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Endothelial Permeability (endothelial + permeability)
Selected AbstractsAbrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell functionARTHRITIS & RHEUMATISM, Issue 8 2009Lars Stangenberg Objective To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin,selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil,endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor , was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions. [source] HIGH GLUCOSE-INDUCED HUMAN UMBILICAL VEIN ENDOTHELIAL CELL HYPERPERMEABILITY IS DEPENDENT ON PROTEIN KINASE C ACTIVATION AND INDEPENDENT OF THE Ca2+,NITRIC OXIDE SIGNALLING PATHWAYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2005Lei Dang SUMMARY 1.,Endothelial barrier dysfunction plays a pivotal role in the pathogenesis of diabetic vascular complications. The precise molecular mechanisms by which hyperglycaemia causes the increased permeability in endothelial cells are not yet well understood. In the present study, we investigated whether high concentrations of glucose induce endothelial permeability through the activation of protein kinase C (PKC) and/or the calcium,nitric oxide (NO) signalling pathway in human umbilical vein endothelial cells (HUVEC). 2.,Endothelial permeability was measured by albumin diffusion across endothelial monolayers under the stimuli of high glucose (HG; 20 mmol/L), 100 nmol/L phorbol-myristate-acetate (PMA) or 100 nmol/L histamine. The intracellular calcium concentration ([Ca2+]i) was detected in HUVEC using the fluorescent probe fura-2 AM. The effects of PKC inhibitors (LY379196 and hypocrellin A) and the NO synthase (NOS) inhibitor NG -monomethyl- l -arginine (l -NMMA) on endothelial permeability and [Ca2+]i were determined. 3.,High glucose and PMA increased endothelial permeability associated with decreased [Ca2+]i, whereas histamine triggered significant increases in endothelial permeability, accompanied by increases in [Ca2+]i in HUVEC. Hypocrellin A (HA) and LY379196 reversed both HG- and histamine-induced endothelial permeability. The NOS inhibitor l -NMMA only abolished histamine- and not HG-induced endothelial permeability. Neither LY379196, HA nor l -NMMA had any significant effects on alterations in [Ca2+]i caused by HG and histamine. 4.,These results indicate that increased endothelial permeability in HUVEC induced by HG is dependent on PKC activity and is independent of the [Ca2+]i,NO pathway. Increased endothelial permeability due to other inflammatory factors, such as histamine, may also be mediated by the PKC pathway. Thus, PKC inhibitors would be a potential therapeutic approach to endothelial dysfunction induced by hyperglycaemia, as well as other inflammatory factors, in diabetes. [source] Effects of Arg-Gly-Asp Sequence Peptide and Hyperosmolarity on the Permeability of Interstitial Matrix and Fenestrated Endothelium in JointsMICROCIRCULATION, Issue 6 2004A. POLI ABSTRACT Objectives: The aims were to assess the contribution of arg-gly-asp (RGD) mediated cell integrin,matrix bonds to interstitial hydraulic resistance and to fenestrated endothelial permeability in joints. Joint fluid is generated by filtration from fenestrated capillaries and drains through a fibronectin-rich synovial intercellular matrix. The role of parenchymal cell,matrix bonding in determining tissue hydraulic resistance is unknown. Methods: The knee cavity of anesthetized rabbits was infused with saline or the competitive hexapeptide blocker GRGDTP, with or without added osmotic stress (600 mosm saline). Intra-articular pressure Pj, net trans-synovial drainage rate s, and the permeation of Evans blue-labeled albumin (EVA) from plasma into the joint cavity were measured. Results: GRGDTP increased the hydraulic conductance of the synovial drainage pathway, ds/dPj, by 71% (p = .02, paired t test, n = 6 animals). Synovial plasma EVA clearance (control 7.1 ± 0.8 ,L h,1, mean ± SEM, n = 15) was unaffected by GRGDTP (7.0 ± 2.3 ,L h,1, n = 6) or hyperosmolarity (4.9 ± 1.5 ,L h,1, n = 8) but was increased by GRGDTP and hyperosmolarity together (15.9 ± 4.8 ,L h,1, n = 5) (p = .01, ANOVA). Changes in dPj/dt evoked by GRGDTP plus hyperosmolarity, but neither alone, demonstrated increased microvascular filtration into the joint cavity (p < .001, ANOVA), as did changes in fluid absorption from the infusion system at fixed Pj. Conclusions: RGD-mediated bonds between the parenchymal cells and interstitial polymers reduce the interstitial hydraulic conductance by 42%. This helps to retain the lubricating fluid inside a joint cavity. RGD-mediated bonds also support the macromolecular barrier function of fenestrated endothelium, but in vivo this is evident only in stressed endothelium (cf. in vitro). [source] Hypertonic saline attenuates end-organ damage in an experimental model of acute pancreatitisBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 10 2000C. J. Shields Background Hypertonic saline (HTS) has been noted previously to reduce neutrophil activation. The aim of this study was to elucidate the effect of hypertonic resuscitation on the development of end-organ damage in an animal model of pancreatitis. Methods Pancreatitis was induced in Sprague,Dawley rats by intraperitoneal injection of 20 per cent l -arginine. Animals were randomized into four groups (each n = 8): controls; pancreatitis without intervention; pancreatitis plus intravenous resuscitation with normal saline (0·9 per cent sodium chloride 2 ml/kg) at 24 and 48 h; or HTS (7·5 per cent sodium chloride 2 ml/kg) at these time points. Pulmonary endothelial leakage was assessed by measurement of lung wet: dry ratios, bronchoalveolar lavage protein and myeloperoxidase activity. Results Animals that received HTS showed less pancreatic damage than those resuscitated with normal saline (1·0 versus 3·0; P = 0·04). Lung injury scores were also significantly diminished in the HTS group (1·0 versus 3·5; P = 0·03). Pulmonary neutrophil sequestration (myeloperoxidase activity 1·80 units/g) and increased endothelial permeability (bronchoalveolar lavage protein content 1287 ,g/ml) were evident in animals resuscitated with normal saline compared with HTS (1·22 units/g and 277 ,g/ml respectively; P < 0·02). Conclusion HTS resuscitation results in a significant attenuation of end-organ injury following a systemic inflammatory response to severe pancreatitis. © 2000 British Journal of Surgery Society Ltd [source] HIGH GLUCOSE-INDUCED HUMAN UMBILICAL VEIN ENDOTHELIAL CELL HYPERPERMEABILITY IS DEPENDENT ON PROTEIN KINASE C ACTIVATION AND INDEPENDENT OF THE Ca2+,NITRIC OXIDE SIGNALLING PATHWAYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2005Lei Dang SUMMARY 1.,Endothelial barrier dysfunction plays a pivotal role in the pathogenesis of diabetic vascular complications. The precise molecular mechanisms by which hyperglycaemia causes the increased permeability in endothelial cells are not yet well understood. In the present study, we investigated whether high concentrations of glucose induce endothelial permeability through the activation of protein kinase C (PKC) and/or the calcium,nitric oxide (NO) signalling pathway in human umbilical vein endothelial cells (HUVEC). 2.,Endothelial permeability was measured by albumin diffusion across endothelial monolayers under the stimuli of high glucose (HG; 20 mmol/L), 100 nmol/L phorbol-myristate-acetate (PMA) or 100 nmol/L histamine. The intracellular calcium concentration ([Ca2+]i) was detected in HUVEC using the fluorescent probe fura-2 AM. The effects of PKC inhibitors (LY379196 and hypocrellin A) and the NO synthase (NOS) inhibitor NG -monomethyl- l -arginine (l -NMMA) on endothelial permeability and [Ca2+]i were determined. 3.,High glucose and PMA increased endothelial permeability associated with decreased [Ca2+]i, whereas histamine triggered significant increases in endothelial permeability, accompanied by increases in [Ca2+]i in HUVEC. Hypocrellin A (HA) and LY379196 reversed both HG- and histamine-induced endothelial permeability. The NOS inhibitor l -NMMA only abolished histamine- and not HG-induced endothelial permeability. Neither LY379196, HA nor l -NMMA had any significant effects on alterations in [Ca2+]i caused by HG and histamine. 4.,These results indicate that increased endothelial permeability in HUVEC induced by HG is dependent on PKC activity and is independent of the [Ca2+]i,NO pathway. Increased endothelial permeability due to other inflammatory factors, such as histamine, may also be mediated by the PKC pathway. Thus, PKC inhibitors would be a potential therapeutic approach to endothelial dysfunction induced by hyperglycaemia, as well as other inflammatory factors, in diabetes. [source] | ||||||||||