Barrier Permeability (barrier + permeability)

Distribution by Scientific Domains

Kinds of Barrier Permeability

  • brain barrier permeability


  • Selected Abstracts


    The Effect of Ovariectomy and Estrogen on Penetrating Brain Arterioles and Blood-Brain Barrier Permeability

    MICROCIRCULATION, Issue 8 2009
    Marilyn J. Cipolla
    ABSTRACT Objective: We investigated the effect of estrogen replacement on the structure and function of penetrating brain arterioles (PA) and blood-brain barrier (BBB) permeability. Materials and Methods: Female ovariectomized Sprague-Dawley rats were replaced with estradiol (E2) and estriol (E3) (OVX + E;N=13) and compared to ovariectomized animals without replacement (OVX; N=14) and intact controls (CTL, proestrous; N=13). Passive and active diameters, percent tone, and passive distensibility of pressurized PA were compared. In addition, BBB permeability to Lucifer Yellow, a marker of transcellular transport, was compared in cerebral arteries. Results: Ovariectomy increased myogenic tone in PA, compared to CTL, that was not ameliorated by estrogen treatment. Percent tone at 75 mmHg for CTL vs. OVX and OVX + E was 443% vs. 511% and 543% (P<0.01 vs. CTL for both). No differences were found in passive diameters or distensibility between the groups. BBB permeability increased 500% in OVX vs. CTL animals; however, estrogen replacement restored barrier properties: flux of Lucifer Yellow for CTL, OVX, and OVX + E was (ng/mL): 3.41.2, 20.25.3 (P<0.01 vs. CTL), and 6.151.2 (n.s.). Conclusions: These results suggest that estrogen replacement may not be beneficial for small-vessel disease in the brain, but may limit BBB disruption and edema under conditions that cause it. [source]


    Regulation of Blood,Brain Barrier Permeability

    MICROCIRCULATION, Issue 2 2001
    WILLIAM G. MAYHAN
    ABSTRACT The blood-brain barrier minimizes the entry of molecules into brain tissue. This restriction arises by the presence of tight junctions (zonulae occludens) between adjacent endothelial cells and a relative paucity of pinocytotic vesicles within endothelium of cerebral arterioles, capillaries, and venules. Many types of stimuli can alter the permeability characteristics of the blood-brain barrier. Acute increases in arterial blood pressure beyond the autoregulatory capacity of cerebral blood vessels, application of hyperosmolar solutions, application of various inflammatory mediators known to be elevated during brain injury, and/or activation of blood-borne elements such as leukocytes can produce changes in permeability of the blood-brain barrier. The second messenger systems that account for increases in permeability of the blood-brain barrier during pathophysiologic conditions, however, remain poorly defined. This review will summarize studies that have examined factors that influence disruption of the blood-brain barrier, and will discuss the contribution of various cellular second messenger pathways in disruption of the blood-brain barrier during pathophysiologic conditions. [source]


    CODES/Neural Network Model: a Useful Tool for in Silico Prediction of Oral Absorption and Blood-Brain Barrier Permeability of Structurally Diverse Drugs

    MOLECULAR INFORMATICS, Issue 2-3 2004
    Isabel Dorronsoro
    Abstract Two different neural network models able to predict both oral absorption (OA) and blood-brain barrier (BBB) permeability of structurally diverse drugs in use clinically are presented here. Using the descriptors generated by CODES, a program which codifies molecules from a topological point of view, we avoid the uncertain choice of molecular conformation and physicochemical parameters. In this work, a method called Reduction of Dimensions, designed for compressing data, is applied for the first time in order to minimize the bias factor added to a QSAR study when the selection of descriptors are performed. [source]


    CPU-86017 improves the compromised blood,brain barrier permeability mediated by impaired endothelial no system and oxidative stress caused by L -thyroxine

    DRUG DEVELOPMENT RESEARCH, Issue 3 2005
    Rong-Hui Du
    Abstract Impaired endothelial cell (EC) function leads to alterations in the permeability of the blood,brain barrier (BBB). There are two aspects of the transport through the BBB: from the blood to the brain (influx) and from the brain to the blood (efflux). An impaired EC model induced by L -thyroxine that compromises the influx and efflux properties of the BBB was used to assess responses to the intervention of CPU-86017 (an antioxidant and calcium channel blocker) and propranolol. CPU-86017 (t1/2=1.5 h) was also used as a target drug, leaving no traces in the brain and blood 24 h after administration. The permeability of the BBB was evaluated by using CPU-86017 after iv and icv injection and concentrations in the blood and brain being measured by high-performance liquid chromatography. The bidirectional permeability of CPU-86017 was impaired and associated with a reduced NO bioavailability assessed functionally by the vasoactivity in the model. Partial relief of NO bioavailability and oxidative stress induced by propranolol was consistent with a recovery of BBB efflux alone. Complete recovery in the efflux and influx of the BBB by CPU-86017 was a result of the complete restoration of NO bioavailability and reduction in oxidative stress. Normal BBB influx is dependent on an intact endothelial NO system, and efflux could be restored easily by partial improvement of NO bioavailability. CPU-86017 is thus more effective than propranolol in protecting the endothelium from damage produced by L -thyroxine through oxidative stress. Drug Dev. Res. 64:145,156, 2005. 2005 Wiley-Liss, Inc. [source]


    Magnesium sulphate treatment decreases blood,brain barrier permeability during acute hypertension in pregnant rats

    EXPERIMENTAL PHYSIOLOGY, Issue 2 2008
    Anna G. Euser
    Eclampsia is associated with increased blood,brain barrier (BBB) permeability and formation of cerebral oedema. Magnesium sulphate is used to treat eclampsia despite an unclear mechanism of action. This study was to determine the effect of magnesium sulphate on in vivo BBB permeability and formation of cerebral oedema during acute hypertension and on brain aquaporin-4 (AQP4) protein expression. An in vivo model of hypertensive encephalopathy was used in late-pregnant (LP) rats following magnesium sulphate treatment, 270 mg kg,1i.p. injection every 4 h for 24 h. Permeability of the BBB was determined by in situ brain perfusion of Evan's Blue (EB) and sodium fluorescein (NaFl), and dye clearance determined by fluorescence spectrophotometry. Cerebral oedema was determined following acute hypertension by measuring brain water content. The effect of magnesium treatment on AQP4 expression was determined by Western blot analysis. Acute hypertension with autoregulatory breakthrough increased BBB permeability to EB in both brain regions studied (P < 0.05). Magnesium attenuated BBB permeability to EB during acute hypertension by 41% in the posterior cerebrum (P < 0.05) but had no effect in the anterior cerebrum (P > 0.05). Treatment with magnesium did not change NaFl permeability, cerebral oedema formation or AQP4 expression. In summary, BBB permeability to Evan's Blue was increased by acute hypertension in LP rats, and this was attenuated by treatment with magnesium sulphate. The greatest effect on BBB permeability to EB was in the posterior cerebrum, an area particularly susceptible to oedema formation during eclampsia. [source]


    Effects of induced hyperthermia on pharmacokinetics of ropivacaine in rats

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2010
    Romain Guilhaumou
    Abstract Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentrations. Our results (median inter quartile range) reveal a significant increase of the total apparent clearance (0.0151 0.000800 L/min vs. 0.0134 0.00134 L/min), apparent volume of distribution (Vd) (2.19 0.27 L vs. 1.57 0.73 L) and a significant decrease in exposure (488 50.6 mg.min/L vs. 572 110 mg.min/L) in induced-hyperthermia group. We observed a significant increase in brain ropivacaine concentration in hyperthermic rats (8.39 8.42 ,g/g vs. 3.48 3.26 ,g/g) and no significant difference between cardiac concentrations in the two groups (5.38 4.83 ,g/g vs. 3.73 2.44 ,g/g). Results suggest a higher tissular distribution of ropivacaine and an increase in blood,brain barrier permeability during hyperthermia. The hyperthermia-induced increase in Vd could be responsible for an increase in cerebral ropivacaine toxicity. These experimental data provide a basis for future clinical investigations in relation to local anaesthetic use in hyperthermic patients. [source]


    Blood,brain barrier breakdown in septic encephalopathy and brain tumours*

    JOURNAL OF ANATOMY, Issue 6 2002
    D. C. DaviesArticle first published online: 28 JUN 200
    Abstract Septic encephalopathy is associated with breakdown of the blood,brain barrier and cerebral oedema. These features are also common properties of brain tumours. Perimicrovessel oedema, disruption of associated astrocyte end feet and neuronal injury occur in a porcine model of acute septic encephalopathy. The adrenergic system has been implicated in the inflammatory response to sepsis and may play a role in controlling blood,brain barrier permeability, since the ,2 -adrenoceptor agonist dopexamine inhibits perimicrovessel oedema formation whereas the ,1 -adrenoceptor agonist methoxamine provokes it. Electron microscopy revealed tight junction opening in high-grade astrocytoma microvessels. Expression of the tight junction protein occludin is reduced in these microvessels and this reduction is inversely correlated with the degree of cerebral oedema. Normal astrocytes secrete factors that induce barrier properties in endothelial cells, whereas high-grade astrocytomas secrete vascular endothelial growth factor, which stimulates angiogenesis, down regulates occludin and increases endothelial cell permeability. The water channel protein aquaporin-4 is normally expressed in astrocyte foot processes around cerebral microvessels. Its expression is massively up-regulated in high-grade astrocytoma and around metastatic adenocarcinoma. There is a significant correlation between aquaporin-4 expression and the degree of cerebral oedema, but it is not clear whether increased aquaporin-4 expression enhances oedema formation or clearance. These results suggest that the pathophysiology of brain oedema is multifactorial, but that there may be common processes operating regardless of the aetiology. [source]


    Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia

    JOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2009
    Rajanikant G. Krishnamurthy
    Abstract Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or ,-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood,brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood,brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia. 2009 Wiley-Liss, Inc. [source]


    Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats

    JOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2006
    Tamiji Tsubokawa
    Abstract Calpains and cathepsins are two families of proteases that play an important role in ischemic cell death. In this study, we investigated the effect of E64d, a ,-calpain and cathepsin B inhibitor, in the prevention of neuronal and endothelial apoptotic cell death after focal cerebral ischemia in rats. Rats underwent 2 hr of transient focal ischemia from middle cerebral artery occlusion (MCAO) and were sacrificed 24 hr later. E64d (5 mg/ kg intraperitoneally) was administered 30 min before MCAO. Assessment included neurological function, infarction volume, brain water content, blood,brain barrier permeability, histology, and immunohistochemistry. The E64d-treated rats had significant brain protection against ischemic damage. We observed a reduction of infarction volume, brain edema, and improved neurological scores in E64d-treated rats compared with the nontreated control. Furthermore, there was a remarkable reduction in both proteases and caspase-3 activation and apoptotic changes in both neurons and endothelial cells in E64d-treated rats. These results suggest that E64d protects the brain against ischemic/reperfusion injury by attenuating neuronal and endothelial apoptosis. 2006 Wiley-Liss, Inc. [source]


    Ionization-specific prediction of blood,brain permeability

    JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009
    Kiril Lanevskij
    Abstract This study presents a mechanistic QSAR analysis of passive blood,brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo log,PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log,PS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSE,<,0.5) and simple physicochemical interpretations (log,P and pKa), thus providing a clear route towards property-based design of new CNS drugs. 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:122,134, 2009 [source]


    The orally combined neuroprotective effects of sodium ferulate and borneol against transient global ischaemia in C57 BL/6J mice

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2010
    Xiao-hong Chen
    Abstract Objectives, This study aimed to investigate the possible modification of the neuroprotective effect of sodium ferulate, when orally co-administered with borneol, in transient global cerebral ischaemia-induced functional, histological and cellular alterations in mice. Methods, The bilateral common carotid artery occlusion was conducted in C57 BL/6J mice for 25 min. The mice were then subjected to a water maze test over an extended recovery period, followed by an assessment of neuronal loss in the CA1 region of the hippocampus (haematoxylin and eosin staining). The blood,brain barrier permeability (Evans blue tracing), brain oedema and oxidative stress were assayed and histological sections were also immunostained for gliofibrillar acid protein (GFAP) expression. Key findings, The ischaemia reperfused mice were associated with long-lasting spatial learning deficits in the absence of other behavioural impairments and with neurodegeneration in the hippocampal CA1 region. However, the histological injuries were significantly attenuated by oral co-administration of sodium ferulate and borneol. Furthermore, combined treatment with sodium ferulate and borneol resulted in a significant reduction in brain oedema, GFAP-positive cells, malonaldialdehyde levels and blood,brain barrier permeability, but an increase in superoxide dismutase activity. Conclusions, Borneol may have benefits for the neuroprotective effect of sodium ferulate against injury induced in the brain by ischaemia/reperfusion. [source]


    Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood,brain barrier permeability after transient focal cerebral ischemia in mice

    JOURNAL OF PINEAL RESEARCH, Issue 2 2006
    Hung-Yi Chen
    Abstract:, We have recently shown that melatonin decreases the late (24 hr) increase in blood,brain barrier (BBB) permeability and the risk of tissue plasminogen activator-induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin-treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell-expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin-treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke. [source]


    Tumour necrosis factor-, affects blood,brain barrier permeability and tight junction-associated occludin in acute liver failure

    LIVER INTERNATIONAL, Issue 8 2010
    Sa Lv
    Abstract Background: Cerebral oedema leading to cerebral herniation is a major cause of death during acute liver failure (ALF), but the underlying mechanism is not clear. Aims: We investigated the role of tumour necrosis factor (TNF)-, in changing the permeability of the blood,brain barrier (BBB) during ALF. Methods: ALF animal models were generated by administering d -galactosamine (GalN) and lipopolysaccharide, or GalN and TNF-,. ALF induction was blocked by first administering anti-TNF-,,IgG or anti-TNF-,-R1. We investigated the BBB permeability with Evans blue staining, and the structure with electron microscopy. Results: BBB permeability increased in ALF mice and correlated with elevated serum TNF-, levels. No vascular endothelial cell (EC) apoptosis was detected, but electron microscopy of cells from human and mouse ALF tissues revealed tight junction (TJ) disruptions and EC shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein occludin was significantly decreased in both ALF mice and patients, although the expression of occludin mRNA did not change. Changes in BBB permeability, brain tissue ultrastructure and occludin expression in ALF-induced mice could be prevented by prophylaxis treatment with either antibody to TNF-,,IgG or antibody to TNF-,-R1. Conclusions: Our results suggest that TNF-, plays a critical role in the development of brain oedema in ALF, and that both vasogenic and cytotoxic mechanisms may be involved. Increased BBB permeability may be because of the disruption of TJs, and loss of the TJ-associated protein occludin. [source]


    Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex

    NEUROPATHOLOGY, Issue 6 2008
    Karin Boer
    Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. In the present study we discuss the neuropathological findings of a 32-year-old patient with a germ-line mutation in the TSC2 gene. Post mortem MRI combined with histology and immunocytochemical analysis was applied to demonstrate widespread anatomical abnormalities of gray and white matter structure. TSC brain lesions were analyzed for loss of heterozygosity (LOH) on chromosome 16p13. The neuropathological supratentorial abnormalities were represented by multiple subependymal nodules (SENs) and cortical tubers. In addition to cerebral cortical lesions, cerebellar lesions and hippocampal sclerosis were also observed. LOH was not found in the cortical tubers and SENs of this patient. Immunocytochemical analysis of the TSC brain lesions confirmed the cell-specific activation of the mTOR pathway in cortical tubers, SENs and cerebellum, as well as differential cellular localization of hamartin and tuberin, the TSC1 and TSC2 gene products. Examination of the pathological brain regions revealed activated microglial cells and disruption of blood-brain barrier permeability. Predominant intralesional cell-specific distribution was also detected for the multidrug transporter protein P-gp, possibly explaining the mechanisms underlying the pharmacoresistance to antiepileptic drugs. Autopsy findings confirm the complexity of the brain abnormalities encountered in TSC patients and proved useful in clarifying certain aspects of the pathogenesis, epileptogenesis and pharmacoresistance of TSC lesions. [source]


    Blood,spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced MRI

    NMR IN BIOMEDICINE, Issue 3 2009
    David M. Cohen
    Abstract After a primary traumatic injury, spinal cord tissue undergoes a series of pathobiological changes, including compromised blood,spinal cord barrier (BSCB) integrity. These vascular changes occur over both time and space. In an experimental model of spinal cord injury (SCI), longitudinal dynamic contrast-enhanced MRI (DCE-MRI) studies were performed up to 56 days after SCI to quantify spatial and temporal changes in the BSCB permeability in tissue that did not show any visible enhancement on the post-contrast MRI (non-enhancing tissue). DCE-MRI data were analyzed using a two-compartment pharmacokinetic model. These studies demonstrate gradual restoration of BSCB with post-SCI time. However, on the basis of DCE-MRI, and confirmed by immunohistochemistry, the BSCB remained compromised even at 56 days after SCI. In addition, open-field locomotion was evaluated using the 21-point Basso,Beattie,Bresnahan scale. A significant correlation between decreased BSCB permeability and improved locomotor recovery was observed. Copyright 2008 John Wiley & Sons, Ltd. [source]


    Increased blood,brain barrier permeability of morphine in a patient with severe brain lesions as determined by microdialysis

    ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2001
    R. Bouw
    Intracerebral microdialysis was utilised to obtain information regarding how morphine is transported across the blood,brain barrier (BBB). In a patient with a severe brain injury, we measured simultaneously unbound extracellular fluid (ECF) concentrations of morphine in human brain and in subcutaneous fat tissue, which were compared to morphine levels in arterial blood. This report shows an increase in morphine levels near the trauma site in the brain compared to uninjured brain tissue. The half-life of morphine in uninjured and injured brain tissue of 178 min and 169 min, respectively, were comparable but were longer than in blood (64 min) and adipose tissue (63 min). This indicates that morphine is retained in brain tissue for a longer time than what could be expected from the blood concentration,time profile. These results show the potential of the microdialysis technique in providing new information regarding the pharmacokinetics of drug in the human brain close to the trauma site and in macroscopically intact tissue. [source]


    Effect of exposure to 50,Hz magnetic field with or without insulin on blood,brain barrier permeability in streptozotocin-induced diabetic rats,

    BIOELECTROMAGNETICS, Issue 4 2010
    Sefa Gulturk
    Abstract We investigated the effect of long-term exposure to modulation magnetic field (MF), insulin, and their combination on blood,brain barrier (BBB) permeability in a diabetic rat model. Fifty-three rats were randomly assigned to one of six groups: sham, exposed to no MF; MF, exposed to MF; diabetes mellitus (DM), DM induced with streptozotocin (STZ); DM plus MF (DMMF); DM plus insulin therapy (DMI); and DM plus insulin therapy plus MF (DMIMF). All the rats underwent Evans blue (EB) measurement to evaluate the BBB 30 days after the beginning of experiments. The rats in MF, DMMF, and DMIMF groups were exposed to MF (B,=,5,mT) for 165,min every day for 30 days. Mean arterial blood pressure (MABP), body mass, and serum glucose level of the study rats were recorded. The extravasation of brain EB of the MF, DM, DMMF, DMI, and DMIMF groups was higher than that of the sham group and the extravasation of right hemisphere of the DMIMF group was highest (P,<,0.05). The post-procedure body mass of the sham and MF groups were significantly higher than those of the DM and DMMF groups (P,<,0.05). In the DM, DMMF, DMI, and DMIMF groups, the baseline glucose was significantly lower than the post-procedure glucose (P,<,0.05). DM and MF increase BBB permeability; in combination, they cause more increase in BBB permeability, and insulin decreases their effect on BBB. Improved glucose metabolism may prevent body mass loss and the hypoglycemic effect of MF. DM increases MABP but MF causes no additional effect. Bioelectromagnetics 31:262,269, 2010. 2009 Wiley-Liss, Inc. [source]


    Peroxisome proliferator-activated receptors in cutaneous biology

    BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2003
    S. Kuenzli
    Summary Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of target genes involved in many cellular functions including cell proliferation, differentiation and immune/inflammation response. The PPAR subfamily consists of three isotypes: PPAR,, PPAR,/, and PPAR,, which have all been identified in keratinocytes. PPAR,/, is the predominant subtype in human keratinocytes, whereas PPAR, and PPAR, are expressed at much lower levels and increase significantly upon keratinocyte differentiation. PPAR,/, is not linked to differentiation, but is significantly upregulated upon various conditions that result in keratinocyte proliferation, and during skin wound healing. In vitro and in vivo evidence suggests that PPARs appear to play an important role in skin barrier permeability, inhibiting epidermal cell growth, promoting epidermal terminal differentiation and regulating skin inflammatory response by diverse mechanisms. These proprieties are pointing in the direction of PPARs being key regulators of skin conditions characterized by hyperproliferation, inflammatory infiltrates and aberrant differentiation such as psoriasis, but may also have clinical implications in inflammatory skin disease (e.g. atopic dermatitis), proliferative skin disease, wound healing, acne and protease inhibitor associated lipodystrophia. [source]


    Modification of epithelial cell barrier permeability and intercellular junctions by Clostridium sordellii lethal toxins

    CELLULAR MICROBIOLOGY, Issue 7 2006
    Catherine Boehm
    Summary Clostridium sordellii lethal toxin (LT) is a glucosyltransferase which inactivates small GTPases from the Rho and Ras families. In the present work, we studied the effects of two variants, LT82 and LT9048, on the integrity of epithelial cell barrier using polarized MCCD (Mouse Cortical Collecting Duct) and MDCK (Madin-Darby Canine Kidney) cells. Our results demonstrate for the first time that LTs have very limited effects on tight junctions. In contrast, we show that both toxins modified the paracellular permeability within 2,4 h. Concomitantly LT82 and LT9048 induced a disorganization of basolateral actin filaments, without modifying apical actin. Both toxins mainly altered adherens junctions by removing E-cadherin-catenin complexes from the membrane to the cytosol. Similar effects on adherens junctions have been observed with other toxins, which directly or indirectly depolymerize actin. Thereby, Rac, a common substrate of both LTs, might play a central role in LT-dependent adherens junction alteration. Here, we show that adherens junction perturbation induced by LTs results neither from a direct effect of toxins on adherens junction proteins nor from an actin-independent Rac pathway, but rather from a Rac-dependent disorganization of basolateral actin cytoskeleton. This further supports that a dynamic equilibrium of cortical actin filaments is essential for functional E-cadherin organization in epithelia. [source]


    The action of pro-inflammatory cytokines on retinal endothelial cell barrier permeability: protective effect of corticosteroids

    ACTA OPHTHALMOLOGICA, Issue 2008
    AF AMBROSIO
    Purpose The pro-inflammatory cytokines interleukin-1, (IL-1,) and tumor necrosis factor-alpha (TNF-,) were found to be increased in the vitreous of diabetic patients and in diabetic rat retinas, and increased cytokine levels were correlated with elevated retinal vascular permeability. In this work, we investigated the mechanisms underlying IL-1,- and TNF-,-induced retinal endothelial cell permeability and evaluated the ability of a glucocorticoid, dexamethasone (DEX), to prevent changes in permeability. Methods Primary cultures of bovine retinal endothelial cells (BRECs) were grown on transwell filters and exposed to IL-1, and TNF-,. BRECs permeability to 70 kDa RITC-dextran was measured. The content and localization of tight junction proteins was assessed by Western blotting and immunocytochemistry. Results IL-1, and TNF-, increased retinal endothelial cell permeability in a concentration- and time-dependent manner, but TNF-, was more effective (increased permeability at a lower dose and shorter time-point). The increase in permeability was not due to changes in cell viability. IL-1, and TNF-, altered ZO-1 and claudin-5 content. TNF-, also decreased ZO-1 staining at the cell border. Pre-treatment with DEX prevented TNF-,-induced cell permeability, and the protective effect of DEX was partially abolished by the glucocorticoid receptor antagonist RU486. Conclusion These data demonstrate that TNF-, and IL-1, potently induce endothelial cell permeability through alterations in tight junctions. Also, the study supports the potential therapeutic use of glucocorticoids to reduce retinal vascular permeability. Support: FCT (Portugal), NIH, JDRF and Allergan [source]