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PubMed2006

Plasma obtained during human endotoxemia increases endothelial albumin permeability in vitro.

To gain insight in the pathogenesis of increased vascular permeability during sepsis, we studied the effect of plasma obtained during human experimental endotoxemia on the permeability of cultured endothelial monolayers. Eight healthy subjects received an i.v. dose of 2 ng/kg Escherichia coli O:113 lipopolysaccharide (LPS). The concentration of various plasma mediators that supposedly induce vascular permeability was measured over time. Plasmas that were obtained before, and 2 and 4 h after the administration of LPS were added to human umbilical venular endothelial cells that were cultured on semipermeable membranes.The permeability of the endothelial monolayers to fluorescein isothiocyanate-labeled bovine serum albumin was determined and expressed as the relative concentration of fluorescein isothiocyanate-bovine serum albumin when compared with that measured across empty Transwell-COL (Corning Life Sciences B.V., Schiphol-Rijk, The Netherlands) membranes (i.e., without endothelial monolayers). The permeability levels were correlated with the concentrations of various mediators.Experimental endotoxemia resulted in elevated levels of tumor necrosis factor alpha, interleukin (IL) 1beta, IL-6, IL-8, IL-10, and vascular endothelial growth factor and a moderate increase of IL-12 and IFN-gamma (all P values < 0.01). Incubation of human umbilical venular endothelial cells with plasma obtained 2 and 4 h after the administration of LPS increased the relative permeability from a baseline level (median) of 17% (range, 14% - 31%) to 23% (range, 12% - 39%; P = not significant) and 28% (range, 11% - 40%; P < 0.05), respectively. Plasma levels of vascular endothelial growth factor and IL-10, but not TNF-alpha or any other mediators, significantly correlated with the increase in endothelial permeability (r = 0.47, P = 0.038; r = 0.43, P = 0.038, respectively). The data presented here demonstrate that plasmas obtained from experimental human endotoxemia increase endothelial albumin permeability in vitro. Thus, cultured human endothelial monolayers provide a model to study sepsis-associated vascular changes.

Adult↗

PubMed1991

Lipid content and water permeability of skin and oral mucosa.

It has been claimed that total lipid content may be the critical factor determining the water permeability of skin. The present study examined this relationship in various oral epithelia and epidermis. Epithelia was heat separated from specimens of porcine skin, gingiva, buccal mucosa, palate, and floor of mouth. Lipids were solvent extracted and separated by thin layer chromatography with appropriate standards. The plates were sprayed with sulfuric acid and charred, and the concentration of lipids was determined by densitometry as mg lipid/gm tissue dry weight. Permeability constants were determined for each tissue by using tritiated water in perfusion chambers. When these values were compared over all regions, total lipid did not appear to be related to the permeability of these tissues. However, in the keratinized regions (epidermis, gingiva, and palate) a lower water permeability was related to a greater content of total lipid, nonpolar lipid, ceramide, and glucosylceramide. In non-keratinized tissues, a lower permeability corresponded to increased amounts of an unidentified glycosylceramide. The role of lipid in the permeability barrier of these tissues was further demonstrated by extracting specimens of skin and oral mucosa with chloroform/methanol and then determining Kp values; in both tissue regions, there was a significant increase in water permeability. Thus, although lipid is a component of the water permeability barrier in both skin and oral mucosa, different lipid components subserve this function in keratinized and non-keratinized tissues.

Animals↗

PubMed1976

The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water.

The permeability of whole human skin, human dermis, whole pig skin, and canine buccal mucosa have been determined for four chemically different solutes: tritiated water, amphetamine, estradiol, and ouabain. Several new in vitro techniques for isolation, preservation, and permeability determination of these membranous tissues are described. Water permeabilities of human epidermis and dermis using these techniques agree well with published results. Human and porcine skins are very similar with respect to water permeability, while buccal mucosa is similar to dermis in its permeability characteristics to the four representative test agents. The permeability of hydrated whole skin is determined by the permeability of the epidermis, and the dermis and buccal mucosa behave as if they are water barriers exhibiting a permeability of about 30% of the diffusion through pure water, a difference that can be ascribed to the porosity and/or tortuosity of the tissue matrix.

Amphetamines↗

PubMed1992

The mechanism of the increase in mitochondrial proton permeability induced by thyroid hormones.

Three possible mechanisms by which different levels of thyroid hormones in rats might cause the observed sevenfold change in the apparent proton permeability of the inner membrane of isolated liver mitochondria were investigated. (a) Cytochrome c oxidase was isolated from the livers of hypothyroid, euthyroid and hyperthyroid rats and incorporated into liposomes made with soya phospholipids. There was no difference between the proton current/voltage curves of the three types of vesicles. The hormonal effects, therefore, were not an inherent property of the enzymes, and were not due to different coupling of electron flow through the enzyme to proton transport. (b) The surface area of the mitochondrial inner membrane was shown by three different assays to be greater by a factor of between two and three in mitochondria from hyperthyroid animals than in mitochondria from hypothyroid animals; euthyroid controls were intermediate. This difference in surface area of the inner membrane explains less than half of the difference in apparent proton permeability. (c) The proton permeability of liposomes prepared from phospholipids extracted from mitochondrial inner membranes of hyperthyroid rats was three times greater than the proton permeability of those from hypothyroid rats; euthyroid controls were intermediate. This suggests, first, that the proton permeability of the phospholipid bilayer is an important component of the proton permeability in intact mitochondria and, second, thyroid hormone-induced changes in the bilayer are a major part of the mechanism of increased proton permeability. Such changes may be due to the known differences in fatty acid composition of mitochondrial phospholipids in different thyroid states. Thus we have identified two mechanisms by which thyroid hormone levels in rats change proton flux/mass protein in isolated liver mitochondria: a change in the area of the inner membrane/mass protein and a change in the intrinsic permeability of the phospholipid bilayer.

Animals↗

PubMedDate not supplied

Extended theory of the early diffusion of multiple indicators: bounds on permeability ratios, with applications to intestinal capillaries.

The determination of ratios of capillary permeabilities to multiple indicators is secured by constructing upper bounds on effects of early back-diffusion following a single arterial injection. The analysis does not exclude highly extracted indicators, and it allows for effects of asymmetric blood-tissue exchange and of tissue concentration gradients. The concept of flow limitation of uptake is delimited operationally. It is shown how to identify effects of heterogeneity of uptake for data sets extended over large ranges of rate of blood flow. These new methods are used to show, for several sets of previously published data from muscle, that back-diffusion cannot change appreciably the permeability ratios determined previously without any quantification of back-diffusion. The main application is to data published by Perry and Granger (1981) on the permeability of cat intestinal capillaries to raffinose and inulin. The permeability ratios deduced from these data imply paradoxically restricted diffusion; it is shown that this cannot be attributed to effects of back-diffusion, heterogeneity of extraction, or of solvent drag. It is shown that the paradox is removed if tissue-to-blood permeability to raffinose is at least double the blood-to-tissue permeability, possibly as part of the active transport of sugars from the intestinal lumen. It is shown that corresponding results on permeability ratios in dog gastric capillaries are not paradoxical (against the standard of unrestricted diffusion) under symmetric permeability to raffinose.

Animals↗

PubMed1988

Effect of pH on vasopressin-induced water permeability in collecting ducts of isolated rat papillae.

1. The effects of basolateral and luminal pH on diffusional water permeability of microperfused collecting ducts of isolated rat papillae were examined in the presence and absence of vasopressin at two concentrations. 2. In the absence of vasopressin, collecting duct diffusional water permeabilities did not differ when the pH of the luminal fluid was varied. Similarly, in the absence of vasopressin, collecting duct diffusional water permeabilities did not differ when the bath pH was varied. 3. In the presence of 50 microU/ml vasopressin, increases in diffusional water permeability of collecting ducts perfused with solutions at pH 5.0, 7.4 or 9.0 did not differ significantly. Similarly, increases in diffusional water permeability induced by 200 microU/ml vasopressin were not different when collecting ducts were perfused with solutions at pH 5.0, 7.4 or 9.0. 4. The presence of vasopressin (50 microU/ml) in the bathing medium at pH 6.4, 7.4 and 8.4 induced increments in diffusional water permeability of 0.40 +/- 0.21 (n = 14, P greater than 0.05), 1.56 +/- 0.27 (n = 27, P less than 0.001) and 1.67 +/- 0.24 (n = 12, P less than 0.001) microns/s, respectively. The increment in water permeability at pH 6.4 was significantly less than that at pH 7.4 (P less than 0.001). 5. The presence of vasopressin (200 microU/ml) in the bathing medium at pH 6.4, 7.4 and 8.4 induced increments in diffusional water permeability of 2.16 +/- 0.54 (n = 9, P less than 0.01), 2.55 +/- 0.51 (n = 17, P less than 0.001) and 0.98 +/- 0.34 (n = 11, P less than 0.05) microns/s respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Role of eicosanoids in PAF-induced increases of the vascular permeability in rat airways.

1. Platelet activating factor (PAF; 1.0 and 5.0 micrograms kg-1) injected in the tail vein of unanaesthetized rats dose-dependently increased the vascular permeability of the trachea, upper and lower bronchi (up to 400%) as measured by the extravasation of Evans blue dye. The permeability of the parenchyma was not affected by PAF treatment. 2. Pretreatment of the animals with an intravenous injection of the PAF antagonist BN-52021 (10 mg kg-1) abolished almost totally the vascular permeability changes elicited by PAF injection (5.0 micrograms kg-1). 3. Pretreatment of the animals with intravenous injections of inhibitors of thromboxane formation, indomethacin (10 mg kg-1) and compound OKY-046 (10 mg kg-1), and thromboxane antagonist, compound L-655,240 (5 mg kg-1), partially reduced PAF effects in the airways (from 28 to 69%). The thromboxane mimic U-44069 (5.0 micrograms kg-1) did not modify the vascular permeability of rat airways. The effect of a low dose of PAF (0.1 microgram kg-1) on the vascular permeability of the trachea and bronchi (but not of the parenchyma) was potentiated by compound U-44069 (5.0 micrograms kg-1) or noradrenaline (400 ng kg-1) whereas the effect of a high dose of PAF (5.0 micrograms kg-1) was not affected. 4. Neither the peptidoleukotriene antagonist MK-571 (10 mg kg-1) nor the 5-lipoxygenase inhibitor, L-663,536 (10 mg kg-1) given before the injection of PAF (5.0 micrograms kg-1) affected the protein extravasation in rat lung tissues. 5. These data suggest that the effect of PAF on rat vascular permeability is partly modulated by thromboxane formation although thromboxanes have no direct effect on the permeability. Thromboxane may act via a vasoconstriction that increases hydrostatic pressure and potentiates the extravasation elicited by PAF effect on endothelial cells. 6. Leukotrienes do not appear to be involved in the changes of rat airway permeability induced by PAF.

Animals↗

PubMed2001

Intestinal permeability is increased in a proportion of spouses of patients with Crohn's disease.

OBJECTIVE: Increased small intestinal permeability has been found in patients with Crohn's disease and in a proportion of their healthy relatives. This may reflect a shared environment or shared genes. The finding of abnormal permeability in the healthy spouses of patients would favor an environmental cause for this observation. METHODS: The healthy spouses of patients with Crohn's disease attending three gastroenterology clinics were invited to participate. Eligible subjects consumed a 350-ml solution containing lactulose, mannitol, and sucrose before bedtime. All overnight urine was collected, assayed by high performance liquid chromatography, and the ratio of fractional excretion of lactulose to mannitol was calculated as an index of permeability. The results were compared with those of a previously determined control group. RESULTS: Sixty spouses completed the study. Increased permeability was present in eight (13.3%, 95% CI = 6.0-24.6%). The presence of increased permeability was not related to age, gender, duration of cohabitation, alcohol use, nonsteroidal anti-inflammatory drug use or to disease activity in the patient with Crohn's disease. There was a nonsignificant trend for abnormal permeability to occur in those spouses cohabiting with the patient with Crohn's disease at the time of disease diagnosis (p = 0.128). CONCLUSIONS: Small intestinal permeability is increased in a proportion of healthy spouses of patients with Crohn's disease. The presence of abnormal permeability studies in patients with Crohn's disease and a proportion of their healthy close contacts suggests that this phenomenon is caused by environmental factors.

Adult↗

PubMed2006

Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes.

OBJECTIVES: Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls. METHODS: Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12). RESULTS: Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and controls (0.07 [0.035-0.19]) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious IBS (0.43 [0.29-0.63], p=0.028) or controls (0.27 [0.2-0.39]), p=0.001). CONCLUSIONS: Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.

Adolescent↗

PubMed1997

Human jejunal effective permeability and its correlation with preclinical drug absorption models.

This review focuses on intestinal permeability measurements in humans and various aspects of in-vivo transport mechanisms. In addition, comparisons of human data with preclinical models and the blood-brain barrier is discussed. The regional human jejunal perfusion technique has been validated by several crucial points. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. We have also shown that it is possible to determine the effective permeability (Peff) for carrier-mediated transported compounds, and to classify them according to the proposed Biopharmaceutical Classification System (BCS). Furthermore, it is possible to predict human in-vivo permeability using preclinical permeability models, such as in-situ perfusion of rat jejunum, the Caco-2 model and excized intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. It is also suggested that it is possible to roughly estimate the permeability of the blood-brain barrier using measurements of intestinal permeability, even if the quantitative role of efflux of P-glycoprotein(s) in-vivo still remains to be clarified. Finally, the data obtained in-vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in-vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It is also important to study the effect of anti-transport mechanisms, such as efflux by P-glycoprotein(s), and gut wall metabolism, for example CYP 3A4, on the bioavailability.

Animals↗

PubMed1997

Regional intestinal permeability in rats of compounds with different physicochemical properties and transport mechanisms.

Because the absorption of orally administered drugs depends on intestinal permeability, we have investigated how absorptive capacity varies from the proximal to distal intestine in rats. The effective permeabilities of compounds with a range of physicochemical properties and different absorption mechanisms were estimated by use of a previously validated in-situ, single-pass perfusion model. The low colonic permeabilities of D-glucose and L-dopa indicate the absence or low capacity of the glucose- and amino-acid-transporters in this region. With the exception of the small and moderately lipophilic non-steroidal anti-inflammatory drug, naproxen, for which permeability was maintained throughout the intestine, the passive intestinal permeabilities for hydrophilic and lipophilic drugs were approximately twice as high in the jejunum and ileum as in the colon. These observations are in accord with those made in recent studies. However, the reasons for the high colonic permeability of non-steroidal anti-inflammatory drugs, and results obtained in previous animal experiments demonstrating that the colon is the region of the intestine with the highest absorptive capacity were not fully clarified. These data show that the permeability to hydrophilic and lipophilic drugs decreases along the intestine, whereas it is maintained throughout the intestine for the small and moderately lipophilic naproxen. Further investigations are required to clarify the interplay between membrane composition, fluidity and permeability under various conditions in different absorption models.

Administration, Oral↗

PubMed1978

Calcium-induced increase in membrane permeability in the guinea-pig taenia coli: evidence for involvement of a sodium-calcium exchange mechanism.

1. High-Na tissues exposed to a Na-free solution with dimethyldiethanol ammonium chloride (DDA) or sucrose replacing Na, develop an increase in membrane permeability to small ions and molecules such as Na, K, sucrose and CoEDTA. 2. The increase in permeability only occurs when the Na gradient across the cell membrane is reversed, and is not due to damaging effects of the Na-free solution. It does not occur in normal or high-K tissues, and 15 mM-[Na]0 is enough to prevent the permeability change in high-Na tissues. 3. Tissues with increased permeability maintain high levels of Ca and the increased permeability does not occur in Ca-free solutions, or in solutions containing 5 mM-La3+. The rate of development of membrane leakiness depends on the level of extracellular Ca. 4. Tissues exposed to iodoacetic acid (IAA) and dinitrophenol (DNP) also develop a membrane leakiness, dependent on extracellular Ca and blocked by La3+. 5. The time taken for development of the increase in membrane permeability in metabolically inhibited tissues can be affected by the Na gradient. With no gradient, or a slightly reversed gradient the membrane break-down occurs more rapidly. 6. It is concluded that the increase in permeability is caused by an increase in internal Ca ions, and that the Na gradient as well as the levels of ATP are important in controlling Ca movements. 7. Tension recordings also support the some form of Na--Ca exchange mechanism operating in the taenia, and this mechanism is not completely blocked by La3+ ions, although they suppress the break-down in membrane permeability.

Animals↗

PubMed2004

PAR2 activation alters colonic paracellular permeability in mice via IFN-gamma-dependent and -independent pathways.

Activation of colonic proteinase-activated receptor-2 (PAR(2)) caused inflammation and increased mucosal permeability in mouse colon. The present study was aimed at characterizing the possible links between these two phenomena. We evaluated the effects of intracolonic infusion of PAR(2)-activating peptide, SLIGRL, on colonic paracellular permeability and inflammation at two different doses, 5 and 100 microg per mouse, in an attempt to discriminate between both PAR(2)-mediated effects. We further investigated the possible involvement of interferon gamma (IFN-gamma) and calmodulin-dependent activation of myosin light chain kinase (MLCK), and alterations of zonula occludens-1 (ZO-1) localization in PAR(2)-induced responses. Thus, at the lower dose, SLIGRL increased colonic permeability without causing inflammation. Western blotting showed phosphorylation of mucosal myosin light chain (MLC) expression after both doses of SLIGRL. Moreover, while the MLCK inhibitor, ML-7, abolished the permeability effects of the low dose of SLIGRL, it only partially inhibited that of the high dose. In IFN-gamma-deficient mice (B6 ifng(-/-)), the increases in permeability were similar for both doses of SLIGRL and prevented by ML-7. In addition, MLCK immunoprecipitation revealed an increase of calmodulin binding to MLCK in the mucosa of mice treated with either dose of SLIGRL. Finally, we have shown that direct activation of PAR(2) on enterocytes is responsible for increased permeability and ZO-1 disruption. Moreover, SLIGRL at a dose that does not produce inflammation increases permeability via calmodulin activation, which binds and activates MLCK. The resulting tight junction opening does not depend upon IFN-gamma secretion, while the increased permeability in response to the high dose of PAR(2) agonist involves IFN-gamma secretion.

Animals↗

PubMed2006

Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood-brain barrier permeability.

The objective of the study was to establish primary cultured porcine brain microvessel endothelial cells (PBMECs) as an in vitro model to predict the blood-brain barrier (BBB) permeability in vivo. The intercellular tight junction formation of PBMECs was examined by electron microscopy and measured by transendothelial electrical resistance (TEER). The mRNA expression of several BBB transporters in PBMECs was determined by reverse transcriptionpolymerase chain reaction analysis. The in vitro permeability of 16 structurally diverse compounds, representing a range of passive diffusion and transporter-mediated mechanisms of brain penetration, was determined in PBMECs. Except for the perfusion flow rate marker diazepam, the BBB permeability of these compounds was determined either in our laboratory or as reported in literature using in situ brain perfusion technique in rats. Results in the present study showed that PBMECs had a high endothelium homogeneity, an mRNA expression of several BBB transporters, and high TEER values. Culturing with rat astrocyte-conditioned medium increased the TEER of PBMECs, but had no effect on the permeability of sucrose, a paracellular diffusion marker. The PBMEC permeability of lipophilic compounds measured under stirred conditions was greatly increased compared with that measured under unstirred conditions. The PBMEC permeability of the 15 test compounds, determined under the optimized study conditions, correlated with the in situ BBB permeability with an r2 of 0.60. Removal of the three system L substrates increased the r2 to 0.89. In conclusion, the present PBMEC model may be used to predict or rank the in vivo BBB permeability of new chemical entities in a drug discovery setting.

Animals↗

PubMed2000

Multiparameter flow cytometric analysis of antibiotic effects on membrane potential, membrane permeability, and bacterial counts of Staphylococcus aureus and Micrococcus luteus.

Although flow cytometry has been used to study antibiotic effects on bacterial membrane potential (MP) and membrane permeability, flow cytometric results are not always well correlated to changes in bacterial counts. Using new, precise techniques, we simultaneously measured MP, membrane permeability, and particle counts of antibiotic-treated and untreated Staphylococcus aureus and Micrococcus luteus cells. MP was calculated from the ratio of red and green fluorescence of diethyloxacarbocyanine [DiOC(2)(3)]. A normalized permeability parameter was calculated from the ratio of far red fluorescence of the nucleic acid dye TO-PRO-3 and green DiOC(2)(3) fluorescence. Bacterial counts were calculated by the addition of polystyrene beads to the sample at a known concentration. Amoxicillin increased permeability within 45 min. At concentrations of <1 microg/ml, some organisms showed increased permeability but normal MP; this population disappeared after 4 h, while bacterial counts increased. At amoxicillin concentrations above 1 microg/ml, MP decreased irreversibly and the particle counts did not increase. Tetracycline and erythromycin caused smaller, dose- and time-dependent decreases in MP. Tetracycline concentrations of <1 microg/ml did not change permeability, while a tetracycline concentration of 4 microg/ml permeabilized 50% of the bacteria; 4 microg of erythromycin per ml permeabilized 20% of the bacteria. Streptomycin decreased MP substantially, with no effect on permeability; chloramphenicol did not change either permeability or MP. Erythromycin pretreatment of bacteria prevented streptomycin and amoxicillin effects. Flow cytometry provides a sensitive means of monitoring the dynamic cellular events that occur in bacteria exposed to antibacterial agents; however, it is probably simplistic to expect that changes in a single cellular parameter will suffice to determine the sensitivities of all species to all drugs.

Anti-Bacterial Agents↗

PubMed1985

A serratial protease causes vascular permeability reaction by activation of the Hageman factor-dependent pathway in guinea pigs.

The 56-kilodalton (56K) protease isolated from a culture filtrate of Serratia marcescens caused vascular permeability enhancement followed by edema formation when injected into guinea pig peripheral corneas and subconjunctival space or skin. The character and the mechanism of permeability enhancement were analyzed in vivo. The enhancement was maximum at 5 to 10 min. The permeability reaction increased exponentially by the amount of enzyme used. The enhancement of permeability induced by the 56K protease was not affected by treatment with an antihistamine but was greatly augmented by simultaneous injection of a kinin potentiator, Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro-OH (SQ 20,881). Furthermore, the permeability activity of the protease, but not the amidolytic activity, was inhibited by soybean trypsin inhibitor, a well-known inhibitor of plasma kallikrein, as well as by corn trypsin inhibitor, the best inhibitor of activated Hageman factor. Results of these in vivo studies indicate that the permeability-enhancing reaction induced by the 56K protease is caused by activation of the Hageman factor-dependent pathway in the tissue. The permeability-increasing activity of the 56K protease was parallel with the enzyme activity. Serratial lipopolysaccharide did not produce a permeability enhancement reaction within 30 min when injected into guinea pig skin. These results are consistent with the results of recent in vitro experiments in which activation of the purified Hageman factor but not of prekallikrein by the 56K protease was elucidated (Matsumoto et al., J. Biochem. (Tokyo) 96:739-749, 1984). Thus, the molecular mechanism described above appears to be operative in the pathogenesis of corneal edema and chemosis, which is induced by S. marcescens, in addition to the direct tissue destruction by the protease.

Animals↗

PubMed2005

A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm's canal endothelial cells.

AIM: To test the hypothesis that trabecular meshwork endothelial cells (TMEs) increase the permeability of Schlemm's canal endothelial cells (SCEs) by actively releasing ligands that modulate the barrier properties of SCEs. METHODS: The TMEs were first irradiated with a laser light and allowed to condition the medium, which is then added to SCEs. The treatment response is determined by both measuring SCE permeability (flow meters) and the differential expression of genes (Affymetrix chips and quantitative polymerase chain reaction (PCR)). The cytokines secreted by the treated cells were identified using ELISA and the ability of these cytokines to increase permeability is tested directly after their addition to SCEs in perfusion experiments. RESULTS: SCEs exposed to medium conditioned by the light activated TMEs (TME-cm) respond by undergoing a differential expression (DE) of 1,120 genes relative to controls. This response is intense relative to a DE of only 12 genes in lasered SCEs. The TME-cm treatment of SCEs increased the SCE permeability fourfold. The role of cytokines in these responses is supported by two findings: adding specific cytokines established to be secreted by lasered TMEs to SCEs increases permeability; and inactivating the TME-cm by boiling or diluting, abrogates these conditioned media permeability effects. CONCLUSION: These experiments show that TMEs can regulate SCE permeability and that it is likely that TMEs have a major role in the regulation of aqueous outflow. This novel TME driven cellular mechanism has important implications for the pathogenesis of glaucoma and the mechanism of action of laser trabeculoplasty. Ligands identified as regulating SCE permeability have potential use for glaucoma therapy.

Aqueous Humor↗

PubMed1996

Consequences of alteration in capillary permeability.

In this review paper, three aspects related to alteration in capillary permeability, based on a series of recent observations from this laboratory, are examined. Firstly, the determinants of capillary extravasation, which include pre- and post-capillary resistances in different microcirculation networks, as well as endothelial permeability per se, are described with particular reference to the heterogeneous character of both regulatory components, reported by this and other groups. Secondly, the endothelium-interstitium relationship, responsible in part for the maintenance of the interstitial compartment physicochemical characteristics, is introduced as an important factor in regulating the traffic of vital nutrients delivered to the cell mass, and the removal of waste products from the cellular compartment to the microcirculation, for ultimate excretion. Examined in this manner, it appears that modulation of capillary permeability is essential for the maintenance of cellular life, yet the neurohumoral mechanisms involved in the control of microcirculation networks are just starting to be identified. A number of morbid conditions characterized by multiorgan involvement exhibit a common pathophysiological denominator which involves endothelium-interstitium relationships, as illustrated in experimental animal models of arterial hypertension, diabetes mellitus, heart failure, and degenerative renal diseases. Enhanced capillary permeability associated with local interstitial edema in specific organs, such as the heart and the kidney, in arterial hypertension and diabetes mellitus, as well as decreased permeability in peripheral tissues, such as the skeletal muscle and the skin, in congenital cardiomyopathy, have been documented. It is likely that alteration in the characteristics of interstitial matrix composition contributes to target organ damage in these examples of systemic disorders from different etiologies. Thirdly, the recent identification of autocoids and hormones involved in the direct and indirect control of capillary permeability has led to the development of pharmacological tools capable of modulating pre- and post-capillary vascular tonus, as well as endothelial permeability. Angiotensin II antagonism, bradykinin B1-receptor inhibition, and modulation of eicosanoid production, in particular thromboxane A2, are associated in some of the above-described disorders, with normalization of capillary permeability defects, and occasionally with improvement in organ function. The eventual development of agents capable of directly controlling the physicochemical characteristics of the interstitial matrix should be of interest, not only for preventing the development of irreversible matrix structural alterations but also for facilitating the traffic of metabolites between capillaries and the cell mass of vital organs.

Angiotensin-Converting Enzyme Inhibitors↗