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1.
FASEB J ; 28(1): 131-42, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24022401

RESUMEN

Proliferative vitreoretinopathy (PVR) is a severe, vision-threatening disorder characterized by the fibrous membrane formation that leads to tractional retinal detachment. There has been no effective therapeutic approach other than vitreoretinal surgery. In this study, DNA microarray analysis of the fibrous membranes revealed significant up-regulation of periostin. We also found increased periostin expression in the vitreous and retinal pigment epithelial (RPE) cells from fibrous membranes of PVR patients. In vitro, periostin increased proliferation, adhesion, migration, and collagen production in RPE cells through integrin αV-mediated FAK and AKT phosphorylation. Periostin blockade suppressed migration and adhesion induced by TGFß2 and PVR vitreous. In vivo, periostin inhibition had the inhibitory effect on progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells. These results identified periostin as a pivotal molecule for fibrous membrane formation as well as a promising therapeutic target for PVR.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Vitreorretinopatía Proliferativa/metabolismo , Vitreorretinopatía Proliferativa/patología , Adulto , Anciano , Animales , Adhesión Celular/efectos de los fármacos , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/farmacología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Electrorretinografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
2.
BMC Ophthalmol ; 14: 55, 2014 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-24766841

RESUMEN

BACKGROUND: Several retinal ischemic diseases can cause neovascular glaucoma (NVG). Trabeculectomy with mitomycin C (MMC) is a relatively better treatment modality in the management of eyes with NVG than other glaucoma surgeries. The aim of this study was to investigate the factors that may influence the outcome of trabeculectomy with MMC for NVG. METHODS: Forty-nine NVG eyes from 43 patients (26 males and 17 females) underwent primary trabeculectomy with MMC. The mean follow-up period was 16.8 ± 8.1 months (range, 6 to 34 months). Twenty-one eyes of 21 patients received intravitreal bevacizumab (IVB) 3.6 ± 1.8 days before trabeculectomy with MMC. A Kaplan-Meier survival-curve analysis was used to summarize the cumulative probability of success. We examined the relationship between the surgical outcome and the following surgical factors: gender, age, history of panretinal photocoagulation, history of cataract surgery, history of vitrectomy, preoperative IVB, NVG in the fellow eye, and postoperative complications (hyphema, choroidal detachment, and formation of fibrin) by multivariate analysis. RESULTS: The survival rate was 83.7% after 6 months, 70.9% after 12 months, and 60.8% after 24 months. The Kaplan-Meier survival curves showed no significant difference in the survival rate between the eyes with preoperative IVB (n = 21) and the eyes without preoperative IVB (n = 28) (p = 0.14). The multiple logistic regression analysis showed that postoperative hyphema (odds ratio, 6.54; 95% confidence interval, 1.41 to 35.97) was significantly associated with the surgical outcome (p = 0.02). CONCLUSIONS: Postoperative hyphema was significantly correlated with the outcome of trabeculectomy for NVG. There was no significant association between preoperative IVB and postoperative hyphema or the results of trabeculectomy.


Asunto(s)
Glaucoma Neovascular/cirugía , Hipema/etiología , Hemorragia Posoperatoria/etiología , Trabeculectomía/efectos adversos , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Femenino , Estudios de Seguimiento , Glaucoma Neovascular/diagnóstico , Glaucoma Neovascular/fisiopatología , Humanos , Hipema/diagnóstico , Hipema/epidemiología , Incidencia , Presión Intraocular , Inyecciones Intravítreas , Japón/epidemiología , Masculino , Persona de Mediana Edad , Hemorragia Posoperatoria/epidemiología , Hemorragia Posoperatoria/prevención & control , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual
3.
Blood ; 117(3): 1081-90, 2011 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-20705758

RESUMEN

Angio- and lymphangiogenesis are inherently related processes. However, how blood and lymphatic vessels regulate each other is unknown. This work introduces a novel mechanism explaining the temporal and spatial relation of blood and lymphatic vessels. Vascular endothelial growth factor-A (VEGF-A) surprisingly reduced VEGF-C in the supernatant of blood vessel endothelial cells, suggesting growth factor (GF) clearance by the growing endothelium. The orientation of lymphatic sprouting toward angiogenic vessels and away from exogenous GFs was VEGF-C dependent. In vivo molecular imaging revealed higher VEGF receptor (R)-2 in angiogenic tips compared with normal vessels. Consistently, lymphatic growth was impeded in the angiogenic front. VEGF-C/R-2 complex in the cytoplasm of VEGF-A-treated endothelium indicated that receptor-mediated internalization causes GF clearance from the extracellular matrix. GF clearance by receptor-mediated internalization is a new paradigm explaining various characteristics of lymphatics.


Asunto(s)
Vasos Sanguíneos/metabolismo , Endotelio Vascular/metabolismo , Vasos Linfáticos/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Animales , Línea Celular , Córnea/irrigación sanguínea , Citoplasma/metabolismo , Técnica del Anticuerpo Fluorescente , Expresión Génica/efectos de los fármacos , Humanos , Linfangiogénesis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor C de Crecimiento Endotelial Vascular/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo
4.
Proc Natl Acad Sci U S A ; 105(45): 17504-9, 2008 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-18952846

RESUMEN

Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-beta is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-beta is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-beta's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-beta2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of alpha-smooth muscle actin (alpha-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-beta blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted alpha-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-beta in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-beta and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.


Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Vitreorretinopatía Proliferativa/tratamiento farmacológico , Vitreorretinopatía Proliferativa/metabolismo , Quinasas Asociadas a rho/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Actinas/metabolismo , Animales , Western Blotting , Inmunohistoquímica , Músculo Liso/metabolismo , Fosforilación/efectos de los fármacos , Conejos , Vitreorretinopatía Proliferativa/patología , Cicatrización de Heridas/fisiología
5.
Nippon Ganka Gakkai Zasshi ; 115(11): 985-97, 2011 Nov.
Artículo en Japonés | MEDLINE | ID: mdl-22171504

RESUMEN

The rapid increase in diabetic retinopathy (DR), a common ocular complication of diabetes mellitus, necessitates the development of new therapeutic strategies for the amelioration and treatment of DR, especially in the earlier stages. In the present study, involvement of the Rho/Rho-kinase (ROCK) pathway in diabetic microvasculopathy and the therapeutic potential of fasudil, a selective ROCK inhibitor, were investigated. Retinal microvascular damage secondary to increased leukocyte adhesion substantially contributes to DR in its early stages. Significant Rho/ ROCK activation was observed in the retinal microvasculature of diabetic rats. The ROCK inhibitor, fasudil, protects the vascular endothelium by inhibit- ing leukocyte adhesion and reducing leukocyte-induced endothelial injury mediated through the restoration of endothelial nitric oxide synthase activity, in the retinas of diabetic rats. In co-culture assay of DR leukocytes and microvascular endothelial cells, we investigated the protective mechanisms of fasudil on endothelial damage using L-NAME, an inhibitor of nitric oxide synthase. Leukocytes from DR patients caused endothelial apoptosis via Fas/ FasL interaction, which was significantly reduced by a ROCK inhibition dependent on nitric oxide. The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy and ROCK inhibition may become a new strategy in the amelioration and treatment of DR, especially in its early stages.


Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Retinopatía Diabética/metabolismo , Ratas
6.
Graefes Arch Clin Exp Ophthalmol ; 248(5): 667-73, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20155363

RESUMEN

BACKGROUND: While statins have an anti-angiogenic property, their underlying mechanisms are not fully understood. We investigated intracellular mechanisms of simvastatin-mediated reduction in VEGF-induced signalings. METHODS: The effects of simvastatin on cell proliferation and viability were evaluated by [(3)H]-thymidine incorporation in retinal endothelial cells (RECs) and cell counting. The impact of simvastatin on VEGF-induced phosphorylation of p44/42 mitogen-activated protein (MAP) kinase, myosin light chain (MLC), and VEGF-receptor (VEGFR) 2 were examined by Western blotting. Involvement of the mevalonate pathway in VEGF-induced signaling was also examined. RESULTS: Simvastatin (1 and 10 microM) suppressed VEGF-induced RECs proliferation in a concentration-dependent manner, without affecting cell viability. Simvastatin significantly inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream mediators, p44/42 MAP kinase and MLC. Mevalonate completely reversed VEGF-induced VEGFR2 phosphorylation, but only partially reversed the phosphorylation of p44/42 MAP kinase and MLC. CONCLUSION: These data indicate that simvastatin exerts its anti-angiogenic effects through the reduction of VEGFR2 phosphorylation in RECs at least in part. However, there seems to be both mevalonate-dependent and independent pathway in simvastatin's anti-angiogenic property.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Endotelio Vascular/efectos de los fármacos , Simvastatina/farmacología , Animales , Western Blotting , Bovinos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endotelio Vascular/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Cadenas Ligeras de Miosina/metabolismo , Fosforilación , Vasos Retinianos/citología , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
7.
Graefes Arch Clin Exp Ophthalmol ; 247(9): 1173-7, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19421766

RESUMEN

PURPOSE: To investigate the anatomical features of vitreoretinal interface in eyes with asteroid hyalosis (AH) with optical coherence tomography (OCT) and intravitreal triamcinolone acetonide (TA) during vitreous surgery. METHODS: This study was an interventional clinical case series. Records relating to ten eyes from ten patients who underwent a TA-assisted vitrectomy for the treatment of diverse vitreoretinal diseases complicated with AH. The posterior vitreoretinal interface was examined by preoperative OCT and by intraoperative visualization of posterior vitreous cortex utilizing TA. RESULTS: In eight of ten AH eyes, preoperative OCT revealed abnormal vitreoretinal adhesions. In four of these eight eyes, posterior vitreoschisis could be seen on OCT. In the other four of these eight eyes, a clear no posterior vitreous detachment (PVD) pattern could be seen on OCT. Although posterior vitreous cortex could not be clearly identified with preoperative OCT in two of ten AH eyes, a complete PVD was refuted by intraoperative visualization of the posterior vitreous cortex with TA identical to the other eight eyes. CONCLUSION: These results indicate that complete PVD appears to be unlikely to occur in eyes with AH. In addition, spontaneous PVD in eyes with AH might lead to vitreoschisis or residual whole layer or posterior vitreous cortex, possibly due to anomalous vitreoretinal adhesion.


Asunto(s)
Oftalmopatías/diagnóstico , Enfermedades de la Retina/diagnóstico , Cuerpo Vítreo/patología , Anciano , Anciano de 80 o más Años , Femenino , Glucocorticoides , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Coherencia Óptica , Triamcinolona Acetonida , Vitrectomía
8.
Graefes Arch Clin Exp Ophthalmol ; 247(11): 1455-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19544065

RESUMEN

BACKGROUND: To evaluate the effect of tamponade by room air after vitrectomy for the treatment of idiopathic macular hole (MH). METHODS: There were 156 eyes of 151 patients studied. The patients' ages ranged from 35 to 88 years old (mean: 65.1 years). After conventional pars plana vitrectomy with internal limiting membrane peeling, fluid air exchange was performed using 20% SF(6) (Gas group: 91 eyes) or room air (Air group: 65 eyes). Surgical outcomes were retrospectively analyzed. RESULTS: Mean preoperative hole diameter was 352 microm in the Gas group and 370 microm in the Air group (P = 0.558). The closure rate of all cases was 91.0% after first surgery and 98.7% at last follow-up. The primary closure rate was 90.1% in the Gas group after 7.44 +/- 1.66 (mean +/- SD) days prone positioning period, and 92.3% in the Air group after 3.83 +/- 0.97 days of prone positioning. There was significant difference in prone positioning period (P < 0.0001), but not in the first closure rate (P = 0.132). CONCLUSION: This study suggests that room air may have an equivalent tamponade effect, in spite of the shorter prone positioning period, than SF(6) after MH surgery.


Asunto(s)
Aire , Perforaciones de la Retina/cirugía , Hexafluoruro de Azufre/administración & dosificación , Vitrectomía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Posición Prona , Perforaciones de la Retina/fisiopatología , Estudios Retrospectivos , Agudeza Visual/fisiología
9.
Ocul Immunol Inflamm ; 25(5): 654-662, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27070953

RESUMEN

PURPOSE: Systemic metastatic retinal lymphoma (SMRL) originates in systemic organs. It has been reported to exhibit clinical features similar to those of primary vitreoretinal lymphoma (PVRL). We report six cases of SMRL in a single-center survey in Japan. METHODS: The clinical and pathologic features in SMRL at the Kyushu University Hospital were retrospectively studied. RESULTS: The mean patient age at the onset of ocular involvement was 75.3 years. Four patients had brain involvement. The primary sites were: breast (2); chest (1); testis (1); intestinal tract (1); and nasal sinus (1). In all patients, the cytology of vitreous samples indicated diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: DLBCL is the most common subtype in our study. The prevalence of CNS involvement in patients with SMRL is similar to that with PVRL. The testis and breast may be common sites of origin for SMRL.


Asunto(s)
Metástasis Linfática , Linfoma de Células B Grandes Difuso/diagnóstico , Neoplasias de la Retina/diagnóstico , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/etnología , Neoplasias de la Mama/patología , Femenino , Reordenamiento Génico , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Neoplasias Intestinales/patología , Japón/epidemiología , Linfoma de Células B Grandes Difuso/etnología , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Neoplasias de los Senos Paranasales/patología , Reacción en Cadena de la Polimerasa , Neoplasias de la Retina/etnología , Neoplasias de la Retina/metabolismo , Estudios Retrospectivos , Neoplasias Testiculares/patología , Neoplasias Torácicas/patología , Vitrectomía , Cuerpo Vítreo/patología
10.
Invest Ophthalmol Vis Sci ; 57(4): 2264-76, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-27124322

RESUMEN

PURPOSE: In this study, we investigated the therapeutic potential of a Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor ripasudil (K-115) eye drop on retinal neovascularization and hypoxia. METHODS: In vitro, human retinal microvascular endothelial cells (HRMECs) were pretreated with ripasudil and then stimulated with VEGF. ROCK activity was evaluated by phosphorylation of myosin phosphatase target protein (MYPT)-1. Endothelial migration and cell viability were assessed by cell migration and MTT assay, respectively. The concentration of ripasudil in the retina was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo, normal saline, 0.4%, or 0.8% ripasudil were administered three times a day to mice with oxygen-induced retinopathy (OIR). The areas of neovascularization and avascular retina were also quantified with retinal flat-mounts at postnatal day (P) 15, P17, or P21. The retinal hypoxic area was evaluated using hypoxia-sensitive drug pimonidazole by immunohistochemistry at P17. The vascular normalization was also evaluated by immunohistochemistry at P17. RESULTS: Ripasudil but not fasudil significantly reduced VEGF-induced MYPT-1 phosphorylation in HRMECs at 30 µmol/L. Ripasudil significantly inhibited VEGF-induced HRMECs migration and proliferation. The concentration of ripasudil in the retina was 3.8 to 10.4 µmol/L and 6.8 to 14.8 µmol/L after 0.4% and 0.8% ripasudil treatment, respectively. In the 0.4% and 0.8% ripasudil treated OIR mice, the areas of neovascularization as well as avascular area in the retina was significantly reduced compared with those of saline-treated mice at P17 and P21. Pimonidazole staining revealed that treatment with 0.4% and 0.8% ripasudil significantly inhibited the increase in the hypoxic area compared with saline. 0.8% ripasudil could cause intraretinal vascular sprouting and increase retinal vascular perfusion. CONCLUSIONS: Novel ROCK inhibitor ripasudil eye drop has therapeutic potential in the treatment of retinal hypoxic neovascular diseases via antiangiogenic effects as well as vascular normalization.


Asunto(s)
Endotelio Vascular/citología , Isoquinolinas/uso terapéutico , Neovascularización Retiniana/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Endotelio Vascular/efectos de los fármacos , Humanos , Hipoxia/tratamiento farmacológico , Técnicas In Vitro , Isoquinolinas/administración & dosificación , Isoquinolinas/análisis , Ratones , Ratones Endogámicos C57BL , Fosfatasa de Miosina de Cadena Ligera/metabolismo , Soluciones Oftálmicas , Fosforilación/efectos de los fármacos , Retina/química , Sulfonamidas/administración & dosificación , Sulfonamidas/análisis , Espectrometría de Masas en Tándem , Factor A de Crecimiento Endotelial Vascular/farmacología
11.
Clin Ophthalmol ; 10: 1623-30, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27601877

RESUMEN

BACKGROUND AND OBJECTIVE: Existing ophthalmoscopy methods are unable to obtain clear fundus autofluorescence (FAF) images in gas-filled eyes. The purpose of this study was to evaluate the capability of wide-field laser ophthalmoscopy (Optos) in obtaining FAF images in gas-filled eyes for the assessment of macular hole (MH) closure after surgery. METHODS: This was an interventional case series. Eighteen consecutive patients with unilateral MH underwent vitrectomy with internal limiting membrane peeling and 20% sulfur hexafluoride gas tamponade. FAF images using Optos were recorded preoperatively and postoperatively (days 1, 2, and 7). RESULTS: On postoperative days 1, 2, and 7, FAF images were obtained from 11/18 (61.1%), 9/18 (50.0%), and 17/18 eyes (94.4%), respectively, using Optos. The quality of FAF images using Optos was sufficient to determine MH closure in 9/18 (50.0%) of gas-filled eyes postoperatively. Quantitative analysis of FAF images was helpful in determining complete or partial closure of the MH. CONCLUSION: FAF imaging using Optos might be a useful adjunct to optical coherence tomography as a supportive method to guide the release from facedown posturing in some cases of MH.

13.
Br J Ophthalmol ; 99(5): 629-34, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25355804

RESUMEN

PURPOSE: We recently demonstrated that M2 macrophages were involved in the development of fibrovascular membranes (FVM) associated with proliferative diabetic retinopathy (PDR) possibly through the induction of periostin. The purpose of this study was to determine whether macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-13, inducers of the M2 polarisation of macrophages from monocytes, are elevated in the vitreous of patients with PDR, and whether M2-polarised macrophages induce periostin production. METHODS: We measured the levels of M-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, IL-13, soluble (s)CD163, periostin and vascular endothelial growth factor by sandwich ELISA in vitreous samples collected from 61 eyes of 47 patients with PDR, and 39 eyes of 36 patients with non-diabetic ocular diseases (control group). Human monocytes were polarised in vitro with GM-CSF, interferon-γ, and lipopolysaccharide for M1 macrophages, and M-CSF, IL-4, and IL-13 for M2 macrophages. Quantitative real-time PCR was used to determine the mRNA level of periostin. RESULTS: The concentrations of M-CSF and IL-13 in the vitreous were significantly higher in patients with PDR than in non-diabetic controls (p<0.0001). There was a strong positive correlation between the vitreous concentrations of M-CSF and sCD163 and periostin. The mean vitreous level of IL-13 was significantly higher in eyes with FVMs than in those without FVMs (epicentre only). In vitro studies showed that M2-polarlised macrophages significantly increased the expression of the mRNA of periostin. CONCLUSIONS: These findings indicate that the M2 polarisation of macrophages is induced by M-CSF and IL-13 in diabetic retinas. The presence of M-CSF and IL-13 would then promote FVM formation by periostin production.


Asunto(s)
Retinopatía Diabética/metabolismo , Interleucina-13/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/metabolismo , Neovascularización Retiniana/metabolismo , Vitreorretinopatía Proliferativa/metabolismo , Cuerpo Vítreo/metabolismo , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Moléculas de Adhesión Celular/genética , Retinopatía Diabética/cirugía , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación de la Expresión Génica/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Superficie Celular/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vitrectomía
14.
Br J Ophthalmol ; 99(4): 451-6, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25281471

RESUMEN

AIM: To determine whether CD163, a specific marker for M2 macrophages, is involved in the formation of preretinal fibrovascular membranes (FVMs) present in eyes with proliferative diabetic retinopathy (PDR). METHODS: We measured the levels of soluble (s)CD163, periostin and vascular endothelial growth factor by sandwich ELISA in vitreous samples from 74 eyes of 62 patients with PDR, 20 eyes of 18 patients with proliferative vitreoretinopathy, and 56 eyes of 54 patients with non-diabetic ocular diseases (control group). Immunohistochemical analyses were performed to determine the expressions of CD68, CD163 and periostin in the surgically resected FVMs and idiopathic epiretinal membranes (ERMs). RESULTS: The concentrations of sCD163 and periostin in the vitreous were significantly higher in patients with PDR than in non-diabetic controls (p<0.0001). There was a strong correlation between the vitreous concentrations of sCD163 and periostin. The mean vitreous level of sCD163 was significantly higher in eyes with FVMs than in those without FVMs (epicentre only). The number and percentage of CD163+ macrophages were significantly higher in the FVMs than in the idiopathic ERMs. Immunohistochemical analysis showed co-localisation of CD163 and periostin in FVM cells. CONCLUSIONS: These findings indicate that the overexpression of CD163 by macrophages may be involved in the development of FVMs partly through periostin production.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Retinopatía Diabética/metabolismo , Membrana Epirretinal/metabolismo , Receptores de Superficie Celular/metabolismo , Cuerpo Vítreo/metabolismo , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vitreorretinopatía Proliferativa/metabolismo
15.
Br J Ophthalmol ; 99(7): 960-6, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25631486

RESUMEN

PURPOSE: To determine whether vitreal concentrations of MCP-1, IL-6 and IL-8 are altered after vitrectomy in patients with proliferative diabetic retinopathy (PDR) and to investigate whether the altered levels of these cytokines are associated with postoperative macular oedema. METHODS: Vitreous samples were collected from 36 eyes of 33 patients with PDR before pars plana vitrectomy without intraocular lens (IOL) implantation, and also from the same 36 eyes during IOL implantation surgery approximately 7 months after the initial vitrectomy. Levels of MCP-1, IL-6, IL-8 and vascular endothelial growth factor were measured by flow cytometry using cytometric bead array (CBA) technology. RESULTS: The mean vitreous levels of MCP-1, IL-6 and IL-8 in the samples collected before vitrectomy were significantly higher in patients with PDR than in control patients (p<0.0001). The levels of MCP-1 and IL-6 in the samples collected at the time of IOL implantation were significantly higher than those collected before vitrectomy (p<0.05). In contrast, the level of IL-8 was significantly lower after vitrectomy (p<0.05). The levels of IL-6 and IL-8, but not MCP-1, in the vitreous from eyes with PDR were inversely correlated with the interval between the initial vitrectomy and the time of implantation surgery. Among the vitrectomised patients, the mean vitreous level of MCP-1 in eyes with diabetic macular oedema (DME) was significantly higher than in those without DME (p=0.028). CONCLUSIONS: The elevated levels of MCP-1 and IL-6 may indicate prolonged inflammation even after successful vitrectomy, which can cause postoperative DME.


Asunto(s)
Quimiocina CCL2/metabolismo , Retinopatía Diabética/cirugía , Interleucina-6/metabolismo , Edema Macular/metabolismo , Complicaciones Posoperatorias , Vitrectomía , Cuerpo Vítreo/metabolismo , Retinopatía Diabética/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Interleucina-8/metabolismo , Implantación de Lentes Intraoculares , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Facoemulsificación , Factor A de Crecimiento Endotelial Vascular/metabolismo , Agudeza Visual
16.
Invest Ophthalmol Vis Sci ; 56(12): 7516-23, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26595610

RESUMEN

PURPOSE: To determine the profiles of soluble cytokine receptors and cytokines, including mostly their ligands, in the vitreous humor of patients with B-cell vitreoretinal lymphoma (VRL) and uveitis. METHODS: Vitreous samples were collected from immunocompetent patients with VRL (n = 21), uveitis (n = 20), and idiopathic epiretinal membrane (n = 21) as controls. Cytometric beads assay were used to determine the vitreous concentrations of soluble receptors and cytokines. RESULTS: Vitreous levels of soluble IL-2 receptor α (sIL-2Rα), sIL-6R, soluble tumor necrosis factor receptor (TNFR) 1, sTNFR2, soluble vascular endothelial growth factor receptor (sVEGFR) 1, sVEGFR2, and IL-10 were higher in patients with VRL than in those with uveitis and controls, whereas those of sIL-1R1, sIL-1R2, and sIL-4R were higher in patients with uveitis than those with VRL and controls. In analyses in patients with VRL, elevation of sVEGFR1 and sVEGFR2 levels was more prominent in patients with systemic metastatic retinal lymphoma (SMRL) than in those with primary VRL/primary central nervous system lymphoma (PVRL/PCNSL). Furthermore, sIL-2Rα levels were increased in patients with VRL who developed subretinal lesions compared with in those who mainly had vitreous cavity opacity, positively correlated with the density of CD3+ cells in the vitrectomy cell blocks. CONCLUSIONS: The profiles of soluble cytokine receptors and cytokines in patients with VRL were different from those with uveitis. In addition, sVEGFR1 and sVEGFR2 levels may be differential diagnostic markers between PVRL/PCNSL and SMRL, and sIL-2Rα levels can anticipate infiltration of VRL cells into the subretina and/or retina.


Asunto(s)
Linfoma de Células B/metabolismo , Receptores de Citocinas/metabolismo , Neoplasias de la Retina/metabolismo , Uveítis/metabolismo , Cuerpo Vítreo/metabolismo , Anciano , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B/patología , Linfoma de Células B/cirugía , Masculino , Persona de Mediana Edad , Neoplasias de la Retina/patología , Neoplasias de la Retina/cirugía , Uveítis/patología , Uveítis/cirugía , Vitrectomía , Cuerpo Vítreo/patología
17.
Cell Rep ; 10(7): 1173-86, 2015 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-25704819

RESUMEN

Age is a major risk factor in age-related macular degeneration (AMD), but the underlying cause is unknown. We find increased Rho-associated kinase (ROCK) signaling and M2 characteristics in eyes of aged mice, revealing immune changes in aging. ROCK isoforms determine macrophage polarization into M1 and M2 subtypes. M2-like macrophages accumulated in AMD, but not in normal eyes, suggesting that these macrophages may be linked to macular degeneration. M2 macrophages injected into the mouse eye exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them, supporting a causal role for macrophage subtypes in AMD. Selective ROCK2 inhibition with a small molecule decreased M2-like macrophages and choroidal neovascularization. ROCK2 inhibition upregulated M1 markers without affecting macrophage recruitment, underlining the plasticity of these macrophages. These results reveal age-induced innate immune imbalance as underlying AMD pathogenesis. Targeting macrophage plasticity opens up new possibilities for more effective AMD treatment.


Asunto(s)
Macrófagos/metabolismo , Quinasas Asociadas a rho/metabolismo , Envejecimiento , Animales , Células de la Médula Ósea/citología , Diferenciación Celular/efectos de los fármacos , Polaridad Celular , Células Cultivadas , Coroides/irrigación sanguínea , Neovascularización Coroidal , Citocinas/farmacología , Humanos , Macrófagos/citología , Degeneración Macular/metabolismo , Degeneración Macular/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Transducción de Señal , Quinasas Asociadas a rho/antagonistas & inhibidores
18.
Am J Ophthalmol ; 138(4): 670-1, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15488808

RESUMEN

PURPOSE: To identify the genetic defect in the FZD4 gene responsible for familial exudative vitreoretinopathy (FEVR) in a Japanese family. DESIGN: Interventional case report. METHODS: Complete ophthalmologic examinations were performed, and the FZD4 gene was analyzed by direct genomic sequencing. RESULTS: Fundus examination of a 13-year-old Japanese girl who had had esotropia and exudative retinal detachment at 3 years exhibited peripheral avascular areas bilaterally, a dragged disk, and retinal holes unilaterally. In contrast, her asymptomatic father had only bilateral avascular areas in the peripheral retina. Molecular genetic analysis revealed that both the proband and her father had a heterozygous missense mutation of A to G at 1026 bp of the FZD4 gene (Met342Val). CONCLUSIONS: A novel mutation in the FZD4 gene was identified in Japanese patients with FEVR. Our observations support the hypothesis that the FZD4-associated FEVR might represent a milder form than that associated with other genetic origins.


Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Mutación Missense , Proteínas/genética , Enfermedades de la Retina/genética , Cuerpo Vítreo , Adolescente , Codón sin Sentido/genética , Análisis Mutacional de ADN , Enfermedades Hereditarias del Ojo/patología , Femenino , Receptores Frizzled , Humanos , Japón , Linaje , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G , Enfermedades de la Retina/patología
19.
Invest Ophthalmol Vis Sci ; 54(8): 5288-93, 2013 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-23860759

RESUMEN

PURPOSE: The purpose of this study was to investigate the application of wide-field laser ophthalmoscopy (Optos) for the evaluation of established models of angiogenesis and the healthy retina in mice. METHODS: To investigate whether angiogenesis and leakage in the retina and choroid can be evaluated with Optos, we used two models of angiogenesis: oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV). Fundus imaging and fluorescein angiography (FAG) were performed with the Optos system without a contact lens. Furthermore, to evaluate in vivo leukocyte infiltration in these models, we injected acridine orange (AO) and performed imaging using Optos. RESULTS: In vivo fundus imaging with Optos did not require any additional optical device. Additionally, Optos enabled us to repeatedly obtain high-resolution color images and FAG images in the OIR model as well as in the CNV model in mice. Through a combination of Optos imaging and AO fluorography, the number and location of the infiltrating leukocytes could be identified in these models. CONCLUSIONS: Optos is a wide-viewing imaging tool for the noninvasive in vivo evaluation of common angiogenesis models, oxygen-induced retinopathy and laser-induced choroidal neovascularization, as well as the healthy retina in mice.


Asunto(s)
Neovascularización Coroidal/diagnóstico , Rayos Láser , Oftalmoscopios , Oftalmoscopía/métodos , Neovascularización Retiniana/diagnóstico , Naranja de Acridina , Animales , Neovascularización Coroidal/inducido químicamente , Modelos Animales de Enfermedad , Diseño de Equipo , Angiografía con Fluoresceína , Colorantes Fluorescentes , Fondo de Ojo , Ratones , Ratones Endogámicos C57BL , Oxígeno/toxicidad , Reproducibilidad de los Resultados , Neovascularización Retiniana/inducido químicamente
20.
Invest Ophthalmol Vis Sci ; 54(3): 2373-83, 2013 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-23462755

RESUMEN

PURPOSE: Leukocyte adhesion releases tumor necrosis factor (TNF)-α that contributes to endothelial damage in early diabetic retinopathy (DR). Rho/Rho-kinase (ROCK) signaling mediates retinal endothelial damage in early DR. However, whether ROCK regulates TNF-α-mediated diabetic vascular damage is unknown. Here, the contribution of ROCK to TNF-α-mediated microvascular damage is investigated. METHODS: In DR patients and nondiabetic control subjects, the levels of membranous (m) TNF-α on neutrophils, soluble (s) TNF-α and its receptors in sera, were measured. In cultured microvascular endothelial cells, phosphorylation of myosin phosphatase target protein (MYPT)-1, a downstream target of ROCK, was investigated with TNF-α or DR sera pretreatment. TNF-α-induced intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS) phosphorylation were measured with and without ROCK inhibition by fasudil or ROCK-specific small-interfering RNA (siRNA). In isolated neutrophils from control subjects, MYPT-1 phosphorylation was investigated in the presence of TNF-α. The impact of ROCK inhibition by fasudil on TNF-α-induced integrin (CD18, CD11a, CD11b) and intracellular cytoskeletal changes were investigated. RESULTS: The serum levels of mTNF-α, sTNF-α, and its receptors were significantly elevated in DR patients. TNF-α as well as DR sera promoted MYPT-1 phosphorylation in endothelial cells, which was significantly reduced by anti-TNF-α neutralizing antibody. TNF-α-induced ICAM-1 expression, eNOS dephosphorylation, cytoskeletal changes, and CD11b/18 expression in neutrophils were significantly suppressed by fasudil as well as ROCK-specific siRNA. CONCLUSIONS: ROCK is a key mediator of TNF-α signaling in diabetic microvessels. The important role of TNF-α in early DR provides a new rationale for ROCK inhibition beyond the previously shown mechanisms.


Asunto(s)
Angiopatías Diabéticas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Quinasas Asociadas a rho/fisiología , Anciano , Anciano de 80 o más Años , Células Cultivadas , Retinopatía Diabética/metabolismo , Células Endoteliales , Endotelio Vascular/metabolismo , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Persona de Mediana Edad , Fosfatasa de Miosina de Cadena Ligera/metabolismo , Neutrófilos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Receptores del Factor de Necrosis Tumoral/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores
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