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1.
BMC Infect Dis ; 17(1): 350, 2017 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-28514947

RESUMEN

BACKGROUND: Chlorhexidine (CHG) penetrates poorly into skin. The purpose of this study was to compare the depth of CHG skin permeation from solutions containing either 2% (w/v) CHG and 70% (v/v) isopropyl alcohol (IPA) or 2% (w/v) CHG, 70% (v/v) IPA and 2% (v/v) 1,8-cineole. METHODS: An ex-vivo study using Franz diffusion cells was carried out. Full thickness human skin was mounted onto the cells and a CHG solution, with or without 2% (v/v) 1,8-cineole was applied to the skin surface. After twenty-four hours the skin was sectioned horizontally in 100 µm slices to a depth of 2000 µm and the concentration of CHG in each section quantified using high performance liquid chromatography (HPLC). The data were analysed with repeated measures analysis of variance. RESULTS: The concentration of CHG in the skin on average was significantly higher (33.3% [95%, CI 1.5% - 74.9%]) when a CHG solution which contained 1,8-cineole was applied to the skin compared to a CHG solution which did not contain this terpene (P = 0.042). CONCLUSIONS: Enhanced delivery of CHG can be achieved in the presence of 1,8-cineole, which is the major component of eucalyptus oil. This may reduce the numbers of microorganisms located in the deeper layers of the skin which potentially could decrease the risk of surgical site infection.


Asunto(s)
Clorhexidina/farmacocinética , Ciclohexanoles/farmacocinética , Monoterpenos/farmacocinética , Absorción Cutánea/efectos de los fármacos , 2-Propanol/administración & dosificación , 2-Propanol/química , Antiinfecciosos Locales/administración & dosificación , Antiinfecciosos Locales/farmacocinética , Clorhexidina/administración & dosificación , Clorhexidina/química , Ciclohexanoles/administración & dosificación , Ciclohexanoles/química , Eucaliptol , Femenino , Humanos , Persona de Mediana Edad , Monoterpenos/administración & dosificación , Monoterpenos/química , Soluciones/química
2.
Am J Infect Control ; 44(12): 1678-1680, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27566872

RESUMEN

The use of a positive-displacement needleless intravenous access device was associated with lower microbial contamination rates compared with a neutral-displacement device when used on central venous catheters in hemato-oncology patients. In addition, rates of central line-associated bloodstream infection did not differ when either device was used.


Asunto(s)
Cateterismo Venoso Central/instrumentación , Catéteres Venosos Centrales/microbiología , Contaminación de Equipos , Adulto , Anciano , Infecciones Relacionadas con Catéteres/epidemiología , Recuento de Colonia Microbiana , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Sepsis/epidemiología , Adulto Joven
3.
J Antimicrob Chemother ; 70(8): 2255-60, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25904727

RESUMEN

OBJECTIVES: The antimicrobial efficacy of an iodine-impregnated incise drape against MRSA was evaluated in a skin model. The permeation of iodine from this drape into the skin was also assessed. METHODS: The antimicrobial efficacy was evaluated in ex vivo studies following application of the surgical incise drape for various times on the surface of donor skin, which was inoculated with either 1 × 10(3) or 1 × 10(6) cfu MRSA/cm(2) skin and mounted on Franz diffusion cells. In some experiments the MRSA-inoculated skin was pre-incubated for 18 h at room temperature prior to applying the drape. Permeation of iodine into the skin using this model was also determined following application of the incise drape for 6 h. RESULTS: The iodine-impregnated drape demonstrated antimicrobial activity compared with the non-use of drape. This reached significance when a high inoculum of MRSA was applied with no pre-incubation period and when a low inoculum of MRSA was applied with a pre-incubation period (P = 0.002 and P = 0.014, respectively). Furthermore, in experiments wherein a high inoculum of MRSA was applied with no pre-incubation period, the iodine-impregnated drape demonstrated superior antimicrobial activity compared with the use of a non-antimicrobial drape (P < 0.001). MIC and MBC values of iodine were attained to 1500 µm below the skin surface. CONCLUSIONS: The iodine-impregnated surgical incise drape had detectable antimicrobial activity. Furthermore, iodine penetrated into the deeper layers of the skin. This property should suppress microbial regrowth at and around a surgical incision site, making its use preferable to the use of a standard drape or non-use of a drape.


Asunto(s)
Antiinfecciosos/farmacología , Yodo/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Piel/efectos de los fármacos , Piel/microbiología , Paños Quirúrgicos , Adulto , Anciano , Antiinfecciosos/farmacocinética , Femenino , Humanos , Yodo/farmacocinética , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Modelos Biológicos
4.
J Hosp Infect ; 80(4): 299-303, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22341495

RESUMEN

BACKGROUND: The potential for microbial contamination of needleless intravascular (IV) connectors and the risk of subsequent infection are currently a subject of debate. AIM: To compare the number of micro-organisms associated with silver-coated and non-coated connectors in a clinical setting. METHODS: Twenty-five patients with haematological malignancies who required a central venous catheter (CVC) as part of their clinical management were studied. Each patient's CVC was randomly designated to have attached either silver-coated or non-coated connectors. Before and after each manipulation of the connectors, the compression seals were decontaminated with a wipe incorporating 2% (w/v) chlorhexidine gluconate in 70% (v/v) isopropyl alcohol. Following four days in situ, the number of micro-organisms recovered from 119 silver-coated and 117 non-coated connectors was determined. FINDINGS: Thirty-six (30.3%) silver-coated connectors had micro-organisms present on the external silicone compression seal compared to 41 (35%) non-coated connectors [odds ratio (OR): 0.8; 95% confidence interval (CI): 0.47-1.39; P = 0.49]. Conversely, the internal fluid pathway of 31 (26.1%) silver-coated connectors had micro-organisms present compared to 55 (47.0%) of the non-coated connectors (OR: 0.40; 95% CI: 0.23-0.69; P = 0.001). In addition, the total number of micro-organisms present was less in the silver-coated connectors as compared to non-coated devices (P = 0.001). CONCLUSION: The use of a silver-coated connector with a dedicated decontamination regime may reduce the risk of catheter-related bloodstream infection acquired via the intraluminal route.


Asunto(s)
Catéteres de Permanencia/microbiología , Materiales Biocompatibles Revestidos , Desinfectantes/farmacología , Plata/farmacología , Adulto , Anciano , Bacterias/aislamiento & purificación , Infecciones Relacionadas con Catéteres/prevención & control , Recuento de Colonia Microbiana , Femenino , Hongos/aislamiento & purificación , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
5.
Infect Control Hosp Epidemiol ; 33(1): 3-9, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22173515

RESUMEN

OBJECTIVE: To determine whether copper incorporated into hospital ward furnishings and equipment can reduce their surface microbial load. DESIGN: A crossover study. SETTING: Acute care medical ward with 19 beds at a large university hospital. METHODS: Fourteen types of frequent-touch items made of copper alloy were installed in various locations on an acute care medical ward. These included door handles and push plates, toilet seats and flush handles, grab rails, light switches and pull cord toggles, sockets, overbed tables, dressing trolleys, commodes, taps, and sink fittings. Their surfaces and those of equivalent standard items on the same ward were sampled once weekly for 24 weeks. The copper and standard items were switched over after 12 weeks of sampling to reduce bias in usage patterns. The total aerobic microbial counts and the presence of indicator microorganisms were determined. RESULTS: Eight of the 14 copper item types had microbial counts on their surfaces that were significantly lower than counts on standard materials. The other 6 copper item types had reduced microbial numbers on their surfaces, compared with microbial counts on standard items, but the reduction did not reach statistical significance. Indicator microorganisms were recovered from both types of surfaces; however, significantly fewer copper surfaces were contaminated with vancomycin-resistant enterococci, methicillin-susceptible Staphylococcus aureus, and coliforms, compared with standard surfaces. CONCLUSIONS: Copper alloys (greater than or equal to 58% copper), when incorporated into various hospital furnishings and fittings, reduce the surface microorganisms. The use of copper in combination with optimal infection-prevention strategies may therefore further reduce the risk that patients will acquire infection in healthcare environments.


Asunto(s)
Aleaciones/farmacología , Antibacterianos/farmacología , Cobre/farmacología , Contaminación de Equipos/prevención & control , Control de Infecciones/métodos , Recuento de Colonia Microbiana , Infección Hospitalaria/prevención & control , Estudios Cruzados , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/crecimiento & desarrollo , Enterococcus/efectos de los fármacos , Enterococcus/crecimiento & desarrollo , Equipos y Suministros/microbiología , Hospitales , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Resistencia a la Vancomicina
6.
J Hosp Infect ; 74(1): 72-7, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19931938

RESUMEN

The environment may act as a reservoir for pathogens that cause healthcare-associated infections (HCAIs). Approaches to reducing environmental microbial contamination in addition to cleaning are thus worthy of consideration. Copper is well recognised as having antimicrobial activity but this property has not been applied to the clinical setting. We explored its use in a novel cross-over study on an acute medical ward. A toilet seat, set of tap handles and a ward entrance door push plate each containing copper were sampled for the presence of micro-organisms and compared to equivalent standard, non-copper-containing items on the same ward. Items were sampled once weekly for 10 weeks at 07:00 and 17:00. After five weeks, the copper-containing and non-copper-containing items were interchanged. The total aerobic microbial counts per cm(2) including the presence of 'indicator micro-organisms' were determined. Median numbers of microorganisms harboured by the copper-containing items were between 90% and 100% lower than their control equivalents at both 07:00 and 17:00. This reached statistical significance for each item with one exception. Based on the median total aerobic cfu counts from the study period, five out of ten control sample points and zero out of ten copper points failed proposed benchmark values of a total aerobic count of <5cfu/cm(2). All indicator micro-organisms were only isolated from control items with the exception of one item during one week. The use of copper-containing materials for surfaces in the hospital environment may therefore be a valuable adjunct for the prevention of HCAIs and requires further evaluation.


Asunto(s)
Bacterias Aerobias/efectos de los fármacos , Cobre/farmacología , Desinfectantes/farmacología , Desinfección/métodos , Microbiología Ambiental , Bacterias Aerobias/aislamiento & purificación , Recuento de Colonia Microbiana , Infección Hospitalaria/prevención & control , Hospitales , Humanos , Control de Infecciones/métodos
8.
Antimicrob Agents Chemother ; 52(10): 3633-6, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18676882

RESUMEN

This study evaluated a model of skin permeation to determine the depth of delivery of chlorhexidine into full-thickness excised human skin following topical application of 2% (wt/vol) aqueous chlorhexidine digluconate. Skin permeation studies were performed on full-thickness human skin using Franz diffusion cells with exposure to chlorhexidine for 2 min, 30 min, and 24 h. The concentration of chlorhexidine extracted from skin sections was determined to a depth of 1,500 microm following serial sectioning of the skin using a microtome and analysis by high-performance liquid chromatography. Poor penetration of chlorhexidine into skin following 2-min and 30-min exposures to chlorhexidine was observed (0.157 +/- 0.047 and 0.077 +/- 0.015 microg/mg tissue within the top 100 microm), and levels of chlorhexidine were minimal at deeper skin depths (less than 0.002 microg/mg tissue below 300 microm). After 24 h of exposure, there was more chlorhexidine within the upper 100-microm sections (7.88 +/- 1.37 microg/mg tissue); however, the levels remained low (less than 1 microg/mg tissue) at depths below 300 microm. There was no detectable penetration through the full-thickness skin. The model presented in this study can be used to assess the permeation of antiseptic agents through various layers of skin in vitro. Aqueous chlorhexidine demonstrated poor permeation into the deeper layers of the skin, which may restrict the efficacy of skin antisepsis with this agent. This study lays the foundation for further research in adopting alternative strategies for enhanced skin antisepsis in clinical practice.


Asunto(s)
Antiinfecciosos Locales/farmacocinética , Clorhexidina/farmacocinética , Piel/metabolismo , Administración Tópica , Antiinfecciosos Locales/administración & dosificación , Cateterismo Venoso Central/métodos , Clorhexidina/administración & dosificación , Femenino , Humanos , Técnicas In Vitro , Modelos Biológicos , Permeabilidad , Piel/efectos de los fármacos , Piel/microbiología , Soluciones
9.
J Antimicrob Chemother ; 62(5): 1031-6, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18703525

RESUMEN

OBJECTIVES: Effective skin antisepsis and disinfection of medical devices are key factors in preventing many healthcare-acquired infections associated with skin microorganisms, particularly Staphylococcus epidermidis. The aim of this study was to investigate the antimicrobial efficacy of chlorhexidine digluconate (CHG), a widely used antiseptic in clinical practice, alone and in combination with tea tree oil (TTO), eucalyptus oil (EO) and thymol against planktonic and biofilm cultures of S. epidermidis. METHODS: Antimicrobial susceptibility assays against S. epidermidis in a suspension and in a biofilm mode of growth were performed with broth microdilution and ATP bioluminescence methods, respectively. Synergy of antimicrobial agents was evaluated with the chequerboard method. RESULTS: CHG exhibited antimicrobial activity against S. epidermidis in both suspension and biofilm (MIC 2-8 mg/L). Of the essential oils thymol exhibited the greatest antimicrobial efficacy (0.5-4 g/L) against S. epidermidis in suspension and biofilm followed by TTO (2-16 g/L) and EO (4-64 g/L). MICs of CHG and EO were reduced against S. epidermidis biofilm when in combination (MIC of 8 reduced to 0.25-1 mg/L and MIC of 32-64 reduced to 4 g/L for CHG and EO, respectively). Furthermore, the combination of EO with CHG demonstrated synergistic activity against S. epidermidis biofilm with a fractional inhibitory concentration index of <0.5. CONCLUSIONS: The results from this study suggest that there may be a role for essential oils, in particular EO, for improved skin antisepsis when combined with CHG.


Asunto(s)
Antiinfecciosos/farmacología , Biopelículas/efectos de los fármacos , Clorhexidina/análogos & derivados , Aceites de Plantas/farmacología , Staphylococcus epidermidis/efectos de los fármacos , Timol/farmacología , Clorhexidina/farmacología , Sinergismo Farmacológico , Eucalyptus/química , Melaleuca/química , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos
10.
J Hosp Infect ; 62(3): 353-7, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16406139

RESUMEN

The potential for microbial contamination associated with a recently developed needleless closed luer access device (CLAD) (Q-Syte; Becton Dickinson, Sandy, UT, USA) was evaluated in vitro. Compression seals of 50 multiply activated Q-Syte devices were inoculated with Staphylococcus epidermidis NCTC 9865 in 25% (v/v) human blood and then disinfected with 70% (v/v) isopropyl alcohol followed by flushing with 0.9% (w/v) sterile saline. Forty-eight of 50 (96%) saline flushes passed through devices that had been activated up to a maximum of 70 times remained sterile. A further 25 Q-Syte CLADs that had undergone multiple activations were challenged with prefilled 0.9% (w/v) sterile saline syringes, the external luer tips of which had been inoculated with S. epidermidis NCTC 9865 prior to accessing the devices. None of the devices that had been accessed up to 70 times allowed passage of micro-organisms, despite challenge micro-organisms being detected on both the syringe tip after activation and the compression seals before decontamination. These findings suggest that the Q-Syte CLAD may be activated up to 70 times with no increased risk of microbial contamination within the fluid pathway. The device may also offer protection from the external surface of syringe tips contaminated with micro-organisms.


Asunto(s)
Cateterismo/instrumentación , Descontaminación , Contaminación de Equipos , 2-Propanol , Cateterismo/efectos adversos , Desinfectantes , Contaminación de Medicamentos , Diseño de Equipo , Equipos y Suministros/microbiología , Humanos , Técnicas In Vitro , Riesgo , Staphylococcus epidermidis/aislamiento & purificación
11.
Gene Ther ; 12(5): 388-94, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15647771

RESUMEN

This study was performed to evaluate angiogenic responses of angiopoietin-1 (Ang1) in vivo after adenovirus-mediated gene transfer in the periadventitial space of the rabbit carotid arteries using a collar technique. Adenoviruses encoding LacZ and vascular endothelial growth factor (VEGF) receptor-1-Ig fusion protein (VEGF-R1-Ig) adenoviruses were used as controls. Increased neovessel formation was seen in adventitia of the Ang1 transduced arteries 7 days after the gene transfer. Neovessels in the Ang1 transduced arteries were large in size and well perfused. Ang1 binds to Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptors, which were expressed in the endothelium of the neovessels. When VEGF-R1-Ig was used with Ang1, it resulted in a decrease in the number of neovessels, which implies that VEGF-A or some other VEGF-R1 ligand(s) play a crucial role in angiogenesis occurring in response to Ang1. There were no significant differences in the total number of capillaries in the adventitia of the VEGF-R1-Ig transduced arteries as compared to LacZ controls. Neointima formation was not increased in the Ang1 transduced arteries as compared to the controls. We conclude that in the periadventitial space Ang1 shows angiogenic activity and is a potentially useful factor for the induction of therapeutic vascular growth in vivo.


Asunto(s)
Angiopoyetina 1/genética , Arterias Carótidas , Terapia Genética/métodos , Neovascularización Fisiológica , Transducción Genética/métodos , Adenoviridae/genética , Animales , Expresión Génica , Vectores Genéticos/administración & dosificación , Vectores Genéticos/uso terapéutico , Inmunoglobulinas/genética , Inyecciones , Conejos , Receptor TIE-2/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Transgenes , Túnica Íntima/fisiología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética
12.
Mech Dev ; 109(1): 69-77, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11677054

RESUMEN

Several signalling pathways have been defined by studies of genes originally characterised in Drosophila. However, some mammalian signalling systems have so far escaped discovery in the fly. Here, we describe the identification and characterisation of fly homologs for the mammalian vascular endothelial growth factor/platelet derived growth factor (VEGF/PDGF) and the VEGF receptor. The Drosophila factor (DmVEGF-1) gene has two splice variants and is expressed during all stages, the signal distribution during embryogenesis being ubiquitous. The receptor (DmVEGFR) gene has several splice variants; the variations affecting only the extracellular domain. The most prominent form is expressed in cells of the embryonic haematopoietic cell lineage, starting in the mesodermal area of the head around stage 10 of embryogenesis. Expression persists in hemocytes as embryonic development proceeds and the cells migrate posteriorly. In a fly strain carrying a deletion uncovering the DmVEGFR gene, hemocytes are still present, but their migration is hampered and the hemocytes remain mainly in the anterior end close to their origin. These data suggest that the VEGF/PDGF signalling system may regulate the migration of the Drosophila embryonic haemocyte precursor cells.


Asunto(s)
Empalme Alternativo , Drosophila melanogaster/genética , Factores de Crecimiento Endotelial/genética , Expresión Génica , Genes de Insecto , Hemocitos/citología , Linfocinas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Secuencia de Aminoácidos , Animales , Diferenciación Celular , Drosophila melanogaster/embriología , Factores de Crecimiento Endotelial/clasificación , Humanos , Linfocinas/clasificación , Datos de Secuencia Molecular , Filogenia , Proteínas Tirosina Quinasas Receptoras/clasificación , Receptores de Factores de Crecimiento/clasificación , Receptores de Factores de Crecimiento Endotelial Vascular , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
14.
EMBO J ; 20(17): 4762-73, 2001 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-11532940

RESUMEN

Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells.


Asunto(s)
Apoptosis/fisiología , Factores de Crecimiento Endotelial/farmacología , Factores de Crecimiento Endotelial/fisiología , Endotelio Vascular/fisiología , Endotelio/fisiología , Sistema Linfático/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores de Factores de Crecimiento/fisiología , Apoptosis/efectos de los fármacos , Técnicas Biosensibles , Capilares/embriología , Capilares/fisiología , División Celular , Movimiento Celular , Supervivencia Celular , Células Cultivadas , Endotelio/citología , Endotelio Vascular/citología , Activación Enzimática , Humanos , Cinética , Sistema Linfático/citología , Microcirculación/fisiología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína Quinasa C/metabolismo , ARN Mensajero/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento Endotelial Vascular , Piel/irrigación sanguínea , Venas Umbilicales , Factor C de Crecimiento Endotelial Vascular , Factor D de Crecimiento Endotelial Vascular , Receptor 3 de Factores de Crecimiento Endotelial Vascular
15.
Circ Res ; 88(6): 623-9, 2001 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-11282897

RESUMEN

The growth of blood and lymphatic vasculature is mediated in part by secreted polypeptides of the vascular endothelial growth factor (VEGF) family. The prototype VEGF binds VEGF receptor (VEGFR)-1 and VEGFR-2 and is angiogenic, whereas VEGF-C, which binds to VEGFR-2 and VEGFR-3, is either angiogenic or lymphangiogenic in different assays. We used an adenoviral gene transfer approach to compare the effects of these growth factors in adult mice. Recombinant adenoviruses encoding human VEGF-C or VEGF were injected subcutaneously into C57Bl6 mice or into the ears of nude mice. Immunohistochemical analysis showed that VEGF-C upregulated VEGFR-2 and VEGFR-3 expression and VEGF upregulated VEGFR-2 expression at 4 days after injection. After 2 weeks, histochemical and immunohistochemical analysis, including staining for the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), the vascular endothelial marker platelet-endothelial cell adhesion molecule-1 (PECAM-1), and the proliferating cell nuclear antigen (PCNA) revealed that VEGF-C induced mainly lymphangiogenesis in contrast to VEGF, which induced only angiogenesis. These results have significant implications in the planning of gene therapy using these growth factors.


Asunto(s)
Factores de Crecimiento Endotelial/fisiología , Endotelio Linfático/fisiología , Neovascularización Fisiológica/fisiología , Piel/irrigación sanguínea , Adenoviridae/genética , Animales , División Celular , Línea Celular , Factores de Crecimiento Endotelial/genética , Endotelio Linfático/química , Endotelio Linfático/citología , Endotelio Vascular/química , Endotelio Vascular/citología , Expresión Génica , Vectores Genéticos/genética , Glicoproteínas/análisis , Humanos , Inmunohistoquímica , Linfocinas/genética , Linfocinas/fisiología , Proteínas de Transporte de Membrana , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Antígeno Nuclear de Célula en Proliferación/análisis , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Piel/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factor C de Crecimiento Endotelial Vascular , Receptor 3 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Proteínas de Transporte Vesicular , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismo
16.
EMBO J ; 20(6): 1223-31, 2001 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11250889

RESUMEN

Vascular endothelial growth factor receptor-3 (VEGFR-3) has an essential role in the development of embryonic blood vessels; however, after midgestation its expression becomes restricted mainly to the developing lymphatic vessels. The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane. As VEGF-C also binds VEGFR-2, which is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C. VEGF-D, which binds to the same receptors, has been reported to induce angiogenesis, but its lymphangiogenic potential is not known. In order to define the lymphangiogenic signalling pathway we have created transgenic mice overexpressing a VEGFR-3-specific mutant of VEGF-C (VEGF-C156S) or VEGF-D in epidermal keratinocytes under the keratin 14 promoter. Both transgenes induced the growth of lymphatic vessels in the skin, whereas the blood vessel architecture was not affected. Evidence was also obtained that these growth factors act in a paracrine manner in vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo.


Asunto(s)
Factores de Crecimiento Endotelial/metabolismo , Sistema Linfático/metabolismo , Linfocinas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Piel/metabolismo , Animales , Semivida , Hiperplasia , Sistema Linfático/crecimiento & desarrollo , Sistema Linfático/patología , Ratones , Ratones Transgénicos , Comunicación Paracrina , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Piel/irrigación sanguínea , Piel/crecimiento & desarrollo , Piel/patología , Factor A de Crecimiento Endotelial Vascular , Factor C de Crecimiento Endotelial Vascular , Factor D de Crecimiento Endotelial Vascular , Receptor 3 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
17.
Cancer Res ; 61(5): 1786-90, 2001 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-11280723

RESUMEN

Many solid tumors produce vascular endothelial growth factor C (VEGF-C), and its receptor, VEGFR-3, is expressed in tumor blood vessels. To study the role of VEGF-C in tumorigenesis, we implanted MCF-7 human breast carcinoma cells overexpressing recombinant VEGF-C orthotopically into severe combined immunodeficient mice. VEGF-C increased tumor growth, but unlike VEGF, it had little effect on tumor angiogenesis. Instead, VEGF-C strongly promoted the growth of tumor-associated lymphatic vessels, which in the tumor periphery were commonly infiltrated with the tumor cells. These effects of VEGF-C were inhibited by a soluble VEGFR-3 fusion protein. Our data suggest that VEGF-C facilitates tumor metastasis via the lymphatic vessels and that tumor spread can be inhibited by blocking the interaction between VEGF-C and its receptor.


Asunto(s)
Neoplasias de la Mama/irrigación sanguínea , Factores de Crecimiento Endotelial/fisiología , Sistema Linfático/patología , Neovascularización Patológica/fisiopatología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , División Celular/fisiología , Factores de Crecimiento Endotelial/antagonistas & inhibidores , Factores de Crecimiento Endotelial/biosíntesis , Factores de Crecimiento Endotelial/genética , Femenino , Humanos , Inmunoglobulinas/biosíntesis , Inmunoglobulinas/sangre , Inmunoglobulinas/genética , Ratones , Ratones SCID , Trasplante de Neoplasias , Neovascularización Patológica/metabolismo , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Proteínas Tirosina Quinasas Receptoras/sangre , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento/sangre , Receptores de Factores de Crecimiento/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/sangre , Proteínas Recombinantes de Fusión/genética , Transfección , Trasplante Heterólogo , Factor C de Crecimiento Endotelial Vascular , Receptor 3 de Factores de Crecimiento Endotelial Vascular
18.
Nat Med ; 7(2): 199-205, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11175851

RESUMEN

The lymphatic vasculature transports extravasated tissue fluid, macromolecules and cells back into the blood circulation. Recent reports have focused on the molecular mechanisms regulating the lymphatic vessels. Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema. Here we show that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal. Transgenic mice develop a lymphedema-like phenotype characterized by swelling of feet, edema and dermal fibrosis. They survive the neonatal period in spite of a virtually complete lack of lymphatic vessels in several tissues, and later show regeneration of the lymphatic vasculature, indicating that induction of lymphatic regeneration may also be possible in humans.


Asunto(s)
Linfedema/patología , Neovascularización Patológica , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Transducción de Señal , Animales , Línea Celular , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Humanos , Ganglios Linfáticos/irrigación sanguínea , Ratones , Ratones Transgénicos , Fenotipo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Solubilidad , Factor C de Crecimiento Endotelial Vascular , Factor D de Crecimiento Endotelial Vascular , Receptor 3 de Factores de Crecimiento Endotelial Vascular
19.
Oncogene ; 19(53): 6122-9, 2000 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-11156525

RESUMEN

There is a constant requirement for vascular supply in solid tumors. Tumor-associated neovascularization allows the tumor cells to express their critical growth advantage. Axillary lymph node status is the most important prognostic factor in operable breast cancer, and experimental and clinical evidence suggests that the process of metastasis is also angiogenesis-dependent. Various angiogenic growth factors and cytokines induce neovascularization in tumors, namely members of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang) gene families. A strong correlation has been found between VEGF expression and increased tumor microvasculature, malignancy, and metastasis in breast cancer. Anti-angiogenic therapy approaches offer a new promising anti-cancer strategy and a remarkably diverse group of over 20 such drugs is currently undergoing evaluation in clinical trials.


Asunto(s)
Neoplasias de la Mama/prevención & control , Neovascularización Patológica , Inhibidores de la Angiogénesis/metabolismo , Angiopoyetina 1 , Angiopoyetina 2 , Animales , Neoplasias de la Mama/metabolismo , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Femenino , Humanos , Linfocinas/genética , Linfocinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Metástasis de la Neoplasia , Proteínas/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
20.
J Biol Chem ; 274(45): 32127-36, 1999 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-10542248

RESUMEN

Vascular endothelial growth factor-D (VEGF-D) binds and activates the endothelial cell tyrosine kinase receptors VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3), is mitogenic for endothelial cells, and shares structural homology and receptor specificity with VEGF-C. The primary translation product of VEGF-D has long N- and C-terminal polypeptide extensions in addition to a central VEGF homology domain (VHD). The VHD of VEGF-D is sufficient to bind and activate VEGFR-2 and VEGFR-3. Here we report that VEGF-D is proteolytically processed to release the VHD. Studies in 293EBNA cells demonstrated that VEGF-D undergoes N- and C-terminal cleavage events to produce numerous secreted polypeptides including a fully processed form of M(r) approximately 21,000 consisting only of the VHD, which is predominantly a non-covalent dimer. Biosensor analysis demonstrated that the VHD has approximately 290- and approximately 40-fold greater affinity for VEGFR-2 and VEGFR-3, respectively, compared with unprocessed VEGF-D. In situ hybridization demonstrated that embryonic lung is a major site of expression of the VEGF-D gene. Processed forms of VEGF-D were detected in embryonic lung indicating that VEGF-D is proteolytically processed in vivo.


Asunto(s)
Factores de Crecimiento Endotelial/biosíntesis , División Celular , Línea Celular , Dimerización , Endotelio Vascular/metabolismo , Humanos , Hibridación in Situ , Indicadores y Reactivos , Oligopéptidos , Péptidos , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Receptores Mitogénicos/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular , Factor D de Crecimiento Endotelial Vascular , Receptor 3 de Factores de Crecimiento Endotelial Vascular
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