate any changes in permeability with the severity of injury. DESIGN: Nonrandomized study within patient control. PATIENTS: Consecutive patients admitted to the trauma unit following blunt or penetrating trauma with intra-abdominal injuries warranting emergent celiotomy and jejunal access. INTERVENTIONS: Intestinal permeability was measured in 18 patients within 48 hrs post-trauma by the bolus infusion into the jejunum of nonmetabolized probe molecules, lactulose (molecular weight of 342) and mannitol (molecular weight of 182). Because several patients did not tolerate the bolus infusion, a 3-hr continuous infusion of the probe molecules was used in the last eight patients entered into the study. Intestinal permeability was reassessed before discharge or on days 10 to 12. MEASUREMENTS AND MAIN RESULTS: There was a decrease in urinary lactulose excretion and the lactulose/mannitol ratio between the initial posttrauma measurement and the follow-up permeability measurement using both the bolus infusion (lactulose: initial 0.13 +/- 0.032 vs. follow-up 0.047 +/- 0.012 mmol/6 hrs, p < or = .05; lactulose/mannitol: initial 0.067 +/- 0.012 vs. follow-up 0.044 +/- 0.012, p = .11) and the continuous infusion (lactulose: initial 0.044 +/- 0.013 vs. follow-up 0.014 +/- 0.002 mmol/2 hrs, p < or = .05; lactulose/mannitol: initial 0.055 +/- 0.020 vs. follow-up 0.015 +/- 0.007, p < or = .05). Urine excretion of mannitol was not significantly different between posttrauma and follow-up measurements of intestinal permeability, regardless of the technique used to infuse the lactulose and mannitol. Although the decrease in lactulose and the lactulose/mannitol ratio was significant, only one third of the patients had dramatically increased permeability at the initial measure. Abdominal Trauma Index and Injury Severity Score did not correlate with urinary lactulose excretion or the lactulose/mannitol ratio. Patient tolerance of jejunal administration of lactulose and mannitol was better, using a 3-hr continuous infusion of a dilute solution compared with bolus infusion. CONCLUSIONS: Intestinal permeability is increased in the first 48 hrs posttrauma and decreases with recovery. Although one third of the patients had highly increased lactulose/mannitol ratios posttrauma, severity of injury, assessed by common scoring techniques, did not correlate with the degree of permeability. Tolerance to jejunal administration of lactulose and mannitol is improved with a slow infusion of a dilute solution over a 3-hr period compared with bolus administration.

Abdominal Injuries↗
PubMed2003

Neutrophil transendothelial migration and alteration in vascular permeability: focus on neutrophil-derived azurocidin.

Infiltration and accumulation of polymorphonuclear leukocytes within the tissues is a hallmark of the acute inflammatory response. A prominent feature of acute inflammation is enhanced vascular permeability resulting in edema formation. Such changes in vascular permeability have been known to be dependent upon polymorphonuclear leukocyte interactions with the vascular endothelium. Careful investigation has shown clearly that permeability changes can occur without polymorphonuclear leukocyte transendothelial migration, and that polymorphonuclear leukocyte migration can occur without permeability alteration. The underlying mechanisms of polymorphonuclear leukocyte-stimulated changes in endothelial barrier function have remained elusive. Endothelial activation and polymorphonuclear leukocyte adhesion to the endothelium are both required for polymorphonuclear leukocyte-induced changes in vascular permeability. Polymorphonuclear leukocyte-derived azurocidin plays a major role in this polymorphonuclear leukocyte-evoked alteration in endothelial permeability. Azurocidin is released after activation of polymorphonuclear leukocytes, such as after ligation of the major adhesive integrin CD11b/CD18. Understanding how polymorphonuclear leukocytes alter vascular permeability may provide targets for new drugs for appropriate therapeutic intervention in acute and chronic inflammatory diseases. This review focuses on the role of polymorphonuclear leukocyte-derived azurocidin in alteration of vascular permeability.

Antimicrobial Cationic Peptides↗
PubMed2002

Differential effects of T-cell activation on gastric and small bowel permeability in alcohol-consuming mice.

BACKGROUND: A number of variables influence the effect(s) of alcohol on distinct segments of the intestine. In these studies, we examined the effect of T-cell activation on gastric and small bowel permeability in alcohol-fed mice. METHODS: Gastric permeability was assessed using sucrose absorption, whereas small bowel permeability was followed using the ratio of lactulose to mannitol absorption and inulin absorption. T cells were activated by injecting antigen OVA(323-339) into DO11.10 T-cell receptor transgenic mice. RESULTS: T-cell activation increased gastric and small bowel permeability through a pathway mediated by interferon-gamma and tumor necrosis factor. In mice that were fed a liquid diet that contained 30% ethanol-derived calories for 2 weeks, T-cell activation increased gastric permeability to levels greater than that observed in solid diet or pair-fed, liquid control diet. By comparison, changes in small bowel permeability induced by T-cell activation were abrogated in alcohol-fed mice. Analysis of intestinal cytokine mRNA levels (interferon-gamma and tumor necrosis factor) indicated that relevant mucosal T-cell function was preserved in alcohol-fed mice. CONCLUSIONS: Overall, these data suggest that alcohol potentiates the effects of T-cell activation on gastric permeability, at the same time blunting effects on small bowel permeability

Alcohol Drinking↗
PubMed2005

Intestinal permeability and systemic infections in critically ill patients: effect of glutamine.

OBJECTIVE: This article provides a critical review of the evidence indicating that an increase in intestinal permeability is associated with the installation of bacteremia, sepsis, and the multiple organ failure syndrome and that glutamine in pharmacologic doses reduces the acute increase of intestinal permeability and the infection frequency in critically ill patients. DATA SOURCE: All studies published until December 2004 about intestinal permeability, bacterial translocation, and glutamine were located by search of PubMed and Web of Science. The reference lists of review articles and primary publications were also examined to identify references not detected in the computer search. STUDY SELECTION: Clinical and experimental studies investigating the correlation between intestinal permeability, bacterial translocation, and frequency of infections, associated or not with the effect of glutamine administration. DATA EXTRACTION: Information regarding patient population, experimental design, glutamine doses and routes of administration, nutritional therapy prescribed, methods used to assess intestinal permeability, metabolic variables, and the frequency of infections were obtained from the primary literature. DATA SYNTHESIS: Intestinal permeability is increased in critically ill patients. The results have not always been consistent, but the studies whose results support the association between intestinal permeability and systemic infections have had better design and more appropriate controls. The administration of glutamine by the intravenous or oral route and at the doses recommended before or immediately after surgery, burns, or the administration of parenteral nutrition has a protective effect that prevents or reduces the intensity of the increase in intestinal permeability. Glutamine reduces the frequency of systemic infections and may also reduce the translocation of intestinal bacteria and toxins, but this has not been demonstrated. CONCLUSIONS: Glutamine administration improves the prognosis of critically ill patients presumably by maintaining the physiologic intestinal barrier and by reducing the frequency of infections.

Bacterial Translocation↗