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PubMed1996

Dose-response effects of radiation on the permeability of endothelial cells in culture.

Increased permeability is an early and universal response of the vasculature to radiation injury, yet the biological basis of this reaction is poorly understood. The present study determined the time course and the dose-response relationship of radiation-induced hyperpermeability in cultured bovine pulmonary artery endothelial (BPAE) cells. BPAE cells were grown to a confluent monolayer on microcarrier beads, and column chromatography methods were used to evaluate permeability to two low molecular weight compounds: sodium fluorescein (NaFlsc, mol. wt. = 342) and cyanocobalamin (B12, mol. wt. = 1355). This is a novel in vitro model to study mechanisms and modifiers of radiation-induced permeability of endothelial cells under flow conditions using nonradioactive tracers. Cell-covered beads were exposed to a single dose of 10 Gy Of 137Cs gamma rays and placed in the column, and permeability was measured every 30 min for 3 h. There was a time-dependent increase in permeability to both tracers, reaching significance by 2 h. Increased permeability was accompanied by perturbations in F-actin distribution in the BPAE cells as determined by rhodamine-phalloidin fluorescence microscopy. Neither catalase nor captopril ameliorated this hyperpermeability, but dibutyryl cAMP partially prevented it. At 3 h after 0, 1, 2, 5 and 10 Gy irradiation, permeability values of 11.8 +/- 2.1, 13.9 +/- 2.2, 20.9 +/- 3.6, 24.8 +/- 2.8 and 27.2 +/- 3.3 (10(-5) cm/s, +/- SEM), respectively, were observed using NaFlsc. The increase was significant (P < 0.05) at 2 Gy or higher. Permeability to B12 was significantly elevated after 5 or 10 Gy. These results suggest that permeability of endothelial cells to low molecular weight solutes increases within 3 h after therapeutic doses of radiation, and that cAMP ameliorates this response.

Actins↗
PubMed1996

[The effect of Kaviner and the smear layer on dentin permeability of permanent teeth in children].

The dentin permeability is defined as a moving of fluid, of chemical substances and microbial products as well through the dentin. The clinical protection of children permanent teeth in other words the protection of pulp-dentin complex after their preparation makes a big problem into the restorative stomatology. Caviner is one of the newer means which is used in the protection of pulp-dentin complex which represents the components of powder dispersing within the ethyl-acetate mixture of polystirol. The important variable in this study is the presence or absence of smearing layer which has the important influence onto the dentin permeability. In order to confirm the Caviner and smearing layer working onto the dentin permeability of the children permanent teeth in vitro experiment was designed. We used for it the dentin disks made of the intact first premolar, extracted because of orthodontic reasons at the ten years old children. They were put into the split chamber which represents a part of apparatus made at our Faculty, which is, in fact, a modified apparatus which was formed by prof. D.H. Pashley (Georgia, USA), and it is used for measuring of dentin permeability with the help of hydraulic conductance (Lp) of dentin. The dentin permeability is expressed by the hydraulic conductance term, but the measures are still expressed as the Lp percentage maximum because of better survey of results. Comparing the obtained results with the other authors results we have come to the similar conclusions, and that is in fact, that the smearing layer significantly reduces the dentin permeability, and that the Caviner, as the other layners, reduces the dentin permeability. If we compare the reduction of dentin permeability at the dentin covered with the smearing layer and with the Caviner, it has been noticed that the smearing layer reduces more significantly. It should be accented that the Caviner reduces the dentin permeability less than the most earlier researched means for the protection of pulp-dentin complex.

Acetates↗
PubMed1985

Dentin-predentin complex and its permeability: physiologic overview.

The major channels for solute diffusion across dentin are the dentinal tubules. Since dentin permeation is proportional to the product of tubule number and diameter, both of which increase as the tubules converge on the pulp, we find that dentin permeability increases rapidly as the pulp chamber is approached. The presence of a smear layer of cutting debris on top of cut dentin decreases dentin permeability, especially when permeability is measured by fluid filtration. Further, intratubular material--such as mineral deposits, collagen fibrils, proteoglycan linings, bacteria, etc.--can greatly reduce dentin permeability. Although the presence of irregular or irritation dentin has been thought to greatly reduce dentin permeability, recent in vivo experiments in dogs indicate that the dentin permeability of freshly cut cavities prepared in sound dentin falls very rapidly (i.e., 50-60% in the first six hours) before any histologic changes can be detected, either in the pulp or the dentin. When dogs were depleted of their plasma fibrinogen, this rapid decline in dentin permeability following cavity preparation failed to take place. The results implicate leakage of plasma proteins from the underlying pulpal vessels. The proteins subsequently permeate the tubules, where they are either adsorbed to the tubule walls or physically trapped in such a way as to reduce dentin permeability.

Animals↗
PubMed1993

Nutrient-induced changes in the permeability of the rat jejunal mucosa.

We examined the site of action of nutrients that enhance mucosal permeability by use of D-glucose as an archetype of nutrients of this class. We tested the hypothesis that D-glucose enhances mucosal permeability by either acting outside the intestinal lumen after absorption or acting inside the intestinal lumen to cause mediator release from either endocrine or nerve tissue. The rate of absorption of L-[14C]glucose, a passively absorbed molecule, from the lumen was used as an index of the permeability of the mucosa of a perfused segment. L-Glucose was absorbed more rapidly in the presence of D-glucose than in the presence of an equimolar concentration of mannitol. However, the permeability of the jejunal mucosa was unaffected by elevated blood glucose levels during intravenous infusion of D-glucose. The mucosal permeability was also unaffected by exposure of an adjacent segment to D-glucose, a result suggesting that D-glucose does not alter mucosal permeability by inducing the release of a blood-borne mediator from enteroendocrine cells. Finally, the effect of D-glucose on mucosal permeability could not be blocked by hexamethonium or tetrodotoxin, a result suggesting that the intestinal nerves do not mediate this phenomenon. Lidocaine significantly increased the rate of L-glucose absorption when D-glucose was present in the lumen but had no effect on L-glucose absorption under basal conditions. Our findings indicate that D-glucose must be in contact with the apical membranes of enterocytes to alter mucosal permeability. This suggestion is consistent with the hypothesis that the modulation of mucosal permeability results from the activation of sodium-dependent cotransport systems.

Animal Nutritional Physiological Phenomena↗
PubMed2006

The permeable institution: an ethnographic study of three acute psychiatric wards in London.

In Asylums, Goffman [1961. Asylums. London: Penguin] identified some permeable features of the old mental hospitals but presented them as exceptions to the rule and focused on their impermeable aspects. We argue that this emphasis is no longer valid and offer an alternative ideal type that better represents the reality of everyday life in contemporary 'bricks and mortar' psychiatric institutions. We call this the "permeable institution". The research involved participant observation of between 3 and 4 months and interviews with patients, patient advocates and staff on 3 psychiatric wards. Evidence for permeability includes that ward membership is temporary and changes rapidly (patients tend to have very short stays and staff turnover is high); patients maintain contact with the outside world during their stay; and institutional identities are blurred to the point where visitors or new patients can easily mistake staff and patients for one another. Permeability has both positive consequences (e.g., reduced risk of institutionalism), and negative consequences (e.g., unwanted people coming into hospital to cause trouble, and illicit drug use among patients). Staff employ various methods to regulate their ward's permeability, within certain parameters. The metaphor of the total/closed institution remains valuable, but it fails to capture the highly permeable nature of the psychiatric institutions we studied. Analysts may therefore find the permeable institution a more helpful reference point or ideal type against which to examine and compare empirical cases. Perhaps most helpful is to conceptualise a continuum of institutional permeability with total and permeable institutions at each extreme.

Acute Disease↗
PubMed1998

Prostaglandin-dependent osmotic water permeability of the frog and trout urinary bladder.

Washout of autacoids from serosal Ringer solution, using a repeated change of the solution of the frog and trout urinary bladder, was accompanied by a pronounced rise in the osmotic water permeability: the water transport in the frog rose from 0.05 +/- 0.02 to 1.21 +/- 0.26 microliter min-1.cm-2, in the trout, from 0.041 +/- 0.011 to 0.26 +/- 0.034 microliter min-1.cm-2. Such an increase in the osmotic water permeability in the trout and frog urinary bladder occurred in the background of a decrease in the prostaglandin E2 concentration in the serosal Ringer solution. This permeability increase was accompanied by the formation of aggregates of intramembranous particles in the apical plasma membrane of the trout and frog urinary bladder. A decrease in the osmotic water permeability was achieved by the addition to the serosal Ringer solution of 10-8 M prostaglandin. Experiments on the frog urinary bladder have shown that prostaglandins E1, I2 and F2 alpha also decrease the osmotic water permeability. Vasotocin increased the osmotic water permeability in the frog urinary bladder but did not affect the osmotic water permeability of the trout urinary bladder. The data obtained indicates a role of the endogenous prostaglandin production in maintaining the low osmotic water permeability in the frog and trout urinary bladder. A suggestion is made that in the vertebrate evolution, colonisation of the fresh-water was connected with the maintenance of the low osmotic water permeability via participation of prostaglandins, whereas the vasotocin hydroosmotic effect developed in the vertebrate evolution later and provided for the possibility of the water absorption, osmotic homeostasis and animal migration from fresh-water to the land.

Alprostadil↗
PubMed1993

Patterns of Effective Permeability of Leaf Cuticles to Acids.

Plants in the field are frequently exposed to anthropogenic acid precipitation with pH values of 4 and below. For the acid to directly affect leaf tissues, it must pass through the leaf cuticle, but little is known about the permeability of cuticles to protons, or about the effect of different anions on this permeability. We investigated the movement of protons through isolated astomatous leaf cuticles of grapefruit (Citrus X paradisi Macfady.), rough lemon (Citrus limon [L.] Burm. fils cv Ponderosa), and pear (Pyrus communis L.) using hydrochloric, sulfuric, and nitric acids. Cuticles were enzymically isolated from leaves and placed in a diffusion apparatus with pH 4 acid on the morphological outer surface of the cuticle and degassed distilled water on the inner surface. Changes in pH of the solution on the inner surface were used to determine rates of effective permeability of the cuticles to the protons of these acids. Most cuticles exhibited an initial low permeability, lasting hours to days, then after a short transition displayed a significantly higher permeability, which persisted until equilibrium was approached. The change in effective permeability appears to be reversible. Effective permeabilities were higher for sulfuric acid than for the others. A model of the movement of protons through the cuticle is presented, proposing that dissociated acid groups in channels within the cutin are first protonated by the acid, accounting for the low initial effective permeability; then protons pass freely through the channels, resulting in a higher effective permeability.

Journal Article↗
PubMed1972

Influence of decenylsuccinic Acid on water permeability of plant cells.

Decenylsuccinic acid altered permeability to water of epidermal cells of bulb scales of Allium cepa and of the leaf midrib of Rhoeo discolor. Water permeability, as determined by deplasmolysis time measurements, was related to the dose of undissociated decenylsuccinic acid (mm undissociated decenylsuccinic acid x minute). No relationship was found between permeability and total dose of decenylsuccinic acid, or dose of dissociated decenylsuccinic acid, suggesting that the undissociated molecule was the active factor in permeability changes and injury.At doses which did not damage cells (0.0008 to 0.6 [mm of the undissociated molecule x minute]) decenylsuccinic acid decreased water permeability. At higher doses (e.g., 4 to 8 [mm x minute]) injury to cells was common and decenylsuccinic acid increased permeability. Doses above the 10 to 20 (mm x minute) range were generally lethal. The plasmolysis form of uninjured cells was altered and protoplasmic swelling occasionally was observed. The dose-dependent reversal of water permeability changes (decreased to increased permeability) may reflect decenylsuccinic acid-induced changes in membrane structure. Reported effects of decenylsuccinic acid on temperature dependence of permeability and frost resistance were not verified.

Journal Article↗
PubMed1995

Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells.

Angiotensin II (Ang II) has been implicated in the pathogenesis of the vascular injury associated with hypertension and diabetes mellitus. Increased vascular permeability is an important early manifestation of endothelial dysfunction and the pathogenesis of atherosclerosis. How Ang II contributes to endothelial dysfunction and promotes an increase in vascular permeability is unknown but is classically attributed to its pressor actions. We demonstrate that human vascular smooth muscle cells express abundant mRNA for vascular permeability/endothelial growth factor. Vascular permeability factor is a 34- to 42-kD glycoprotein that markedly increases vascular endothelial permeability and is a potent endothelial mitogen. Ang II potently induced a concentration-dependent (maximal, 10(-7) mol/L) and time-dependent increase in vascular permeability factor mRNA expression by human vascular smooth muscle cells that was maximal after 3 hours and diminished by 24 hours. Ang II-induced vascular permeability factor mRNA expression by human vascular smooth muscle cells was inhibited by the specific Ang II receptor antagonist losartan (DuP 753), confirming that this is an Ang II receptor subtype 1-mediated event. These results describe a new action of Ang II on human vascular smooth muscle, notably the induction of vascular permeability factor mRNA expression. The wide spectrum and potent activity of vascular permeability factor suggest a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hemodynamics.

Angiotensin II↗
PubMed1964

SOLUBILIZATION OF PROTEIN ACCOMPANYING LOSS OF PERMEABILITY OF ESCHERICHIA COLI.

Rogers, Dexter (Utah State University, Logan). Solubilization of protein accompanying loss of permeability of Escherichia coli. J. Bacteriol. 88:279-292. 1964.-Two methods were studied for altering glucose permeability of Escherichia coli, and changes in protein and phosphorus composition were compared with changes in permeability. Protein was solubilized by incubating the cells at pH 7.3 in the presence of chloramphenicol, under conditions known to destabilize permeability. No protein was solubilized at pH 5.3, where permeability is stable. The solubilized protein was one of the first proteins to be extracted from the cells under mild conditions. Permeability was also altered by varying the culture age. It was maximal for logarithmic growth phase cultures, and it decreased rapidly in cultures in the stationary growth phase. Permeability correlated with the ratio of insoluble protein to soluble protein of the cells. Chromatographic analysis of an extract of cells treated at pH 7.3 revealed the presence of one additional protein fraction that was not present in an extract of cells treated at pH 5.3. The solubilized protein was precipitable with uranyl ion, which is a non-penetrating inhibitor of glucose transport in intact cells. Changes in phosphorus composition preceded changes in permeability and protein composition. These changes suggested that a phosphorus metabolite might contribute to the activity of the permeation process.

Bacterial Proteins↗
PubMed1985

Intestinal sugar permeability: relationship to diarrhoeal disease and small bowel morphology.

The permeability of the intestine was studied in 39 children (1 month to 3 years of age) with diarrhoea and in 28 children (6 months to 15 years of age) undergoing duodenal biopsy. Permeability was measured by differential absorption from an isotonic oral load containing 3.5 g lactulose, 0.5 g L-rhamnose, 0.5 g D-xylose, and 5 g lactose. Urinary sugar excretion was determined by quantitative thin-layer chromatography. Children with acute gastroenteritis had a greatly increased permeability, with a mean lactulose/L-rhamnose excretion ratio of 0.43 +/- 0.31 (normal less than 0.07). Children retested 3-16 weeks after complete recovery of their gastroenteritis had normal permeability (0.045 +/- 0.018). Children with chronic diarrhoea also had an increased permeability (0.12 +/- 0.074), but significantly less than the acute gastroenteritis group (p less than 0.01). Abnormal proximal small bowel morphology was associated with increased permeability, and a strong correlation between crypt depth and permeability was observed (r = 0.66, p less than 0.001). Abnormal intestinal permeability was associated with diarrhoeal disease and with mucosal damage. It appears to be a reliable and useful index of mucosal integrity.

Adolescent↗
PubMed2004

Accelerating whole-cell biocatalysis by reducing outer membrane permeability barrier.

Whole-cell biocatalysts are preferred in many biocatalysis applications. However, due to permeability barriers imposed by cell envelopes, whole-cell catalyzed reactions are reportedly 10-100-fold slower than reactions catalyzed by free enzymes. In this study, we accelerated whole-cell biocatalysis by reducing the membrane permeability barrier using molecular engineering approaches. Escherichia coli cells with genetically altered outer membrane structures were used. Specifically, a lipopolysaccarides mutant SM101 and a Braun's lipoprotein mutant E609L were used along with two model substrates that differ substantially in size and hydrophobicity, nitrocefin, and a tetrapeptide N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. The reduction of the outer membrane permeability by genetic methods led to significant increases (up to 380%) in reaction rates of whole-cell catalyzed reactions. The magnitude of increase in biocatalysis rates was dependent on the substrates and on the nature of mutations introduced in the outer membrane structure. Notably, mutations in outer membrane can render the outer membrane completely permeable to one substrate, a barrierless condition that maximizes the reaction rate. The impact of the mutations introduced on the permeability barrier of the membranes was compared to the impact of polymixin B nonapeptide, a known potent permeabilizer acting on lipopolysaccharides. Our results suggest that genetic modifications to enhance the permeability of hydrophilic molecules should target the Lipid A region. However, strategies other than reduction of Lipid A synthesis should be considered. As we have demonstrated with tetrapeptide, membrane engineering can be much more effective in reducing a permeability barrier than are exogenous permeabilizers. This work, to our knowledge, is the first use of a molecular membrane engineering approach to address substrate permeability limitations encountered in biocatalysis applications.

Catalysis↗
PubMed1992

Fibrin contact increases endothelial permeability to albumin.

We studied the effects of contact of bovine pulmonary artery endothelial cell monolayers with fibrin on the endothelial barrier function. Fibrin formed by clotting purified fibrinogen (0.5 to 3.0 mg/ml) with alpha-thrombin (1 U/ml) was added to endothelial monolayers and permeability measurements were made after fibrin removal. Fibrin incubation for 3 hours resulted in 2- to 5-fold increases in transendothelial 125I-albumin permeability. Permeability returned to baseline value within 3 hours after fibrin removal. Direct contact with fibrin was necessary for the response, since fibrin separated from the endothelium did not increase permeability. Contact with agarose (2 mg/ml) or fibrinogen (0.5 to 3.0 mg/ml) also did not increase endothelial permeability. Transmission electron microscopic examination indicated normal appearance of interendothelial junctions at a time when albumin permeability was increased and no overt evidence of endothelial injury. Incubation of fibrin with endothelial monolayers at 4 degrees C prevented the increase in albumin permeability. We examined the possibility that increased albumin transcytosis was responsible for fibrin's effect using 14C-sucrose (Mr = 342D), a lipid insoluble tracer. Fibrin increased sucrose flux by 1.5-fold compared to 2- to 5-fold increases in albumin flux. The results indicate that fibrin contact with the endothelial cell increases endothelial permeability. The effect of fibrin may involve activation of temperature-sensitive bulk phase transcytosis of albumin.

Albumins↗
PubMed1995

Cytoskeletal regulation of Caco-2 intestinal monolayer paracellular permeability.

An abnormal increase in intestinal paracellular permeability may be an important pathogenic factor in various intestinal diseases. The intracellular factors and processes that regulate and cause alteration of intestinal paracellular permeability are not well understood. The purpose of this study was to examine some of the intracellular processes involved in cytoskeletal regulation of intestinal epithelial paracellular permeability using the filter-grown Caco-2 intestinal epithelial monolayers. Cytochalasin-b and colchicine were used to disrupt the cytoskeletal elements, actin microfilaments, and microtubules. Cytochalasin-b (5 micrograms/ml) and colchicine (2 x 10(-5) M) at the doses used caused marked depolymerization and disruption of actin microfilaments and microtubules, respectively. Cytochalasin-b-induced disruption of actin microfilaments resulted in perturbation of tight junctions and desmosomes and an increase in Caco-2 monolayer paracellular permeability. The cytochalasin-b-induced disruption of actin microfilaments and subsequent changes in intercellular junctional complexes and paracellular permeability were not affected by inhibitors of protein synthesis (actinomycin-D or cycloheximide) or microtubule function (colchicine), but were inhibited by metabolic energy inhibitors (2,4-dinitrophenol or sodium azide). The cytochalasin-b-induced disturbance in Caco-2 actin microfilaments and intercellular junctional complexes and increase in paracellular permeability were rapidly reversed. The paracellular pathway "re-tightening" following cytochalasin-b removal was not affected by actinomycin-D, cycloheximide, or colchicine, but was inhibited by 2,4-dinitrophenol and sodium azide. The colchicine-induced disruption of microtubules did not have significant effect on actin microfilaments, intercellular junctions, or paracellular permeability. These findings suggest that cytochalasin-b-induced increase in Caco-2 monolayer paracellular permeability was due to actin microfilament mediated perturbation of intercellular junctional complexes. The re-tightening of paracellular pathways (following removal of cytochalasin-b) resulted from energy-mediated re-assembly of pre-existing actin microfilaments and intercellular junctional complexes. This re-closure process did not require protein synthesis or microtubule-mediated shuttling process.

Actins↗
PubMed1997

Nitric oxide and cGMP regulate endothelial permeability and F-actin distribution in hydrogen peroxide-treated endothelial cells.

We have previously reported that hydrogen peroxide (H2O2) has a concentration-dependent effect on endothelial permeability and F-actin distribution. In the present study, we considered the involvement of endogenous production of nitric oxide (NO) in the indicated effect of H2O2. This was done by measuring endothelial permeability to sodium fluorescein (MW 376 Da, Na-F) and to different-sized fluorescein-isothiocynate-labeled dextrans (FITC-dextrans) and by staining F-actin with rhodamine-labeled phalloidin in cultured bovine aortic endothelial cells growing on filters. A low concentration of H2O2 (10(-5) M) had no effect on either dense peripheral bands of F-actin (DPBs) or permeability. When N-nitro-l-arginine methylester (l-NAME), an inhibitor of NO production, was coadministrated with 10(-5) M H2O2, DPBs were disrupted and the permeability to FITC-dextran 40 and FITC-dextran 70, but not to Na-F and FITC-dextran 20, was increased. Combining of 10(-5) M H2O2 with l-arginine, a substrate for nitric oxide synthase, caused an increase in DPBs and a decrease in permeability to FITC-dextran 40 and FITC-dextran 70. l-arginine or l-NAME alone had no effect on either F-actin structure or endothelial permeability. A 10-fold higher concentration of H2O2 caused a disruption of DPBs and an increase in permeability; this could be prevented by adding l-arginine. An analogue of cGMP, i.e., 8-Br-cGMP, maintained DPBs and abolished the increase in permeability induced by the treatment with either 10(-4) M H2O2 or a combination of H2O2 and l-NAME. These results suggest that the endogenous production of NO is involved in maintaining endothelial junctions in H2O2-treated cells and that this involvement occurs via a cGMP-dependent mechanism.

Actin Cytoskeleton↗
PubMed1996

Junctional permeability measurements in the embryonic chick lens.

The purpose of this paper is two-fold: to measure junctional permeability of different types of dissociated lens cells and to compare the junctional permeability of dissociated lens cells to that of cells in the intact lens. Dissociated embryonic chick lens cells and intact embryonic chick lenses were loaded with the fluorescent dye 5,6 carboxyfluorescein diacetate. The return of fluorescence after bleaching an individual cell was used to estimate cell-to-cell permeability. Use of the confocal microscope facilitated quantitation of the return of fluorescence as well as optical sectioning needed to measure cell-to-cell permeability in an intact lens. Two types of dissociated cells were studied: spherical and short elongated cells. The average rate constant for 5,6 carboxyfluorescein transfer between these cells was 7.9 x 10(-3) sec-1 and 8.1 x 10(-3) sec-1, respectively. The junctional permeability for both types of cells was reduced by lowering internal pH to 6.0 by bathing the cells in a sodium acetate solution. Permeability measurements of the central epithelial cells of an isolated whole lens gave an average rate constant of 2.6 x 10(-3) sec-1, comparable to the rates measured in the dissociated cells. These results establish that the photobleach method can be used in intact lens to quantitatively assess junctional permeability and that dissociated epithelial cells have very nearly the same junctional permeabilities as cells in the intact lens.

Animals↗
PubMed2001

Role of shear and leukocyte adherence on venular permeability in the rat mesentery.

The role of fluid shear stress on permeability has been controversial. In vitro studies have shown higher endothelial permeability with an increase in shear, but in vivo higher shear can also decrease permeability by attenuating leukocyte adherence (e.g., during an inflammatory response). The potential contribution of fluid shear and leukocyte adherence acting simultaneously to determine basal levels of permeability remains unresolved. Therefore, the purpose of this study was to understand the effects of basal shear and leukocyte adherence on venular permeability of the rat mesentery. Using a modification of current measurement techniques, we were able to quantify permeability under physiological flow and estimate its convective and diffusive components. We found that water filtration plays a minor role in the transport of albumin across venular endothelium, that permeability exhibits a moderately linear correlation with shear, and that the number of leukocytes adherent to the endothelium accounts for the majority of the scatter in this correlation. Multiple regression analysis of permeability as a function of shear rate and leukocyte adherence revealed significant roles for both factors (regression P < 0.01, r2 = 73.9%).

Animals↗
PubMed1995

Differential mechanisms of induction of the mitochondrial permeability transition by quinones of varying chemical reactivities.

A nonspecific increase in permeability of the inner mitochondrial membrane is implicated in the mechanism of cell killing by a number of structurally diverse agents possessing vastly different chemical reactivities. The objective of this investigation was to distinguish the mechanisms by which quinones of varying redox cycling and arylating reactivities induce this mitochondrial permeability transition in vitro. All of the naphthoquinones examined caused a dose-dependent release of calcium from hepatic mitochondria. Associated with this was the calcium-dependent depolarization of membrane potential and mitochondrial swelling. For substituted naphthoquinones, 2-methyl-, 2,3-dimethyl-, and 2,3-dimethoxy-1, 4-naphthoquinone, induction of the mitochondrial permeability transition correlated with the rate of mitochondrial redox cycling and was strongly inhibited by cyclosporine A. In contrast, unsubstituted 1,4-naphthoquinone induced the permeability transition at concentrations where redox cycling was minimal. Induction of the permeability transition by 1,4-benzoquinone, which does not redox cycle, required that the mitochondria be preloaded with calcium and was not inhibited by cyclosporine A. With benzoquinone, the initiating event was a calcium-independent depolarization of mitochondrial membrane potential. In summary, the evidence indicates that redox cycling naphthoquinones induce the mitochondrial permeability transition by altering the regulation of the cyclosporine A-sensitive pore. In contrast, arylating quinones directly depolarize the mitochondrial membrane which, depending on the availability of matrix calcium, may be expressed as a cyclosporine A-insensitive permeability transition. These results reveal distinct mechanisms for inducing the mitochondrial permeability transition in vitro by quinones of varying chemical reactivities, which may be manifested as different mechanisms of cell killing.

Animals↗