RPE-associated extracellular matrix changes accompany retinal vascular proliferation and retino-vitreal membranes in a new model for proliferative retinopathy: the dystrophic rat.
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Aging↗
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[Immunologic phenomena in patients with proliferative retinopathy in diabetes mellitus type 1].
As a rule, in long-lasting diabetes type 1 there appear vascular complications in a form of proliferative retinopathy. While looking for the causes of fast vascular changes, the authors considered the possibility of immunological disorders. They started prospective examinations of patients with diabetes type 1 and proliferative retinopathy changes in the fundus of the eye. The authors evaluated the activity of angiogenic factors released by mononuclear cells isolated from peripheral blood of the patients examined. The authors found a significantly higher activity of these factors in patients with proliferative retinopathy in comparison with a control group of healthy persons and a group of patients with diabetes type 1 and simple retinopathy. The results obtained may indicate to immunological changes in the pathogenesis of proliferative retinopathy.
Adult↗
[Retinal pigment epithelial tears after photocoagulation in age-related macular degeneration].
Retinal pigment epithelial tears after photocoagulation for subretinal new-vessels complicating age related macular degeneration were observed in 20 patients between 1980 and 1988. The patients, 4 males and 16 females, aged from 60 to 86 years (mean: 72.5) were followed up between 12 and 53 months (mean: 21 months). Laser photocoagulation was performed for directly visible lacy subretinal new-vessels (6 cases) or vascularized pigment epithelial detachment (10 cases) or both lesions associated (4 cases). Krypton laser (17 cases), blue-green argon laser and/or orange dye laser (625 nm) (3 cases) were applied in one (9 cases) to four sessions. Retreatment (11 cases) was performed for persistent subretinal new-vessels (3 cases) or recurrences (4 cases) or appearance of a pigment epithelial detachment after photocoagulation for isolated SRNV (4 cases). The tear was observed on fluorescein angiography 10 to 180 days after the last session. It was preceded by occurrence of subretinal hemorrhages, increase in size of the PED or newly formed PED. It appeared on the border of the PED (16 cases) usually temporally, or on the immediate border of the laser scar (4 cases). Further evolution was rapidly defavorable with dramatic impairment of vision and constitution of fibrovascular scar in the macular area. Only 4 eyes progressed to flat atrophic scars after retreatment and retained useful central vision (0.1 to 0.2). Factors which could explain this complication following laser treatment of age related macular degeneration are discussed.
Aged↗
[Tear of the pigment epithelium. Natural course of the disease].
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Fluorescein Angiography↗
Intermittent oxygen in retrolental fibroplasia.
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Animals↗
Pars planitis.
We have studied seven eyes from six patients with longstanding pars planitis. Two eyes were phthisical. The remaining five eyes from four patients showed similar findings and included retinal phlebitis, disc and macular oedema, and the presence of a 'snowbank' over the inferior peripheral retina and pars plana. The snowbank consisted of posteriorly detached and collapsed vitreous in which cellular proliferation from the retina with non-pigmented ciliary epithelium was present. Electron microscopy showed the presence of fibrous astrocytes and collagen in two eyes. Retinal neovascularization extended into the snowbank in one case. We have also studied vitreous and preretinal membranes and a portion of a snowbank obtained by pars plana vitrectomy from two eyes of two young patients with active pars planitis. The snowbank and preretinal membranes contained fibrous astrocytes and new collagen and the vitreous snowballs consisted of granulomatous inflammation.
Adolescent↗
The effect of oxygen on vasoformative cell division. Evidence that 'physiological hypoxia' is the stimulus for normal retinal vasculogenesis.
PURPOSE: To assess the role of oxygen in normal retinal vasculogenesis. METHODS: A new preparation for studying cytogenesis in retinal wholemounts was developed. Nuclei of dividing cells were labeled with a monoclonal antibody to bromodeoxyuridine (BrdU), and vascular cells were covisualized with Griffonia simplicifolia lectin. The topography and time course of vasculogenic cell division and vessel formation were determined in the kitten retina during normal development and under experimental hyperoxia and hypoxia. RESULTS: During normal development, vasculogenic cell division was maximal at the leading edge of the forming vessels. Normal vessel formation was initially proliferative, and cell division was high. However, after vessel formation occurred, which presumably relieved tissue hypoxia, the mitogenic process was markedly reduced, and many excess capillary segments underwent retraction. The rate of vasculogenic cell division and vessel formation increased when the inner layers of the retina were made avascular after exposure to hyperoxia, and it decreased when there was an increase in inspired oxygen. CONCLUSIONS: The authors have shown that between 17% and 45% oxygen, the extent of vasculogenic cell division is inversely proportional to the level of oxygen in the inspired gas mixture. They have further shown that dividing vascular cells have a peak density in a region proximal to the edge of the forming vasculature. The density is maximal between P7 and P8, a time when formation of photoreceptor outer segment begins, only a few days before the onset of retinal function. These results led the authors to conclude that the stimulus for normal vasculogenesis is a transient but physiological level of hypoxia induced by the increasing activity of retinal neurons.
Animals↗
Supplemental oxygen therapy. Basis for noninvasive treatment of retinopathy of prematurity.
PURPOSE: To determine the effectiveness of supplemental oxygen therapy (SOT) in ameliorating the proliferative vasculopathy characteristic of the feline model of retinopathy of prematurity (ROP). METHODS: Kittens were exposed to high (70% to 80%) oxygen for the first 4 days of life to induce obliteration of the retinal circulation. The level of inspired oxygen at successive stages after hyperoxia were varied systematically, and the retinas were examined for the extent of revascularization, astrocyte survival, intactness of the blood-retinal barrier, and extent of preretinal vessels. RESULTS: The level of inspired oxygen required to protect the retina from hypoxic damage and yet provide a stimulus for growth of the vasculature varied during a 6-week period. The rate of revascularization of the retina increased as the oxygen content of the inspired gas mixture decreased, with a consequential increase in the pathology observed. However, a regimen that produced a quicker rate of revascularization with a slightly higher level of pathology actually offered the retina greater protection in the long term. The formation of preretinal vessels was effectively prevented by SOT. Supplemental oxygen therapy could be terminated once a significant portion of the retina was revascularized. CONCLUSIONS: The proliferative vasculopathy of a kitten model of ROP can be significantly reduced by a regimen of SOT, which attempts to mimic physiological levels of hypoxia in the retina during its revascularization. Optimal revascularization requires a balance between the rate and quality of vessel growth. With further refinement of the protocol, SOT could provide noninvasive treatment of ROP in neonates.
Animals↗
Renin-containing Müller cells of the retina display endocrine features.
PURPOSE: An ocular renin-angiotensin system has been implicated in the proliferation of retinal blood vessels and blindness in diabetes mellitus. Its cellular basis has not been established. The objective was to identify sites of renin synthesis, secretion, and processing in eyes from humans, BALB/c mice, Sprague-Dawley rats, and a hypertensive transgenic rat model (mREN-2) that displays amplified extrarenal renin synthesis. METHODS: Paraffin sections of eyes were incubated with antisera to renin protein, prorenin, vimentin, and Müller cells. Enzyme kinetic renin assay was performed on extracts of whole eyes (excluding lens and vitreous) and comparisons made with adrenal glands and kidneys. For detection of renin mRNA, retinas were separately pooled from BALB/c and Swiss mice. RESULTS: In normal rodent and autopsy human eyes, labeling for renin, vimentin, and Müller cell protein was observed in the cytoplasm of all macroglial Müller cells, with renin labeling most obvious in endfeet closely apposed to retinal blood vessels. Prorenin labeling was not detected. Less intense renin labeling, again without prorenin, was seen in nonpigmented ciliary epithelium of rodents. In transgenic (mREN-2) rat eyes, renin and prorenin labeling of Müller cells and nonpigmented ciliary epithelium were intense. Prorenin was localized to the posterior region of Müller cells but only sparsely to endfeet in rodent retinas, and renin was present only in an active form in amounts one third that of one adrenal. Renin mRNA was readily detected. In human retina, renin was present in active and pro-forms, and the total amount was approximately one fiftieth that of adrenal. CONCLUSION: Renin is synthesized in the retina and is specifically localized to the macroglial Müller cells. Nonpigmented ciliary epithelium also contains renin. The presence of prorenin in the posterior part of the Müller cell, with active renin throughout but notably in endfeet in apposition to retinal capillaries, suggests directional processing of renin. These findings are consistent with earlier suggestions that retinal neovascularization may be associated with Müller cell dysfunction.
Aged↗
[Retinal vasculitis and antiphospholipid antibodies].
Antiphospholipid antibodies (APAb) are often found in systemic lupus erythematosus (LE) (secondary antiphospholipid syndrome), leading to arterial or venous thrombosis. In primary antiphospholipid syndrome other LE-associated symptoms are not detectable. We present the clinical course and therapy of three patients with this rarely reported disease, discussing immunopathology and therapy. Three young patients (28, 29 and 31 years) were seen at the university eye clinic, presenting severe occlusive vasculitis with vitreal haemorrhages and/or thrombosis. The first patient did not respond to any therapy (various immunosuppressives, plasma-pheresis, laser coagulation) and ended up with defective light perception in both eyes. The second patient also had light perception as final outcome in spite of acetylsalicylic acid, steroids and immunosuppression. The third patient established complete reperfusion on an arteriovenous occlusion after haemodilution and acetylsalicylic acid. Antibodies directed against phospholipids interfere with the blood clotting system in many ways (activation and aggregation of thrombocytes, endothelial function, coagulation cascade). The optimal therapy of this severe disease is unclear, suggesting that acetylsalicylic acid seems to be important, while the effect of immunosuppression or steroids is uncertain.
Adult↗
[Choroid rupture, macular hole and subretinal neovessels following contusions].
We present a case of choroidal rupture of the fovea, progressing to a macular hole and sub retinal new vessels. Blunt trauma of the eye ball and the posterior pole can progress years after the initial trauma.
Adult↗
Inhibition of urokinase by 4-substituted benzo[b]thiophene-2-carboxamidines: an important new class of selective synthetic urokinase inhibitor.
Urokinase-type plasminogen activator (uPA) is an important mediator of cellular invasiveness. Specifically, cell surface receptor-bound uPA activates plasminogen to the potent general protease plasmin, which then degrades extracellular matrix or basement membrane either directly or via proteolytic activation of latent collagenases. Thus, cell surface uPA initiates an extracellular proteolytic cascade with which invasive cells eliminate barriers to movement. Since cellular invasiveness plays important roles in several disease states, including cancer metastasis and invasion, arthritis and inflammation, and diabetic retinal neovascularization, the development of synthetic uPA inhibitors is an attractive therapeutic goal. Here we show that 4-substituted benzo[b]thiophene-2-carboxamidines represent an important new class of potent and selective synthetic uPA inhibitor. Two compounds in this class, B428 and B623, inhibit human uPA in plasminogen-linked assays with median inhibition concentration (IC50) values of 0.32 and 0.07 microM, respectively. This level of inhibition represents 20- and 100-fold increases in potency, respectively, relative to the 6-7 microM potencies reported for amiloride and 4-chlorophenylguanidine, the two most potent selective synthetic uPA inhibitors previously described. Importantly, both compounds show > 300-fold selectivity for uPA relative to tissue-type plasminogen activator and > 1000-fold selectivity relative to plasmin. Lineweaver-Burk analyses show uPA inhibition by B428 and B623 to be competitive in nature with inhibition constants (Ki) of 0.53 and 0.16 microM, respectively. Since it is cell surface uPA and not free or secreted uPA that is primarily responsible for cellular invasiveness, biologically effective uPA inhibitors must be capable of inhibiting cell surface uPA. B428 and B623 meet this criterion by inhibiting cell surface uPA on HT1080 human fibrosarcoma cells with IC50 values of 0.54 and 0.20 microM, respectively. Moreover, degradation of [3H]fibronectin by HT1080 cells via cell surface uPA-mediated, plasminogen-dependent mechanisms is inhibited by B428 and B623, with IC50 values of 1.5 and 0.39 microM, respectively. In summary, 4-substituted benzo[b]thiophene-2-carboxamidines such as B428 and B623 represent the most potent class of competitive synthetic uPA inhibitors currently known. Their ability to selectively inhibit both free and cell surface uPA as well as cell surface uPA-mediated cellular degradative functions suggests that this class of compounds may hold significant promise for further development as antiinvasiveness drugs.
Amidines↗
[Surgical treatment of diabetic retinopathy].
Vitrectomy and associated techniques make up the surgical treatment of diabetic retinopathy. Vitrectomy does not replace laser photocoagulations, but greatly enlarges the range of diabetic retinopathy cases which may benefit from a treatment.
Diabetic Retinopathy↗
Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity.
PURPOSE: To assess the role of vascular endothelial growth factor (VEGF) in the feline model of retinopathy of prematurity (ROP). METHODS: Retinopathy of prematurity was induced in neonatal cats by raising them in an oxygen-enriched (70% to 80%) atmosphere for 4 days to suppress vessel formation and then returning them to room air for 3 to 27 days. In situ hybridization was used to detect the expression of VEGF and its high-affinity receptor, flk-1, in the retina of neonatal cats, and glial fibrillary acidic protein immunocytochemistry was used to assess astrocyte status. RESULTS: The expression of VEGF in the innermost layers of retina fell in hyperoxia and increased on return to room air. Vascular endothelial growth factor expression was transient; it was maximal where vessels were about to form, and it rapidly downregulated after vessels had formed. During the proliferative vasculopathy of ROP, VEGF expression was stronger than in the normally developing retina, and the astrocytes that normally express VEGF degenerated. After the degeneration of astrocytes, VEGF was expressed by neurones of the ganglion cell layer. flk-1 was expressed by intraretinal and preretinal vessels. Supplemental oxygen therapy reduced or eliminated the overexpression of VEGF expression, astrocyte degeneration, and formation of preretinal vessels. CONCLUSIONS: Regulation of VEGF by tissue oxygen mediates the inhibition of vessel growth during hyperoxia and the subsequent proliferative vasculopathy. Degeneration of retinal astrocytes creates conditions for the growth of preretinal vessels.
Animals↗
Vasoproliferation in the neonatal dog model of oxygen-induced retinopathy.
PURPOSE: To examine the time course and relative degree of proliferative response associated with revascularization after hyperoxic insult in the dog model of oxygen-induced retinopathy. METHODS: Mitotic cell profiles (MCPs) were counted in serial cross-sections of ADPase flat-embedded retinas of air-reared control 8-, 15-, and 22-day-old dogs and of age-matched oxygen treated animals (4 days, 100% oxygen) after return to normoxia. Sectioning and analysis were performed along the radial axis of the forming primary vasculature from optic nerve head to periphery. RESULTS: In air-reared control animals, lumenal-associated cell mitosis was low, with an average of 9.6 MCPs/mm2 of nerve fiber layer tissue in the 8-day-old dogs, 6.5 MCPs/mm2 in the 15-day-old dogs, and 8.4 MCPs/mm2 in the 22-day-old dogs. In oxygen-treated animals, however, the number of lumenal-associated MCPs was significantly higher, with an average of 52.5 MCPs/mm2 of tissue in the 8-day-old dogs, 45.1 MCPs/mm2 in the 15-day-old dogs, and 26.8 MCPs/mm2 in the 22-day-old dogs. Additionally, extracellular spaces in avascular retina were obliterated in oxygen-treated animals. CONCLUSIONS: This study demonstrates that in the neonatal dog, revascularization after hyperoxic insult involves a period of marked vasoproliferation that peaks somewhere between 3 to 10 days after return to room air. Oxygen-induced changes in the extravascular milieu are likely to affect the pattern of reforming vasculature and may restrict growth anteriorly.
Aging↗
Vascular endothelial growth factor. 20th-century mechanisms, 21st-century therapies.
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Animals↗
[Serum hepatocyte growth factor as a possible indicator of vascular lesions].
To investigate the possible involvement of hepatocyte growth factor (HGF) with vascular lesions, we studied the relationship between serum HGF concentrations and the grades of retinal arteriosclerosis, coronary atherosclerosis, and the proliferative changes in the retina of diabetic subjects. Individuals with more advanced grades of arteriosclerotic change showed higher serum HGF values (grade 0, 0.056 +/- 0.004ng/ml; grade 1, 0.132 +/- 0.026ng/ml; grade 2-3, 0.271 +/- 0.023ng/ml). The serum HGF concentration was increased (p < 0.05) in subjects with double- (0.323 +/- 0.037ng/ml) or triple-(0.345 +/- 0.027ng/ml) vessel coronary heart diseases, as compared to that in subjects with single-vessel coronary heart disease (0.191 +/- 0.027ng/ml). Serum HGF in diabetics without retinopathy was lower than that in nondiabetic subjects (0.041 +/- 0.003ng/ml vs 0.080 +/- 0.010ng/ml, p < 0.05), but did not differ from other diabetic subjects with background retinopathy (0.058 +/- 0.007ng/ml) or preproliferative retinopathy (0.048 +/- 0.010ng/ml). Serum HGF was increased in proliferative retinopathy without photocoagulation (0.138 +/- 0.035ng/ml, p < 0.01), but not with photocoagulation (0.040 +/- 0.008ng/ml). Increased serum HGF may be involved in the pathogenesis of arteriosclerosis/atherosclerosis or retinal neovascularization, and measurement of serum HGF may be a useful test to predict the presence of these vascular lesions.
Arteriosclerosis↗