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PubMedDate not supplied

Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries.

We asked if the arterial sites most prone to early lesions in cholesterol-fed rabbits have higher permeabilities to low density lipoprotein (LDL) in normolipidemic rabbits or if these sites become more permeable shortly after the onset of cholesterol feeding. We also considered whether the focal increases in the concentration of LDL within the arterial wall in lesion-susceptible sites before fatty streak formation can be explained by increased arterial permeability to LDL or by other mechanisms such as decreased rates of LDL efflux or degradation. 125I-tyramine cellobiose-labeled LDL was injected 1 hour before death to determine the initial rate of LDL entry into lesion-prone and lesion-resistant sites of aorta as a measure of permeability. This was studied in normal rabbits and in rabbits fed cholesterol for 4, 8, or 16 days. Combining this permeability data with the tracer data described in the accompanying article, we fit a kinetic model to calculate the mass and mean residence time of intact LDL within the artery and the fractional rates of LDL degradation and efflux from the artery. In normal rabbits, the permeability of lesion-susceptible branch sites of the abdominal aorta was about four times that of the lesion-resistant, nonbranched areas. However, the permeability of the aortic arch, a susceptible site, was similar to that of the lesion-resistant descending thoracic aorta. Permeability to LDL did not increase in any aortic site during the 16 days of cholesterol feeding, even in sites with the largest increases in arterial LDL concentrations. Plasma LDL cholesterol concentration increased substantially and total LDL cholesterol delivery into the artery increased many fold. Since there was no differential change in permeability between susceptible and resistant sites, the increased entry of LDL did not explain the selective increases in arterial LDL concentration in susceptible sites. Kinetic analysis indicated that the fractional rate of degradation of the arterial LDL pool was lower in lesion-prone sites than in lesion-resistant sites in all animals. Fractional rates of efflux of arterial LDL decreased in lesion-susceptible branch sites of the abdominal aorta and were low in the lesion-susceptible aortic arch. These results suggest that the focal increases in LDL concentration observed in all lesion-susceptible sites of cholesterol-fed rabbits before fatty streak formation are due to localized differences in LDL retention and diminished fractional rates of LDL degradation, not to selectively increased permeability.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1995

cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells.

Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Permeability of human isolated airways increases after hydrogen peroxide and poly-L-arginine.

In asthma, the airway epithelium may be damaged by oxidants and cationic proteins produced by eosinophils. The degree of epithelial damage correlates with the level of bronchial hyperreactivity. An increase in airway permeability to bronchoactive agonists may be one of the factors responsible for airway hyperresponsiveness in asthma. We investigated the effects of the oxidant hydrogen peroxide and the major basic protein (MPB) analogue poly-L-arginine on the permeability and morphology of nonasthmatic human peripheral airways. In addition, we examined whether airway permeability depends on airway size. Human airway tubes (generation 7 to 12) mounted in an organ bath were luminally perfused with Krebs-Henseleit buffer containing the hydrophilic tracer 111In-diethyletriamine pentaacetic acid (111In-DTPA) or the lipophilic tracer 14C-antipyrine (14C-AP). Permeability of the airways was calculated from the fluxes of the tracer molecules across the airway wall. After experiments, light- and electromicroscopic examination of the airway epithelium was performed. Baseline permeability to 14C-AP was five times greater than to 111In-DTPA. Luminal exposure of the airways to 100 mmol/L H2O2 produced a significant, sixfold increase in permeability to 111In-DTPA but not to 14C-AP, indicating the opening of paracellular pathways. The H2O2-induced increase in permeability was partly reversible. Luminal exposure to polyarginine for 3 h and 16 h produced a significant 4.5- and 7-fold increase in permeability to 111In-DTPA, respectively. Histologic examination of epithelium exposed to H2O2 of poly-L-arginine showed focal loss of superficial cells with preservation of basal cells. Baseline airway permeability increased with decreasing airway size (rs = -0.75, p < 0.01). These results suggest that epithelial damage due to eosinophil products may increase airway permeability, and that this may at least partly explain the increased responsiveness to inhaled stimuli in asthma.

Adult↗
PubMed1997

CT measurements of capillary permeability within nodal masses: a potential technique for assessing the activity of lymphoma.

Analysis of time-attenuation data has enabled CT to measure capillary permeability within the brain and kidney. As yet, such techniques have not been applied to nodal masses in patients with lymphoma. Tumour angiogenesis is known to produce capillaries that exhibit increased permeability and CT measurements of permeability could therefore potentially provide a marker of tumour viability. This study aims to determine the feasibility and limitations of CT measurement of capillary permeability within lymphoma nodal masses. Six patients with biopsy proven lymphoma have been studied. Time-attenuation curves from the aorta and nodal mass were generated from a single-location dynamic sequence of images acquired over 3 min following an intravenous bolus of iopamidol. A nuclear medicine data processing technique, Patlak analysis, was used to calculate capillary permeability and blood volume within the nodal mass. Renal blood vessel permeability was also determined in four patients. Median lymph node permeability to iopamidol was 88.5 microliters min-1 ml-1 (range 36.4-198.5 microliters min-1 ml-1). The correlation coefficient of the linear fit for the Patlak analysis ranged from 0.74 to 0.95 and was greater than 0.9 for regions of interest of 150 pixels or more (256 x 256 matrix). The values for renal permeability (442 microliters min-1 ml-1; range: 349-589 microliters min-1 ml-1) were comparable to those previously reported. Functional images of permeability were also obtained. The study has confirmed the feasibility of CT measurements of capillary permeability within nodal masses. The technique combines anatomical imaging and functional information within one examination and has potential application in monitoring the response of lymphoma to therapy.

Adult↗
PubMed1993

Hormonal modulation of ionic permeability in human red blood cells.

It has previously been reported that both exogenous adenosine cAMP analogs and forskolin-induced elevations in intracellular cAMP concentrations selective increase relative ionic chloride permeability in normal human red blood cells (RBC). A similar selectively increase in relative ionic chloride permeability was observed in untreated uremic subjects in whom endogenous RBC cAMP concentrations are chronically elevated. To detect which hormones might modulate RBC cAMP and ionic permeabilities, RBC were exposed to norepinephrine, epinephrine, and parathyroid hormone. Thereafter, RBC cAMP concentrations were measured by RIA and relative ionic permeabilities were determined in human RBC ghosts with the potential sensitive fluorescent probe diS-C3-(5). In ghosts prepared from normal RBC, norepinephrine and epinephrine significantly increased intracellular cAMP concentrations; in these ghosts, relative ionic chloride permeability (permeability of chloride/permeability of potassium (PCI/PK)), but not PNa/PK (permeability of sodium/permeability of potassium), was significantly increased. In contrast, exposure to parathyroid hormone did not affect either cAMP concentrations or relative ionic permeabilities. These results are consistent with the presence of adrenergic receptors and the absence of parathyroid hormone receptors in RBC. These studies demonstrate that hormonally induced changes in cAMP can modulate RBC relative ionic chloride permeability and suggest that, in uremic RBC, increased relative ionic chloride permeability could be consequent to elevated plasma levels of epinephrine or norepinephrine.

Cell Membrane Permeability↗
PubMed2001

Physicochemical profiling (solubility, permeability and charge state).

About 30% of drug candidate molecules are rejected due to pharmacokinetic-related failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by "formulation" can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption. Poor solubility and poor permeability account for many PK failures. FDA's Biopharmaceutics Classification System (BCS) is an attempt to rationalize the critical components related to oral absorption. The core idea in the BCS is an in vitro transport model, centrally embracing permeability and solubility, with qualifications related to pH and dissolution. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In principle, the framework of the BCS could serve the interests of the earliest stages of discovery research. The BCS can be rationalized by considering Fick's first law, applied to membranes. When molecules are introduced on one side of a lipid membrane barrier (e.g., epithelial cell wall) and no such molecules are on the other side, passive diffusion will drive the molecules across the membrane. When certain simplifying assumptions are made, the flux equation in Fick's law reduces simply to a product of permeability and solubility. Many other measurable properties are closely related to permeability and solubility. Permeability (Pe) is a kinetic parameter related to lipophilicity (as indicated by the partition and distribution coefficients, log P and log D). Retention (R) of lipophilic molecules by the membrane (which is related to lipophilicity and may predict PK volumes of distribution) influences the characterization of permeability. Furthermore, strong drug interactions with serum proteins can influence permeability. The unstirred water layer on both sides of the membrane barrier can impose limits on permeability. Solubility (S) is a thermodynamic parameter, and is closely related to dissolution, a kinetic parameter. The unstirred water layer on the surfaces of suspended solids imposes limits on dissolution. Bile acids effect both solubility and dissolution, by a micellization effect. For ionizable molecules, pH plays a crucial role. The charge state that a molecule exhibits at a particular pH is characterized by the ionization constant (pKa) of the molecule. Buffers effect pH gradients in the unstirred water layers, which can dramatically affect both permeability and dissolution of ionizable molecules. In this review, we will focus on the emerging instrumental methods for the measurement of the physicochemical parameters Pe, S, pKa, R, log P, and log D (and their pH-profiles). These physicochemical profiles can be valuable tools for the medicinal chemists, aiding in the prediction of in vivo oral absorption.

Humans↗
PubMed1995

Ocular permeability of FITC-dextran with absorption promoter for ocular delivery of peptide drug.

The purpose of this study is to characterize an ocular permeability of FITC-dextran, as a model of peptide drug, and to evaluate the effects of absorption promoters on the ocular permeability of FITC-dextran. The in vitro penetrations of FITC-dextrans (average molecular weight 4400 and 9400: FD-4 and FD-10) were measured across the isolated corneal and conjunctival membranes of albino rabbits using a two-chamber glass diffusion cell. The corneal permeabilities of FD-4 and FD-10 were much lower than the conjunctival permeabilities. Scraping of corneal epithelium extremely increased the corneal permeabilities. The penetration parameters were estimated according to Fick's equation. Absorption promoters such as EDTA, taurocholic acid, benzalkonium chloride and saponin significantly increased corneal permeabilities of FD-4 and FD-10. Saponin showed the highest promoting activity. Conjunctival permeabilities of FD-4 and FD-10 were also enhanced by absorption promoters although the improvements of conjunctival permeabilities by absorption promoters were smaller than those of corneal permeabilities. Ratios of corneal to conjunctival permeabilities were enhanced by absorption promoters. These results indicate that an ocular delivery of instilled hydrophilic macromolecule is markedly low and a selective use of absorption promoter can improve the extent and pathway of its ocular absorption.

Absorption↗
PubMed2000

Effect of dentin desensitizers and dentin bonding agents on dentin permeability.

PURPOSE: To determine the effect of dentin desensitizing agents (oxalates and glutaraldehyde) and dentin bonding agents, with and without resin-based composite (RBC) on dentin permeability and morphology of the dentin surface. The influence of saliva and toothbrushing on these agents was also evaluated. MATERIALS AND METHODS: Radicular dentin discs +/-1 mm thick were obtained from extracted human teeth. The thickness of the discs was standardized by grinding them with 600 grit silicon carbide powder. Both pulpal and periodontal surfaces of the discs were treated with 6% citric acid for 2 min prior to the baseline measurement of dentin permeability. Permeability was measured for the discs, using a split-chamber apparatus, at four different time points: at baseline, after treatment with each desensitizing modality, after 24 hrs of saliva immersion and after simulated toothbrushing equivalent to 3 weeks of normal brushing. The treatment modalities were: Sensodyne Dentin Desensitizer, Gluma Dentin Desensitizer, All-Bond DS (primers without etching), Etch+Primers (All-Bond 2 system), Etch+Primers+Adhesive and Etch+Primers+Adhesive+RBC (AElite Flo). Radicular dentin discs were prepared separately for scanning electron microscopy (SEM). One group was left untreated as the control group. Discs in the other groups were treated with the modalities listed above. One disc from each group was viewed under the SEM after treatment with the desensitizing modality. The second disc in each group was viewed after 24 hrs of saliva immersion following desensitizing treatment and the third disc after 3 weeks of simulated toothbrushing following desensitizing treatment and saliva immersion. RESULTS: The greatest reduction in permeability was caused by All-Bond DS followed by Sensodyne Dentin Desensitizer and Etch+Primers+Adhesive+RBC. Gluma Dentin Desensitizer, Etch+Primers, and Etch+Primers+Adhesive did not reduce permeability by a significant amount. Saliva immersion increased permeability significantly only for the Gluma and Etch+Primers+Adhesive groups. There was a trend towards increase in permeability after toothbrushing; however, this increase was not statistically significant for any group (P > 0.05). Thus, placement of primers without etching (All-Bond DS) reduced permeability more than any other treatment modality. These data indicate that etching a sensitive dentin area may be appropriate only if RBC is to be placed in the area. Exposure to saliva and toothbrushing countered the decrease in permeability caused by dedicated desensitizers and dentin bonding agents. The SEM micrographs revealed that in most cases, form corroborated function and the morphology of the dentin surface corresponded to the dentin permeability values.

Acid Etching, Dental↗
PubMed2002

Enhancement of HCO(3)(-) permeability across the apical membrane of bovine corneal endothelium by multiple signaling pathways.

PURPOSE: In this study, the involvement of signaling pathways in the regulation of HCO(3)(-) permeability across the apical membrane of the corneal endothelium was examined. METHODS: Cultured bovine corneal endothelial cells (CBCECs) were grown to confluence on permeable membranes. Apical and basolateral sides were perfused with a HCO(3)(-)-rich Cl(-)-free Ringer's solution (28.5 mM; pH 7.5). Relative changes in apical HCO(3)(-) permeability were assayed by pulsing the apical perfusion bath with a low-HCO(3)(-) Cl(-)-free Ringer's solution (2.85 mM; pH 6.5), in the presence or absence of agonists or inhibitors, and comparing the rates of change in intracellular pH (pH(i)), as measured with a pH-sensitive dye. Ca(2+)-activated signaling was measured with the Ca(2+)-sensitive dye Fura-2. Qualitative changes in membrane potential (E(m)) were measured with a voltage-sensitive dye. RT-PCR using calcium-activated chloride channel (CLCA)-specific primers was used to examine the expression of CLCA in the corneal endothelium. RESULTS: The adenoceptor agonist adenosine (20 M) enhanced HCO(3)(-) permeability by a factor of 2. Forskolin (40 microM) exerted a 6.3-fold increase of HCO(3)(-) permeability, which was inhibited by the Cl(-) channel blockers, glibenclamide (50 microM) and niflumic acid (100 microM). Adenosine triphosphate (ATP) and ATPgammaS, P(2) receptor agonists that increased intracellular Ca(2+) in corneal endothelium, enhanced HCO(3)(-) permeability by 87% and 79%, respectively. ATPgammaS induced depolarization of the E(m), consistent with anion channel activation, rather than activation of Ca(2+)-dependent K(+) channels, which could secondarily increase extrusion of anions by E(m) hyperpolarization. Cyclopiazonic acid (CPA), an endoplasmic reticulum (ER) Ca(2+)-pump inhibitor that increased [Ca(2+)](i), also enhanced HCO(3)(-) permeability by 95%. Both the calmodulin kinase II (CaMKII) inhibitor KN-62 and the PKC inhibitor bisindolylmaleimide I (BIMI), decreased HCO(3)(-) permeability induced by ATPgammaS. The PKC activator PMA also increased HCO(3)(-) permeability by a factor of 1.8. RT-PCR using CLCA-specific primers showed the expression of CLCA1 in both fresh and cultured BCECs. CONCLUSIONS: Activation of adenoceptors and purinoceptors enhances HCO(3)(-) permeability across the apical membrane of the cultured corneal endothelium. Multiple signaling pathways (PKA, PKC, and Ca(2+)/CaMKII) contribute to the HCO(3)(-) transport in cultured corneal endothelium. Both cAMP and Ca(2+)-activated Cl(-) channels (possibly CLCA) may be involved in HCO(3)(-) transport.

Animals↗
PubMed2002

Ice reduces edema. A study of microvascular permeability in rats.

BACKGROUND: Ice is applied following a soft-tissue injury on the basis of clinical information. This study investigates the relationship between ice therapy (cryotherapy) and edema by determining microvascular permeability before and after contusion with and without ice therapy and provides data supporting a reduction in edema following cryotherapy. METHODS: A dorsal microvascular chamber was created in rats to allow the direct examination of microvascular parameters in intact, pre-established microvascular beds of the cutaneous maximus muscle in conscious rats. The rats received a contusion or sham contusion and were treated with cryotherapy or were not treated. Microvascular permeability (edema) was assessed by measuring fluorescent-labeled albumin in the interstitial fluid before and after contusion. RESULTS: Microvascular permeability following contusion was significantly increased in the group that received the contusion without cryotherapy compared with that in the group that received the sham contusion without cryotherapy (control) (p < 0.001). When ice was applied fifteen minutes after the contusion for twenty minutes, microvascular permeability (edema) decreased significantly (p < 0.001) compared with that in the group that did not receive cryotherapy after contusion. Permeability was increased in the group that received cryotherapy following the contusion compared with that in the control group (p = 0.012), although the increase was not as great as that between the group that received the contusion without cryotherapy and the control group. Sham contusion with cryotherapy significantly reduced microvascular permeability compared with that in the control group (p = 0.004). Sham contusion without cryotherapy did not cause a significant change in the microvascular permeability of postcapillary venules after 300 minutes compared with baseline measurements. CONCLUSIONS: The application of ice significantly decreased microvascular permeability following striated muscle contusion. The results of this study demonstrated that microvascular permeability is increased following a contusion coincident with significant leukocyte-endothelial interactions. However, microvascular permeability was significantly reduced following cryotherapy, a treatment demonstrated to reduce the number of rolling and adherent leukocytes. This association suggests that the reduction in edema in injured skeletal muscle following cryotherapy may be due to a reduction in leukocyte-endothelial interactions.

Animals↗
PubMed1989

An electrophysiological study of microvascular permeability and its modulation by chemical mediators.

In continuous microvessels the permeability barrier is constituted by the endothelium, consisting of a single layer of endothelial cells separated by hydrophilic clefts. Ions and small hydrophilic solutes permeate the endothelium via the intercellular spaces, and the dimensions of this pathway determine the permeability. Endothelial permeability characteristics have been extensively studied by physiological techniques used on whole organs. It is known that permeability of venules increases after stimulation with inflammatory mediators, probably by a mechanism involving formation of widenings of the interendothelial cleft, termed leaks. To the present knowledge about the function of the microvascular endothelium my studies have added the following information: 1. The electrical resistance or conductance of endothelium recorded on single frog microvessels in vivo vary by at least three orders of magnitude from the tight brain endothelium (Rm = 1870 omega cm2, Gm = 0.53 mScm-2) to the microvascular endothelia of skin (Rm = 24-70 omega cm2, Gm = 14-42 mScm-2), muscle (Rm = 23-36 omega cm2, Gm = 28-43 mScm-2) and mesentery (Rm = 1-3 omega cm2, Gm = 0.33-1.0 Scm-2). 2. Potassium ion permeabilities calculated from the electrical conductances average 8.5 x 10(-7), 3.4 x 10(-5), 5.7 x 10(-5), and 80 x 10(-5) cm sec-1 for brain, skin, muscle and mesenteric microvessels, respectively. These values comply with what has been predicted from whole-organ experiments. 3. Venules are 1.5-2 x more permeable to ions than arterioles. 4. Ion permeabilities of capillaries are not much different from those of venules, and since the surface area of venules is comparable to that of capillaries, venules may be important exchange vessels for small solutes. 5. The specific electrical resistance of frog blood-brain barrier is similar to that of a tight epithelium, resembling brain endothelium by several criteria. 6. The electrical resistance of brain endothelium is at least one order of magnitude smaller than that of the endothelial cell membrane, strongly indicating that microvascular permeability to small solutes is mainly paracellular in brain, as it is in other organs. 7. Ion permeability of frog blood-brain barrier is reversibly increased by various autacoids: serotonin, bradykinin, ATP, ADP, AMP, og LTC4. These receptor-agonists all induce similar changes: permeability increases within 1-2 sec after administration, rapidly peaks with values less than two-fold the control value and reverses at a much slower rate (5-15 min).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Permeability decay in CAVH hemofilters.

Change in hydraulic permeability over time was measured in four types of continuous arteriovenous hemofiltration (CAVH) hemofilters in order to characterize permeability decay and demonstrate that permeability decay occurs without membrane protein exposure. Polyamide, polysulfone, and polyacrylonitrile membrane hemofilters were placed in a gravity-driven in vitro CAVH apparatus. Distilled and deionized water or saline was used to perfuse the hemofilters. A biphasic pattern of permeability decay was seen in all hemofilter types. A large exponential decline in permeability occurred over the first 1 to 6 hours, with a more gradual decay thereafter. Of all membranes studied, polysulfone hemofilters were the most permeable upon initiation of use but showed the most pronounced early and late permeability decay. Both polyamide and polyacrylonitrile hemofilters showed little permeability decay after a brief exponential decay. These data suggest that early membrane hydraulic permeability decay may not be primarily due to membrane protein coating. Initial high permeability may place some CAVH systems at risk for hemofilter plugging.

Acrylic Resins↗
PubMed1978

Studies on the capillary permeability of experimental liver metastases.

By using a quantitative Evans blue technique, vascular permeability of Walker carcinosarcomas implanted in the liver was compared with that of the host liver tissue. Rats were sacrificed at intervals from one minute to 96 hours after the intravenous injection of the dye. Permeability activity curves were significantly different for tumors and normal liver. Permeability activity was lower in the tumor at one and five minutes, approximately the same in the tumor and liver from 15 minutes to one hour but, from two hours to 48 hours, the permeability activity was significantly higher in the tumor. The peak tumor-liver permeability activity ratio of 1.87 occurred at six hours, and the highest tumor permeability activity values were seen at 18 hours. Liver permeability activity, in contrast, increased gradually after dye injection, reading peak levels at 24 to 72 hours. At 96 hours, both tumor and liver permeability activity were lower and equal. The differences in permeability activity may be explainable on the basis of structural differences in normal and tumor vessels or may be due to chemical substances released as a result of the presence of the tumor. The differences in permeability activity of tumors and normal tissues may be an important factor in determining the effectiveness of diagnostic and therapeutic techniques.

Animals↗
PubMed1993

Autoradiographic determination of permeation pathway of permeability probes across intestinal and tracheal epithelia.

Mucosal permeability studies are used to assess intestinal and respiratory barrier functions. Our ability to interpret results of permeability studies are hampered by our lack of understanding of absorptive pathways of permeability markers. The aim of this study was to visually trace the pathway of permeability probes across the small intestinal and tracheal epithelia by using electron microscopic autoradiography and cytochemistry. We saw a constant rate of mucosal to serosal permeation of intestinal permeability probes polyethylene glycol 400 (PEG-400) and mannitol across the everted small intestinal sac and of the pulmonary permeability probe bovine serum albumin (BSA) across the tracheal epithelia. Electron microscopic tracing of the permeation pathways of tritiated PEG-400 and tritiated mannitol revealed that the majority of the probes traversed the intestinal epithelium paracellularly within 1 half distance (1650 A) of the intercellular space. It is interesting that we also found a small but significant transcellular transport of permeability probes. Goblet cells also absorbed permeability probes transcellularly, but in an "all or none" fashion. Similar pathways were identified in studies utilizing the commonly used pulmonary permeability probes iodine 125-labeled BSA and horseradish peroxidase to determine the routes of transfer in the airway epithelia. In the normal unperturbed trachea, these large permeability probes traversed the pulmonary epithelia transcellularly via endocytosis. On barrier disruption by cytochalasin D, the probes permeated predominantly via the paracellular pathway. This study also demonstrates some of the similarities and differences in transmucosal pathways shared by intestinal and pulmonary epithelia.

Animals↗
PubMed1997

Increased gastric and intestinal permeability in patients with Crohn's disease.

OBJECTIVES: Patients with Crohn's disease exhibit marked changes in intestinal permeability that can be assessed by lactulose and mannitol. Sucrose is a novel marker for gastric permeability. We combined these three sugars to investigate whether patients with Crohn's disease demonstrate changes in gastric permeability and if so, whether these changes are matched with altered intestinal permeability. METHODS: Fifty patients with Crohn's disease and 30 healthy subjects each drank a solution containing 20 g of sucrose, 10 g of lactulose, and 5 g of mannitol. Patients' and subjects' 5-h sugar urinary excretion levels were determined by high performance liquid chromatography and an enzymatic method (sucrose). Furthermore, patients with Crohn's disease underwent endoscopy of the upper GI tract and were grouped according to endoscopic and histological findings. RESULTS: Patients with Crohn's disease showed higher gastric and intestinal permeability compared with healthy control subjects. Gastric permeability was correlated with intestinal permeability. Patients with granuloma had more pronounced changes in both gastric and intestinal permeability than patients with various endoscopic and histological lesions. Patients with normal mucosa had normal permeability. CONCLUSIONS: Alterations in gastric mucosa caused by Crohn's disease are reflected by changes in gastric permeability and can be used to noninvasively screen for Crohn's disease involvement of the upper GI tract.

Adolescent↗
PubMed1989

The relationship between dentin bond strengths and dentin permeability.

The relationship between dentin permeability and the shear bond strength of Scotchbond/Silux was investigated. In the presence of a smear layer, there was no correlation between dentin permeability and dentin bond strengths. After removal of the smear layer with acids, there was an inverse relationship between dentin permeability and dentin bond strength. The bond strengths were high when dentin permeability was low and decreased as dentin permeability increased. Creation of smear layers with abrasive paper or dental burs reduced permeability by 80-85%. When Scotchbond/Silux bonds were made to such smear layers and then broken, the permeability of the dentin remained low. If the smear layer was removed by acid-etching prior to bonding, the permeability increased. When these bonds were broken, the permeability of the dentin remained elevated.

Adolescent↗
PubMed2002

Lipopolysaccharide-induced enterocyte-derived nitric oxide induces intestinal monolayer permeability in an autocrine fashion.

Studies indicate that endotoxin (LPS) causes intestinal injury, increases inducible nitric oxide synthase (iNOS) activity, leads to increased NO production, and promotes bacterial translocation (BT). To investigate the mechanism by which LPS causes gut injury and to test the hypothesis that NO produced by enterocytes promotes gut injury in an autocrine fashion, rat intestinal epithelial cell (IEC-6) monolayers were tested. IEC-6 monolayers grown in a bicameral system were incubated with media or with LPS (25 microg/mL) and tested for permeability to phenol red, BT, and nitrate/nitrite (NO2/NO3) production. To determine the direct effect of NO on permeability, monolayers were incubated with the NO donor S-nitroso-acetylpenicillinamide (SNAP; 1 mM) and tested for permeability. Next, the protective effects of two NOS inhibitors (L-NMMA and L-NIL) were tested. Finally, to determine if LPS-induced permeability occurs via a poly (ADP-ribose) synthetase- (PARS) dependent pathway, monolayers incubated with LPS alone or with the PARS inhibitor, INH2BP (100 microM) were tested. LPS significantly increased IEC-6 permeability to phenol red, as well as increased NO2/NO3 by 20-fold (P < 0.001) and increased BT 10-fold (P < 0.001). SNAP mimicked the effect of LPS and significantly increased both permeability to phenol red and BT. Inhibition of iNOS significantly decreased the LPS-induced increase in monolayer permeability and BT (P < 0.05). Monolayers incubated with INH2BP had significantly decreased permeability to phenol red and BT, suggesting that LPS-induced NO production increases monolayer permeability at least in part via a PARS-dependent mechanism. In summary, LPS-induced disruption of monolayer barrier function appears to be related, at least in part, to enterocyte produced NO. This supports the hypothesis that NO produced by LPS-stimulated enterocytes promotes injury in an autocrine fashion and highlights the fact that enterocytes can be a target as well as a producer of NO.

Animals↗
PubMed2000

Effects of menopause and estrogen on cervical epithelial permeability.

The objective of the study was to characterize the effect and explore the mechanisms by which menopause affects paracellular permeability of cultured human cervical epithelium. The experimental system was cultures of human ectocervical epithelial (hECE) cells on filters. Assays included flux measurements of cell-impermeable molecules and determinations of transepithelial electrical conductance. hECE cells of postmenopausal women formed epithelia with lower paracellular permeability than hECE cells of premenopausal women. Treatment with estrogen increased paracellular permeability, but levels remained lower compared to cultures from premenopausal women. Lowering extracellular calcium or treatment with cytochalasin-D, conditions that decrease the tight junctional resistance (R(TJ)), increased the permeability, and the relative effects were greater in cells of premenopausal women than in postmenopausal women. Treatment of cells with sn-1,2-dioctanoyl diglyceride, an agent that increases the R(TJ), decreased the permeability, and the relative effect was greater in cells of postmenopausal women than in cells of premenopausal women. Estrogen had no significant effect on the responses to low calcium, cytochalasin-D, or sn-1,2-dioctanoyl diglyceride. Hydrostatic and hypertonic gradients in the subluminal to luminal direction, conditions that decrease the resistance of the lateral intercellular space increased the permeability to a similar degree in cultures of cells from premenopausal and from postmenopausal women. Pretreatment with estrogen augmented the increases in permeability in response to hydrostatic and hypertonic gradients. In cells exposed to low extracellular calcium, hydrostatic gradients had an additive increase in permeability. By extrapolation it was determined that in cultures of postmenopausal women R(TJ) contributes 97% to the total paracellular resistance, whereas in hECE cultures of premenopausal women the R(TJ) contributes only 84%. These results indicate that after menopause the transcervical paracellular permeability decreases significantly; this can explain the decrease in lubrication of the cervix and vagina in postmenopausal women. Part of the effect is due to lack of estrogen, and it can be reversed by treatment with the hormone. However, most of the effect is unrelated to estrogen and is caused by an increase in R(TJ).

Adult↗