Increased Sucrose Permeability Research Articles

Atrophic Gastritis Is Associated with Increased Sucrose Permeability Related to Chronic Inflammation

Background: Different theories have been presented to explain how atrophic gastritis may lead to gastric cancer development. One contributing factor could be impaired function of the gastric mucosal barrier. The aim of this study was to investigate if there are changes in gastric mucosal permeability to sucrose in atrophic gastritis.Methods: The study comprised 22 patients with atrophic gastritis and 21 normal controls. Gastritis was classified according to the Sydney system from endoscopic biopsies of the gastric corpus and antrum. All subjects were exposed to oral sucrose load (100 g), and the fraction of sucrose excreted in urine was measured by gas chromatography-mass spectrometry. Results: The fraction of sucrose excreted in urine after oral load was significantly increased in atrophic gastritis compared with controls (median 0.08 vs. 0.04%; p = 0.003). Sucrose excretion was positively related to the degree of chronic inflammation (median fraction excreted: mild inflammation 0.06%, moderate inflammation 0.08%, severe inflammation 0.18%; p = 0.04) rather than to the degree of atrophy in the gastric mucosa. Occurrence of intestinal metaplasia was also associated with significantly higher sucrose excretion. However, in multivariate analysis, including intestinal metaplasia, only the degree of inflammation was positively related to sucrose excretion. Conclusion: Atrophic gastritis is associated with increased sucrose permeability, suggesting paracellular leakage of the gastric mucosa. This leakage seems to be related to the degree of inflammation rather than the degree of atrophy. The findings may have implications for the diseases and complications associated with atrophic gastritis.

Effect of drug release rate on therapeutic outcomes: formulation dependence of gastrointestinal toxicity of diclofenac in the rat.

- The use of the non-steroidal anti-inflammatory drug, diclofenac, is associated with occasional serious side effects in the gastrointestinal (GI) tract. We examined the effect of altering the site of release of diclofenac sodium on GI tract side effects. Dissolution and pharmacokinetic studies were carried out to substantiate the sustained-release nature of crushed sustained release tablet. Adult male Sprague-Dawley rats were administered diclofenac 10 mg/kg orally as either immediate-release or sustained-release preparations. Upper and lower GI permeability, as a surrogate marker of toxicity, were measured using sucrose and 51Cr-EDTA, respectively. Immediate- and sustained-release preparations similarly increased upper GI permeability. The induced toxicity in the lower GI tract, however, caused by the sustained-release formulation lasted longer than that of the immediate release formulation. Since both immediate- and sustained-release preparations of diclofenac increased sucrose permeability, the upper GI damage caused by diclofenac may be attributable mainly to a systemic mechanism. The prolonged lower GI toxicity following the sustained-release preparation may be related to a greater residence time therein.

VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly.

Tight junctions between brain microvessel endothelial cells (BMECs) maintain the blood-brain barrier. Barrier breakdown is associated with brain tumors and central nervous system diseases. Tumor cell-secreted vascular endothelial growth factor (VEGF) increases microvasculature permeability in vivo and is correlated with the induction of clinically severe brain tumor edema. Here we investigated the permeability-increasing effect and tight junction formation of VEGF. By measuring [(14)C]sucrose flux and transendothelial electrical resistance (TER) across BMEC monolayer cultures, we found that VEGF increased sucrose permeability and decreased TER. VEGF also caused a loss of occludin and ZO-1 from the endothelial cell junctions and changed the staining pattern of the cell boundary. Western blot analysis of BMEC lysates revealed that the level of occludin but not of ZO-1 was lowered by VEGF treatment. These results suggest that VEGF increases BMEC monolayer permeability by reducing occludin expression and disrupting ZO-1 and occludin organization, which leads to tight junction disassembly. Occludin and ZO-1 appear to be downstream effectors of the VEGF signaling pathway.

Sugar tests detect celiac disease among first-degree relatives

OBJECTIVES: First-degree relatives of patients with celiac disease are at high risk for developing the disease themselves. Detection of serum antibodies and intestinal permeability tests have been useful to identify candidates for intestinal biopsies. Recently it was demonstrated that abnormal sucrose permeability is a very sensitive marker of active disease. Our objectives in this prospective study were (1) to assess the screening value of permeability tests, and (2) to compare the usefulness of these markers with that of the celiac disease-related serology in screening for celiac disease in a cohort of first-degree relatives of well-known patients. METHODS: We performed sugar tests in 66 first-degree relatives of probands. Subjects ingested 450 ml of a solution containing sucrose (100 g), lactulose (5 g), and mannitol (2 g). Subsequently, a complete overnight urine collection was obtained. Measurement of sugars was performed by high-performance liquid chromatography. All relatives were evaluated for antigliadin (type IgA and IgG) and endomysial antibodies and subjects positive for any test underwent intestinal biopsy. RESULTS: Twelve relatives were diagnosed as having small intestinal mucosal atrophy. Increased sucrose permeability was detected in 9 (75%) of these patients. Four false-positive determinations were found but all had gastric erosions, which is known to increase sucrose permeability independently of duodenal damage. Increased lactulose/mannitol ratios were observed in all new celiac patients. An additional nine relatives had positive results; however, four of them did not accept intestinal biopsy and the remaining five did not seem to have histological evidence of disease. Endomysial antibodies were detected in 11 of 12 patients and no false-positive cases were observed. Antigliadin antibodies were 75% sensitive and 88% specific. CONCLUSIONS: Our study demonstrated that screening using the endomysial antibody test is highly sensitive and specific for detecting celiac disease; however, almost 10% can be missed. The addition of lactulose/mannitol permeability testing to the screening protocol allowed us to detect all relatives who actually presented with evidence of gluten sensitivity. Sucrose permeability exhibited a lower sensitivity; however, it did detect other endoscopically visible lesions.

Asymptomatic Helicobacter pylori gastritis is associated with increased sucrose permeability.

Our aim was to investigate whether there are changes in permeability to sucrose in asymptomatic Helicobacter pylori gastritis. Nineteen asymptomatic subjects with Helicobacter pylori-associated gastritis with no or mild mucosal atrophy and 19 age- and sex-matched normal controls were studied by peroral load of sucrose (100 g). The fraction of the given oral dose of sucrose excreted in urine was increased in subjects with Helicobacter pylori gastritis (median 0.08% versus 0.04% in controls). Sucrose excretion was not related to atrophy, intestinal metaplasia, or inflammation in the gastric mucosa. However, sucrose permeability was related to the degree of inflammatory (neutrophil) activity, since moderate activity was associated with higher sucrose excretion than mild activity (median 0.13% vs 0.07%). Asymptomatic Helicobacter pylori gastritis was associated with an increased sucrose permeability, which could be a sign of gastric mucosal leakage. This could have implications for the diseases and complications associated with Helicobacter pylori infection.

Gastrointestinal permeability in celiac disease

BACKGROUND & AIMS: Intestinal permeability is increased in patients with active celiac disease. The measurement of sucrose permeability is proposed as a novel means to detect upper gastrointestinal damage, with potentially greater use than conventional methods. The aim of this study was to evaluate the effectiveness of sucrose in the detection of celiac disease. METHODS: Permeability tests were performed in 27 newly diagnosed patients, at diagnosis, after upper gastrointestinal endoscopies were performed to exclude macroscopic gastric lesions, and after 2 months on a gluten-free diet. Results were compared with those obtained in 30 healthy subjects and 7 patients with chronic diarrhea but no evidence of celiac disease. RESULTS: At diagnosis, 25 of 27 patients had increased urinary excretion of sucrose. Mean sucrose excretion in patients with untreated celiac disease was significantly increased compared with healthy controls and controls with disease. Sucrose excretion decreased significantly after treatment and completely normalized in 60% of patients. The lactulose-mannitol ratio was abnormal in 26 of 27 patients, with a mean value significantly greater than that observed in healthy controls. This ratio also significantly declined after treatment; however, no values returned to the normal range. CONCLUSIONS: Increased sucrose permeability is a sensitive marker for advanced celiac disease. Moreover, it decreases rapidly in response to a gluten-free diet and therefore is potentially useful to follow response to therapy. (Gastroenterology 1997 Apr;112(4):1129-36)

Effects of aspirin and Helicobacter pylori on the gastroduodenal mucosal permeability to sucrose.

A non-invasive marker is needed to identify patients with significant gastrointestinal injury due to non-steroidal anti-inflammatory drugs. Gastrointestinal permeability to sucrose has been suggested as such a test. To assess the utility of sucrose permeability as a marker of gastroduodenal mucosal injury after single and multiple doses of aspirin, to identify the site of increased sucrose permeability, to explore the relation between sucrose permeability and endoscopic findings, and to evaluate whether Helicobacter pylori infection influenced gastroduodenal sucrose permeability. After a fasting urine was obtained, 500 ml of a solution containing 100 g of sucrose was ingested. Urine was collected for five hours and assayed for sucrose by high performance liquid chromatography. Sucrose permeability was also assessed 20 minutes after ingestion of 650 mg of aspirin and eight to 12 hours after a 72 hour course of 650 mg aspirin four times a day. The site of increased permeability was identified after pyloric occlusion with a double balloon tube. Thirty seven healthy volunteers participated. Sucrose permeability (mean (SEM)) increased after both single (195.2 (27) mg and multiple (196.4 (31) mg) doses of aspirin compared with baseline (53.7 (10) mg; p < 0.0005). Balloon pyloric occlusion confirmed that the site of increased sucrose permeability was the stomach. The effect of aspirin on sucrose permeability was similar in those with and without H pylori infection. These results confirm the use of sucrose permeability as a marker of aspirin induced gastroduodenal mucosal injury and identify the stomach as the major site of increased permeability. H pylori infection does not seem to change gastric mucosal sucrose permeability either at baseline or after ingestion of aspirin.

Noninvasive detection of nonsteroidal anti-inflammatory drug-induced gastropathy in dogs

SUMMARY Nonsteroidal anti-inflammatory drugs (nsaid) are widely used for treatment of people and animals. Their use is limited by frequent side effects commonly involving the gastrointestinal tract, most important of which is development of ulcerating lesions principally in the stomach. Unfortunately, presence of such lesions is often unsuspected because clinical signs may be overlooked until a complication develops. We reported that such damage can be detected by measuring the increase in gastric permeability that is a hallmark of this condition. Sucrose is a novel probe molecule for determination of site-specific gastric permeability. As a disaccharide, it is large enough to be effectively excluded by the intact gastric epithelium, and because it is rapidly digested within the small intestine, absorption of the intact molecule implies damage proximal to this site. Recently, we found that increased sucrose permeability is useful in predicting presence of endoscopically relevant gastric damage in people. We extended these results to the detection of nsaid-induced gastropathy in dogs. Dogs treated with aspirin developed nsaid-induced gastropathy (including gastric ulceration), and the degree of endoscopically detectable damage correlated well with sucrose permeability. Furthermore, healing of these lesions could also be monitored by sequential measurements of sucrose permeability. Sucrose permeability decreased more rapidly than the disappearance of gastric ulcers, suggesting that this technique is more sensitive to generalized mucosal damage than is the presence of discrete, endoscopically visible ulceration. This was confirmed by creating artificial ulcers in the antrum and observing that sucrose permeability was not increased in this setting. We conclude that determination of increased sucrose permeability is a useful, noninvasive means of predicting presence of gastric damage in dogs treated with nsaid.

Dual effect of nitrogen dioxide on barrier properties of guinea pig tracheobronchial epithelial monolayers cultured in an air interface.

Nitrogen dioxide (NO2) is an oxidant gas that may injure the airway epithelial lining, leading to decrements in barrier and active ion transport properties. The present studies examined alterations of bioelectric properties and solute flux by guinea pig tracheobronchial epithelial (GPTE) monolayers exposed in vitro to NO2. Confluent GPTE monolayers were exposed to NO2 levels between 0.5 and 5 ppm, while controls were exposed to air. Following exposure, monolayers were mounted in Ussing chambers for measurement of transepithelial resistance (Rte) and short-circuit current (SCC). A 1-h exposure to 1 ppm NO2 significantly increased SCC to 131.3 +/- 8.7% of air controls, while Rte with a value of 109.3 +/- 13.8% was unchanged. In contrast, a 1-h exposure to 2 or 5 ppm NO2 significantly decreased Rte to 39.0 +/- 1.6 or 35.5 +/- 7.3% of air controls, respectively, while SCC values of 140.3 +/- 10.4 or 153.3 +/- 8.6%, respectively, were also significantly elevated. A 1-h exposure to 2 or 5 ppm NO2 significantly increased sucrose permeability across GPTE monolayers to 446.8 +/- 117 or 313.3 +/- 39.5% of air controls, respectively, while glycerol permeability was unchanged. In contrast, a 1-h exposure to 1 ppm NO2 produced no alterations of sucrose or glycerol flux. The SCC of control GPTE monolayers (1-h air exposure) consisted of 50% bumetanide-sensitive and 40% amiloride-sensitive current; exposure for 1 h to 2 ppm NO2 led to no changes in the corresponding SCC components. Active ion transport (i.e., SCC) across the airway epithelium was significantly increased after exposure to NO2 levels < or = 1 ppm with no change of paracellular pathways for diffusion, suggesting that this reactive gas alters cell membrane function. The increased SCC may lead to impairment of fluid balance and mucociliary clearance. NO2-mediated tissue injury with levels > or = 2 ppm primarily affects passive airway epithelial barrier functions, probably by altering tight junctions, which could result in increased transepithelial solute and fluid leakage in vivo.

A simple, non-invasive marker of gastric damage: sucrose permeability

Disaccharides do not cross intact gastrointestinal mucosa to any appreciable extent unless there is damage to the epithelium. Furthermore, since sucrose is rapidly broken down in the small intestine, the absorption of intact sucrose implies damage to proximal epithelium. We have reported that measurement of sucrose permeability detects gastric damage in animals. Whilst such a non-specific test could not replace endoscopy, it might represent a clinically useful technique to identify patients who would benefit from endoscopy. 189 patients underwent endoscopy and assessment of sucrose permeability to evaluate the effectiveness of increased sucrose permeability in the prediction of endoscopic findings. The endoscopist was blinded to results of the sucrose assay. Gastric damage, particularly ulcers and severe gastritis, was successfully detected with this technique. Increased sucrose permeability, however, did not reliably detect mild gastritis, oesophagitis, or duodenal disease. The sensitivity of the test for gastric ulceration was 84% and specificity in predicting an abnormal endoscopy was 96%. Measurement of sucrose permeability is a simple way of screening for gastric damage. It has a sensitivity similar to that for upper gastrointestinal radiology and provides a new way to effectively screen large populations at risk of gastric damage.

Effect of ionic changes, amino acids, and metabolic inhibitors on hydraulic conductivity of the isolated rabbit iris-ciliary body.

The hydraulic conductivity (Lp) of the rabbit ciliary epithelium has been measured under various conditions. Of the ionic changes in the bathing medium imposed upon the tissue, replacement of sodium and either depletion of bicarbonate or deletion of potassium all caused an increase in Lp. Chloride replacement had no effect on Lp. The changes in Lp occur more slowly than the changes in electrical parameters caused by the same perturbations and indicate that ions and fluid move across this tissue by different routes. Of the 10 amino acids tested, only three increased Lp; 2 basic and 1 neutral amino acid. No correlation existed between posterior chamber: plasma ratios, or the nature of the amino acid (i.e., basic, neutral, or acidic) and the effect on Lp. Of the metabolic inhibitors, only iodoacetic acid induced an increase in Lp. The transport inhibitor, ouabain, at concentrations up to 10(-4) M for 4 hours was without effect. The effects of these agents on electrophysiological parameters, therefore, must be confined to net ionic pathways. Inulin and sucrose permeabilities were determined under either a zero or 10 mmHg hydrostatic pressure gradient using radioactive tracers. Application of a hydrostatic pressure gradient increased sucrose permeability by ten-fold but only increased inulin permeability by 20%. This data, together with control tissues run in parallel with many of the experimental tissues, indicates that the tissue is not highly leaky and does not change characteristics with time.(ABSTRACT TRUNCATED AT 250 WORDS)

Subcellular fractionation studies on hepatic tissue from a patient with Pompe's disease (type II glycogen-storage disease).

1. An homogenate of liver biopsy taken from a patient with Pompe's disease (type II glycogen-storage disease) was analysed by enzyme microassay and subcellular fractionation by sucrose-density-gradient centrifugation. 2. A strikingly low activity of lysosomal acid alpha-D-glucosidase was noted but there was also increased activity of neutral alpha-D-glucosidase (found in endoplasmic reticulum). 3. Activities of the acid hydrolases, acid phosphatase and beta-N-acetyl-D-glucosaminidase, were elevated compared with those of controls. Measurement of latent beta-N-acetyl-D-glucosaminidase activity and results of subcellular fractionation experiments, indicated a marked fragility of certain populations of lysosomes. Lysosomes containing predominantly acid phosphatase and beta-D-glucuronidase activities appeared to have normal integrity. 4. Assessment of organelle pathology by enzyme microassay indicated low mitochondrial and peroxisomal enzyme activities. In addition there was evidence of mitochondrial damage as reflected by increased sucrose permeability and by ultrastructural studies.

Effects of inhibitors of metabolism on adenine nucleotides and on 22 Na and 42 K and net movements in rat uteri at 25 degrees C.

The effects of 10−3 M iodoacetate (IAA) and (or) 10−3 M dinitrophenol (DNP) on Na and K fluxes and contents and on adenine nucleotide levels of isolated rat uterine horns were studied. Early 22Na efflux was slightly increased by DNP in the fresh and Na-rich tissues. IAA and DNP alone or together reduced 22Na efflux from the larger cellular fraction (No. 2) in both fresh and Na-rich tissues. 22Na efflux from the smaller cellular fraction (No. 3) was accelerated by IAA and by DNP in Na-rich tissues. DNP increased 22Na influx in both types of tissue and caused net Na gain and K loss. In fresh tissues IAA or IAA plus DNP accelerated 22Na influx, but slowed this influx in Na-rich tissues. In fresh tissues the ATP content was reduced by 50% by DNP. After a 60-min exposure with IAA and a 15- to 20-min exposure with IAA plus DNP, the ATP levels were negligible. The onsets of action of IAA or of IAA plus DNP on Na fluxes were correlated with ATP depletion, but early acceleration of 22Na efflux by DNP was not. In fresh tissues 42K influx was slightly decreased at the time of ATP depletion and the influx was further slowed as tissue potassium was replaced by sodium. IAA plus DNP increased K efflux in 10 min and IAA alone increased K efflux after 100 min. Thus K flux changes were not well correlated with ATP depletion. Substitution of K for all the sodium in the bathing media did not alter the quality of the effects of IAA or IAA plus DNP on sodium efflux. When prolonged glucose depletion eliminated ATP and ADP, the effects of IAA could not be duplicated. But IAA alone, or with DNP, still caused alterations in the 22Na efflux. Therefore IAA acted on ion fluxes by a mechanism other than ATP depletion. Both fresh and Na-rich tissues swelled after ATP depletion. An effect on internal osmotic pressure rather than ATP-depletion per se was postulated. Other studies showed that Na-rich tissues were resistant to shrinking by hypertonic sucrose and became more so secondarily after ATP depletion because of increased sucrose permeability. Evidence from studies of swelling, as well as flux data, suggested that at least two Na pumps were present. Both were ATP-dependent. One was ouabain-sensitive and exchanged Na for K, while the other was ouabain-insensitive and controlled movement of Na with water.

Structural changes in microsomal suspensions: V. Interactions with nucleotides

Brain microsomes incubated with 3 m m ATP or cytidine triphosphate (CTP) exhibited diminished changes in light scattering during incubation in a hypotonic medium; this difference was abolished on subsequent addition of the sulfhydryl reagent, p-chloromercuribenzoate (pCMB). Incubation with 3 m M ADP had little effect on the spontaneous changes, but significantly increased changes in light scattering induced by pCMB, thereby demonstrating a second type of structural change. Preincubation of the microsomes with pCMB prevented all these changes, and greatly reduced the binding of ADP to the membranes. These two types of changes in light scattering could be correlated with changes in permeability to sucrose: ATP, but not ADP, decreased sucrose permeability; on the other hand, preincubation with ADP, but not ATP, increased sucrose permeability during subsequent incubation with pCMB. ADP, and to a lesser extent ATP, reduced the content of reactive sulfhydryl groups in the microsomal preparation, suggesting that the structural changes involved a nucleotide-membrane-sulfhydryl system in which ADP reduced the content of reactive sulfhydryl groups while sensitizing the system to sulfhydryl reagents. Possible relevance to the transport ATPase is suggested in which the substrate of the enzyme, ATP, induces one structural change, whereas ADP, a product, induces a second structural state in the enzyme-membrane complex.