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PubMed2002

Role of membrane proteins in permeability barrier function: uroplakin ablation elevates urothelial permeability.

Although water, small nonelectrolytes, and gases are freely permeable through most biological membranes, apical membranes of certain barrier epithelia exhibit extremely low permeabilities to these substances. The role of integral membrane proteins in this barrier function has been unclear. To study this problem, we have ablated the mouse gene encoding uroplakin III (UPIII), one of the major protein subunits in urothelial apical membranes, and measured the permeabilities of these membranes. Ablation of the UPIII gene greatly diminishes the amounts of uroplakins on the apical urothelial membrane (Hu P, Deng FM, Liang FX, Hu CM, Auerbach AB, Shapiro E, Wu XR, Kachar B, and Sun TT. J Cell Biol 151: 961-972, 2000). Our results indicate that normal mouse urothelium exhibits high transepithelial resistance and low urea and water permeabilities. The UPIII-deficient urothelium exhibits a normal transepithelial resistance (normal 2,024 +/- 122, knockout 2,322 +/- 114 Omega. cm(2); P > 0.5). However, the UPIII-deficient apical membrane has a significantly elevated water permeability (normal 0.91 +/- 0.06, knockout 1.83 +/- 0.14 cm/s x 10(-5); P < 0.05). The urea permeability of the UPIII-deficient membrane also increased, although to a lesser extent (normal 2.22 +/- 0.24, knockout 2.93 +/- 0.31 cm/s x 10(-6); P = 0.12). These results indicate that reduced targeting of uroplakins to the apical membrane does not significantly alter the tight junctional barrier but does double the water permeability. We provide the first demonstration that integral membrane proteins contribute to the apical membrane permeability barrier function of urothelium.

Animals↗
PubMed2004

Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery.

Data from permeability profiling using the parallel artificial membrane permeability assay (PAMPA) and cell monolayer (Caco-2 and MDR1-MDCKII) methods were compared for two published compound sets and one in-house set. A majority of compounds in each set correlated (R(2) = 0.76-0.92), indicating the predominance of passive diffusion in the permeation of these compounds. Compounds that did not correlate grouped into two subsets. One subset had higher PAMPA permeability than cell monolayer permeability and consisted of compounds that are subject to secretory mechanisms: efflux or reduced passive diffusion of bases under Caco-2 when run under a pH gradient. The other subset had higher cell monolayer permeability than PAMPA permeability and consisted of compounds that are subject to absorptive mechanisms: paracellular, active transport, or increased passive diffusion of acids under Caco-2 when run under a pH gradient. Given the characteristics of the two methods, these studies suggest how PAMPA and Caco-2 can be synergistically applied for efficient and rapid investigation of permeation mechanisms in drug discovery. During early discovery, all compounds can be rapidly screened using PAMPA at low pH and neutral pH to assess passive diffusion permeability to indicate potential for gastrointestinal and cell assay permeation. During intermediate discovery, selected compounds can be additionally assayed by apical-to-basolateral Caco-2, which, in combination with PAMPA data, indicates susceptibility to additional permeation mechanisms (secretory and absorptive). During mid-to-late discovery, selected candidates can be examined in detail via multiple directional Caco-2 experiments and with transporter inhibitors for complete characterization of permeation mechanisms.

Caco-2 Cells↗
PubMed2006

Permeability assessment of poorly water-soluble compounds under solubilizing conditions: the reciprocal permeability approach.

The objective of this study was to develop a general method to assess the intestinal permeability of poorly water-soluble drugs where low-aqueous drug solubility requires conduct of experiments under solubilizing experimental conditions. The permeability (Papp) of diazepam (DIA) was assessed across excised rat jejunum in the absence (Pappcontrol) and presence (Pappuncorr) of polysorbate-80 (PS-80). The micellar association constant (Ka) of DIA, estimated via equilibrium solubility studies, was used to correct Pappuncorr data and obtain an estimate of the true permeability coefficient (Pappcorr). An alternate approach was also developed (the reciprocal permeability approach) to allow direct estimation of Pappcorr without the need for independent estimation of Ka. The approach was further examined experimentally using a range of model drugs. DIA Pappcorr values obtained using the Ka from equilibrium solubility studies deviated from Papp(control) values, especially at PS-80 concentrations above 0.1% w/v. In contrast, data obtained using the reciprocal permeability method were consistent with Pappcontrol across the PS-80 concentration range. Similar trends were observed with propranolol (PRO), antipyrine (ANT), naproxen (NAP), and cinnarizine (CIN). The reciprocal permeability approach therefore provides a simple and accurate method by which the permeability of poorly water-soluble compounds may be estimated under solubilizing conditions.

Animals↗
PubMed1996

Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody.

The hyperpermeability of tumor vessels to macromolecules, compared with normal vessels, is presumably due to vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) released by neoplastic and/or host cells. In addition, VEGF/VPF is a potent angiogenic factor. Removal of this growth factor may reduce the permeability and inhibit tumor angiogenesis. To test these hypotheses, we transplanted a human glioblastoma (U87), a human colon adenocarcinoma (LS174T), and a human melanoma (P-MEL) into two locations in immunodeficient mice: the cranial window and the dorsal skinfold chamber. The mice bearing vascularized tumors were treated with a bolus (0.2 ml) of either a neutralizing antibody (A4.6.1) (492 micrograms/ml) against VEGF/VPF or PBS (control). We found that tumor vascular permeability to albumin in antibody-treated groups was lower than in the matched controls and that the effect of the antibody was time-dependent and influenced by the mode of injection. Tumor vascular permeability did not respond to i.p. injection of the antibody until 4 days posttreatment. However, the permeability was reduced within 6 h after i.v. injection of the same amount of antibody. In addition to the reduction in vascular permeability, the tumor vessels became smaller in diameter and less tortuous after antibody injections and eventually disappeared from the surface after four consecutive treatments in U87 tumors. These results demonstrate that tumor vascular permeability can be reduced by neutralization of endogenous VEGF/ VPF and suggest that angiogenesis and the maintenance of integrity of tumor vessels require the presence of VEGF/VPF in the tissue microenvironment. The latter finding reveals a new mechanism of tumor vessel regression-i.e., blocking the interactions between VEFG/VPF and endothelial cells or inhibiting VEGF/VPF synthesis in solid tumors causes dramatic reduction in vessel diameter, which may block the passage of blood elements and thus lead to vascular regression.

Animals↗
PubMed1985

The permeability of skin and oral mucosa to water and horseradish peroxidase as related to the thickness of the permeability barrier.

The permeability of porcine skin and keratinized and nonkeratinized oral mucosa to tritium-labeled water and horseradish peroxidase (HRPO) was determined using perfusion chambers. Small blocks from each tissue were also incubated with HRPO and the extent of penetration visualized microscopically; this enabled measurements to be made of the thickness of the permeability barrier to this water-soluble tracer. Results obtained after inverting the oral mucosa in the chambers or adding metabolic inhibitors indicated that both compounds diffuse across the tissue. The permeability constants derived directly in the study showed that skin was less permeable than oral mucosa and that the floor of the mouth was significantly more permeable than all other regions. When these constants were normalized in terms of a standard permeability barrier thickness and the different tissues compared, the values obtained for skin were again less than those of the oral regions but, of these, the buccal mucosa was significantly higher. The difference in permeability between epidermis and keratinized oral epithelium may be due to differences in the volume density of membrane-coating granules known to exist between the tissues; differences between the oral mucosal regions may reflect differences in the nature of the intercellular barrier material.

Animals↗
PubMed2002

Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF.

Tumor necrosis factor (TNF) has marked effects on permeability and procoagulant activity on tumor-associated neovasculature when used in isolation perfusion, the latter effect primarily mediated via induction of cell surface expression of tissue factor (TF) on endothelial tissue. However, the cellular events that result in rapid alterations in endothelial cell (EC) permeability after intravascular TNF administration in isolation perfusion are not well characterized. We demonstrate that short exposure intervals to TNF induces TF expression on ECs but has no effect on permeability as assessed by flux of Evans blue-bound albumin across confluent EC monolayers using a 2-compartment model under basal culture conditions. However, a rapid and significant increase in EC permeability occurred with TNF in the presence of factor VIII-deficient plasma. Permeability was induced only with luminal versus abluminal TNF exposure and was blocked by antithrombin III, TF pathway inhibitor, or anti-TF antibody cotreatment. These data indicate that EC surface expression of TF and extrinsic clotting factors are critical in augmenting capillary leak following intravascular TNF administration. Alterations in permeability were associated with intercellular gap formation at sites of down-regulation of vascular endothelial (VE)-cadherin expression, the primary endothelial intercellular adhesion molecule, and intracellular contraction and alignment of F-actin cytoskeletal elements. Rapid induction of TF by TNF may be the primary EC response that results in alterations in permeability and procoagulant activity observed following intravascular TNF administration in isolation perfusion.

Antibodies, Monoclonal↗
PubMed1984

Membrane permeability of secondary hydatid cysts of Echinococcus granulosus. Determination of the water diffusional and osmotic permeability coefficients through a syncytial membrane.

Diffusional (Pw) and osmotic (Pf) water permeability coefficients were determined for the syncytial epithelium of larval Echinococcus granulosus. Pw was calculated from simultaneous influx measurements of tritiated water and n-[14C]butanol through the hydatid cyst wall. The total diffusional water permeability coefficient, P'w, was found to be 2.2 X 10(-4) cm s-1; which is similar to that previously reported by Rotunno et al. (1974, J. Parasitol. 60, 13-620). Nevertheless, when P'f is corrected for the unstirred water layer effects, a Pw value of 6.2 X 10(-4) cm s-1 is obtained. Thus, the unstirred water layer effects have a very important contribution to P'w. Total steady state osmotic permeability coefficient, P'f, was bound to be about 15 X 10(-4) cm s-1 and it is scarcely affected by those mechanisms that tend to distort the evaluation of Pf. The experimentally determined osmotic coefficient differs from the corrected Pf by only 6%. The Pf/Pw ratio was found to be 2.4. The present study clearly confirms that syncytial membranes can be highly permeable to water, in spite of the fact that they lack tight junctions. Thus, water permeability through epithelial syncytium must be exclusively controlled by the permeability of the apical and/or basocellular membranes.

Animals↗
PubMed2004

Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes: application to prediction of Caco-2 cell permeability.

To evaluate absorption of compounds across the membrane via a transcellular route, the permeability of peptide derivatives and related compounds was measured by the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients by PAMPA were analyzed quantitatively using classical QSAR and Volsurf approaches with the physicochemical parameters. The results from both approaches showed that hydrogen bonding ability of molecules in addition to hydrophobicity at a particular pH were significant in determining variations in PAMPA permeability coefficients. The relationship between Caco-2 cell permeability and artificial lipid membrane permeability was then determined. The compounds were sorted according to their absorption pathway in the plot of the Caco-2 cell and PAMPA permeability coefficients.

Caco-2 Cells↗
PubMed2005

Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes: application to prediction of Caco-2 cell permeability.

To evaluate the absorption of drugs with diverse structures across a membrane via the transcellular route, their permeability was measured using the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients obtained by PAMPA were analyzed using a classical quantitative structure-activity relationship (QSAR) approach with simple physicochemical parameters and 3D-QSAR, VolSurf. We formulated correlation equations for diverse drugs similar to the equation obtained for peptide-related compounds in our previous study. The hydrogen-bonding ability of molecules, not only the hydrogen-accepting ability but also the hydrogen-donating ability, in addition to hydrophobicity at a particular pH, was significant in determining variations in PAMPA permeability coefficients. Based on this result, an in silico good prediction model for the passive transcellular permeability of diverse structural compounds was obtained. The artificial lipid-membrane permeability coefficients of the drugs, except salicylic acid, were well correlated with the Caco-2 permeability in a previous report suggesting the importance of absorption by the transcellular mechanism for these drugs.

Caco-2 Cells↗
PubMed1986

Role of the altered transmural permeability in the pathomechanism of arteriosclerosis. History of arteriosclerosis theories. Role of the altered permeability in experimental arteriosclerosis models.

After presenting an overview on classification and history of arteriosclerosis theories, the physiological factors involved in the transmural permeability of the arteries are discussed in detail. The development and characteristic features of the altered transmural permeability were studied in various experimental models such as in rat's hypercholesterolemia, local aortic hypoxia, lymphedema of the vascular wall and in hypertension. Results appear to show that alterations in permeability invariably developed in all of the pathological conditions examined, they were transient in nature and preceded the onset of intimal proliferation(s). The disturbance of transmural permeability might be the common pathologic clue which initiates uniform vascular responses to injuries produced by a variety of noxious stimuli. The possible role of the altered transmural permeability in the induction of smooth muscle cell proliferation is also discussed and evidence is provided that after withdrawal of stimulus for vascular injury intimal proliferation will not develop despite the manifest disorders in permeability.

Animals↗
PubMedDate not supplied

The "latent membrane permeability" concept: QSPR analysis of inter/intralaboratory variable Caco-2 permeability.

Caco-2 cell monolayers grown on a filter support are the most widely used systems for predicting intestinal absorption. However, inter- and intralaboratory variability in Caco-2 permeability makes it difficult to analyze any QSPR relationship for a large number of compounds. We proposed the "latent membrane permeability" concept, assuming that all Caco-2 permeability data sets share a hidden, common relationship between their membrane permeability and physicochemical properties. An iterative calculation method was developed to handle this conceptual approach and applied to the analysis of Caco-2 permeability data sets from different sources. A thorough statistical analysis revealed that the "latent membrane permeability" concept be reasonable.

Caco-2 Cells↗
PubMed2002

Divergence of angiogenic and vascular permeability signaling by VEGF: inhibition of protein kinase C suppresses VEGF-induced angiogenesis, but promotes VEGF-induced, NO-dependent vascular permeability.

Vascular endothelial growth factor (VEGF) promotes angiogenesis by a variety of mechanisms including stimulation of endothelial cell proliferation and migration and increasing vascular permeability. Although its mitogenic activity is mediated primarily by the beta(2)-isoforms of protein kinase C (PKC), little is known about the signaling pathways transducing its other physiological properties. Accordingly, we used a novel inhibitor molecule to examine the role of PKC isoforms alpha and beta in mediating VEGF-induced angiogenesis and vascular permeability. Because conventional inhibitors of PKC, such as staurosporine or calphostin C, also inhibit a variety of other protein kinases, we used a novel compound to specifically inhibit PKC. A myristoylated peptide, which mimics the pseudosubstrate motif of PKC-alpha and -beta subtypes, has been shown to be a highly selective and cell-permeable inhibitor of PKC. Blocking led, as expected, to abrogation of VEGF-induced endothelial cell proliferation in vitro. In vivo, VEGF-induced angiogenesis was impaired by myristoylated peptide. Surprisingly, selective inhibition of PKC induced vascular permeability in vivo via a NO-dependent mechanism. Moreover, PKC inhibition led to a 6.4-fold induction of NO synthase (NOS) activity in endothelial cells. Our findings demonstrate that activation of PKC is a major signaling pathway required for VEGF-induced proliferation and angiogenesis, whereas vascular permeability was enhanced by blocking PKC. Inhibition of calcium-dependent PKC by itself led to induction of NOS. Although NOS is a downstream target for VEGF-induced angiogenesis, its induction by PKC inhibition was not sufficient to promote neovascularization. These results reveal that angiogenesis and vascular permeability induced by VEGF are mediated by mechanisms which ultimately diverge.

Animals↗
PubMed1996

Determination of lubricating film thickness for permeable hydrogel and non-permeable polyurethane layers bonded to a rigid substrate with particular reference to cushion form hip joint replacements.

The lubricating film thickness in a model of compliant layered bearings, using both permeable hydrogels and non-permeable polyurethane elastomers for total hip joint replacements, has been measured using optical interferometry, under both entraining and squeeze-film motion. The film thickness in the lubricated contact was measured for both water and a 40 per cent glycerol solution in water as a function of entraining velocity and squeeze-film time. The measured lubricating film thickness for the permeable hydrogel was compared to that of the non-permeable polyurethane elastomer and little difference was found when the lubricating film thickness was sufficiently large (greater than 150 nm). Comparison of the experimental results and the theoretical predictions based upon elastohydrodynamic lubrication analysis showed good agreement in the entraining experiments where the film thickness was greater than 150 nm. In the squeeze-film experiments the experimental measurements were greater than the theoretical predictions for all squeeze times due to the formation of a central pocket of fluid which was not predicted by the simple theory used. This also occurred for the hydrogels for films greater than 150 nm. For longer squeeze times the film thickness for the hydrogel fell below the theoretical prediction. This was considered to be due to the permeability of the hydrogel reducing the film thickness when the film thickness was less than 150 nm. The permeability of the hydrogel was not modelled in the theoretical lubrication analysis used in this study.

Biomechanical Phenomena↗
PubMed2001

Evaluation of insulin permeability and effects of absorption enhancers on its permeability by an in vitro pulmonary epithelial system using Xenopus pulmonary membrane.

The permeability of insulin across Xenopus pulmonary membrane and the effects of various absorption enhancers on insulin permeability were examined using an in vitro Ussing chamber technique. Absorption enhancers used in this study were sodium caprate (NaCap), sodium glycocholate (NaGC), sodium salicylate (NaSal) and ethylenediaminetetraacetic acid disodium salt (EDTA). The permeability of insulin across Xenopus pulmonary membrane significantly increased in the presence of NaCap and NaGC, while EDTA and NaSal did not enhance the permeability. In addition, the enhancing effect of NaGC increased as the concentrations of these enhancers increased. Transmembrane resistance (Rm) of Xenopus lung was markedly decreased in the presence of these enhancers, and NaCap showed a greater effect on Rm than NaGC. Furthermore, the amount of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) released from the apical side of the Xenopus pulmonary membrane increased in the presence of these enhancers. These results indicate that NaCap and NaGC improve the pulmonary absorption of insulin, but they are toxic to the pulmonary membrane. These findings suggest that this method is useful for estimating the permeability characteristics of peptides across the pulmonary membrane and for evaluating the effects of various additives on their permeability and their membrane toxicity.

Absorption↗
PubMed1980

A proteaselike permeability factor in guinea pig skin: contact activation of the latent permeability factor and its nature as a prekallikrein activator.

A proteaselike permeability factor in guinea pig skin, which was fractionated in a latent form into pseudoglobulin fractions, was activated by contact with kaolin particles at neutral pH. This contact activation was not prevented by the presence of 1 M KCl but was strongly inhibited by the simultaneous presence of hexadimethrine bromide. In this activation, the latent permeability factor was first bound to kaolin; later an active form permeability factor was released from the kaolin-bound parent molecule. Prekallikrein activator activity was also generated in this supernatant from the pretreated kaolin particle in the same time course as the permeability factor generation. Moreover, since the prekallikrein activator and permeability factor were always observed at the same fractions in every purification step, with DEAE-cellulose column chromatography, Sephadex G-75 gel filtration, and isoelectric focusing, these two molecules were recognized as identical. These results indicate that the latent permeability factor in the guinea pig skin has properties similar to those of the plasma Hageman factor.

Adsorption↗
PubMed2002

Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide.

Vascular endothelial cell growth factor (VEGF) was originally described as a potent vascular permeability factor (VPF) that importantly contributes to vascular pathobiology. The signaling pathways that underlie VEGF/VPF-induced permeability are not well defined. Furthermore, endogenous vascular peptides that regulate this important VPF function are currently unknown. We report here that VPF significantly enhances permeability in aortic endothelial cells via a linked signaling pathway, sequentially involving Src, ERK, JNK, and phosphatidylinositol 3-kinase/AKT. This leads to the serine/threonine phosphorylation and redistribution of actin and the tight junction (TJ) proteins, zona occludens-1 and occludin, and the loss of the endothelial cell barrier architecture. Atrial natriuretic peptide (ANP) inhibited VPF signaling, TJ protein phosphorylation and localization, and VPF-induced permeability. This involved both guanylate cyclase and natriuretic peptide clearance receptors. In vivo, transgenic mice that overexpress ANP showed significantly less VPF-induced kinase activation and vascular permeability compared with non-transgenic littermates. Thus, ANP acts as an anti-permeability factor by inhibiting the signaling functions of VPF that we define here and by preserving the endothelial cell TJ functional morphology.

Actins↗
PubMed2000

The influence of cytotoxicity of macromolecules and of VEGF gene modulated vascular permeability on the enhanced permeability and retention effect in resistant solid tumors.

PURPOSE: To study the influence of cytotoxicity of macromolecules, VEGF gene expression, and vascular permeability on the enhanced permeability and retention (EPR) effect. METHODS: Mice bearing xenografts of A2780 multidrug resistant human ovarian carcinoma were treated by free doxorubicin (DOX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound DOX (P(GFLG)-DOX), Texas Red (P-TR), and FITC (P-FITC). Antitumor activity, drug distribution in tumor, vascular permeability, VEGF gene expression, and DNA fragmentation were studied. RESULTS: The accumulation of free DOX led to the VEGF gene overexpression and increased the vascular permeability, which in turn enhanced the drug accumulation in the same location. This positive feedback loop led to a highly inhomogeneous distribution of the drug within the tumor. In contrast, P(GFLG)-DOX down-regulated the VEGF gene and decreased vascular permeability. This negative feedback seemed to prevent additional drug accumulation in dead necrotic tissue, resulting in a more uniform drug distribution and enhanced the antitumor activity P(GFLG)-DOX. CONCLUSIONS: The EPR effect significantly differed for macromolecules containing DOX when compared to macromolecules without drug. The cytotoxicity of P(GFLG)-DOX amplified the EPR effect, led to a more homogenous distribution of the drug, increased the average drug concentration in tumor and augmented its efficacy.

Animals↗
PubMed2003

QSAR analysis of interstudy variable skin permeability based on the "latent membrane permeability" concept.

A number of QSAR models for skin permeability have been proposed, but these models lack consistency due to interspecies and interlaboratory differences. This study was initiated to extract an essential QSAR from the multiplicity of data sets of skin permeability by using a novel statistical approach. Ten data sets were collected from the literature, which include a total of 111 permeability coefficients in human, hairless mouse, or hairless rat skin for 94 structurally diverse compounds. Following a Potts and Guy's approach, the octanol/water partition coefficient and molecular weight were chosen as molecular descriptors. All of the data sets were analyzed simultaneously, assuming that all of the sets share a latent, common factor as far as the structure/permeability relationship is concerned. Despite the fact that the degree-of-freedom for the present analysis was limited compared with that for individual regression analyses, the determination coefficients (R2) were high enough for all the 10 data sets, with an average R2 of 0.815 (average R2 = 0.825 for individual analyses). Thus, skin permeability of compounds can be well explained from the log P and M.W., where the ratio of the contribution to skin permeability was approximately 1:1.

Animals↗