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It has been demonstrated that normal, uninflamed, anterior uvea and conjunctiva of different species have the capacity to synthesize cyclooxygenase and lipoxygenase products. Cyclooxygenase activity is greater than lipoxygenase activity in both anterior uvea and conjunctival tissues. Other ocular tissues such as cornea, lens, and retina were found to have much lesser capacity than the conjunctiva and anterior uvea to synthesize cyclooxygenase and lipoxygenase products from arachidonic acid. In our preliminary studies, we also observed that human retina have considerably less ability to metabolize AA into cyclooxygenase and lipoxygenase activity. The finding that the anterior uvea of all species studied has a high capacity to synthesize PGs and other cyclooxygenase products maybe of particular physiological significance since several investigators have demonstrated that PGE2 and PGF2 alpha in low doses, lower intraocular pressure in all species studied, including the human eye. Additionally, PGE2 can be shown to have some anti-inflammatory effects. In light of these observations, we must consider that the high endogenous cyclooxygenase activity in normal conjunctiva and anterior uvea may play a role in maintaining normal intraocular pressure and in preventing the development of inflammation in response to normal environmental stimuli. Arachidonic acid is also metabolized into biologically active compounds by cytochrome P450 in corneal endothelium. It is not yet known whether or not other ocular tissues also have the ability to metabolize arachidonic acid via this pathway and whether these compounds, when synthesized from endogenous arachidonic acid stores in vivo have any biological effects on the eye. Studies on omega-3 fatty acid metabolism were done for two main reasons: (1) PGE3 and PGD3 lowered intraocular pressure without causing ocular inflammation in rabbit; and (2) some surveys demonstrated that in Greenland Eskimos whose marine diet is enriched with omega-3 substrate eicosapentaenoic acid, have a lower incidence of open-angle glaucoma as compared to Caucasians, whose diet is rich in arachidonic acid. The ability of anterior uvea to synthesize PGE3 and PGD3 in human, monkey, and rabbit anterior uvea warrants further investigation to determine whether or not these omega-3 PGs play a role in lowering intraocular pressure.
With the use of monoclonal antibodies in an indirect immunofluorescence technique we studied the distribution of Class I (HLA-ABC and B27) and Class II (HLA-DR) antigens in the human uvea. W6/32, directed against the core of HLA-ABC antigens, was used to study the distribution of Class I antigens. The anterior border layer of the iris, the non-pigmented and pigmented epithelium and the external basement membrane of the ciliary body and the vascular endothelium in the uvea showed a positive staining for Class I antigens. B27/M1, directed against an epitope of the HLA-B27 antigen, and the control antibody A11/Aw24, which was directed against an epitope of HLA-A11, revealed the same distribution pattern in respectively HLA-B27 and HLA-A11 positive donor eyes. The intensity of their staining was much weaker than the staining with W6/32. Class II antigens were studied with OkIa1, an antibody directed against the core of HLA-DR antigens. HLA-DR antigens were detectable on single cells scattered throughout the entire uvea. These cells did not seem to relate to any anatomical entity. No staining for Class II antigens was seen in the uveal blood vessel endothelium. The expression of HLA-antigens in the uvea is compatible with the distribution in other tissues. These findings suggest that the expression of HLA-B27 in the human uvea does not explain why the eye is one of the target tissues in HLA-B27 associated disease.
Renal cortex, anterior uvea, lateral choroid plexus and terminal ileum accumulate -14C-cholate, glycocholate, deoxycholate and chenodeoxycholate to considerable tissue/medium ratios. Iodipamide partly inhibits accumulation by kidney, uvea and plexus but not ileum. In renal cortex the sensitive part is similar to 10, 60 and 90 percent for dihydroxy acids, cholate and glycocholate respectively. Hippurate depresses uptake in kidney and uvea but hardly in plexus. Simultaneous uptake by renal cortex and uvea of -14C-cholate or glycocholate, -125I-iodipamide and -131I-o-iodohippurate was studied with unlabelled iodipamide and hippurate as inhibitors. The concentration-dependence of the inhibition required the assumption of 4 partly overlapping iodipamide-sensitive transport systems handling the 4 test substances: the hippurate (H)-system, one moderately (L(1)) and one very hippurate-resistant (L(2)) part of the liverlike L-system and a fourth system called BS, more evenly inhibitable by iodipamide and hippurate than the others. The L(2)-system carries iodipamide but very little bile acids. No iodipamide-sensitive system clearly specialized for bile acid transport was found. The systems have only moderate affinity for bile acids and probably treat them just as large organic anions. A new mathematical procedure to test the degree of complexity of composite transport systems without kinetic assumptions was used.
Neovascularization of the iris (NVI) is one of the most frequently studied intraocular vascular proliferations in animal models. Ectropion uveae has not been a consistent finding in these studies. In this study, a surgical model of ectropion uveae and iris neovascularization was developed that involved lensectomy, vitrectomy, bipolar cautery and transection of all three principal branch veins in the cat eye. Twelve of 14 eyes that received this procedure developed postoperative retinal detachments with a clinical picture of hemorrhagic retinopathy. These eyes progressed to a clinical picture of NVI within 1-7 wk. Eight eyes developed ectropion uveae for as much as 300 degrees. At the light microscopic level, a fibrovascular membrane was apparent on the anterior iris stroma in 9 of 14 eyes and further involved the angle in six eyes.
This lecture summarizes studies on the effects of some of the neuropeptides which seem to be present in somatosensory and autonomic nerves in the uvea. Release of these peptides is likely to explain nerve induced effects in the eye which are not due to classical transmitters. Trigeminal nerve fibres in the eye seem to contain substance P (SP), calcitonin gene-related peptide (CGRP), and cholecystokinin (CCK), parasympathetic nerve fibers from the facial nerve seem to contain vasoactive intestinal polypeptide (VIP), and peptide with histidine and isoleucine terminals (PHI), and sympathetic nerves seem to contain neuropeptide Y (NPY). Retrograde trigeminal nerve stimulation in rabbits causes hyperemia, miosis, a breakdown of the blood-aqueous barrier to plasma proteins and a rise in intraocular pressure (IOP). There is release of SP and CGRP or related peptides. The miosis seems to be due to SP and the other effects to CGRP and small amounts of arachidonic acid metabolites released by the peptides. SP has no miotic effect in monkeys and cats. However, CCK is a potent miotic in monkeys and causes contraction of the human pupillary sphincter muscle. It has no such effect in the lower species. The effect of CCK in primates seems to derive from the presence of CCK receptors of the A-type on the pupillary sphincter muscle, and can be blocked by lorglumide. Miosis can be produced in cats by the peptide endothelin; this effect is due to release of arachidonic acid metabolites. Facial nerve stimulation causes vasodilation in the uvea of rabbits, cats and monkeys. The effect cannot be abolished by muscarinic blocking agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Phthisical eyes of 2 patients revealed clinically unsuspected, partially necrotic and partially vital malignant melanomas of the uvea and extensive intraocular ossification. Both eyes had had recurrent intraocular inflammatory episodes for years before they were enucleated because of pain. Intraocular ossification does not rule out the presence of clinically unsuspected malignant melanoma of the uvea.
After sympathectomy we have studied the re-appearance of nerve fibers showing catecholaminergic characteristics in the uvea of the guinea pig. Immunoreactivities for two catecholamine symthetizing enzymes, tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), were used as markers. Both TH-like and DBH-like immunoreactive nerve fibers disappeared after the extirpation of ipsilateral superior cervical ganglion. In the choroid the TH-like and DBH-like immunoreactive nerve fibers re-appeared within 2 weeks. In the iris and the ciliary body both of these types of immunoreactive nerve fibers re-appeared 10 weeks after the denervation. The morphological appearance of these re-appearing nerve fibers was not similar to those in the non-denervated uvea.
The capacity of cynomolgus and rhesus monkey conjunctiva, anterior uvea and eyelids to synthesize cyclo-oxygenase and lipoxygenase products from arachidonic acid was assessed. Both conjunctiva and eyelid tissues of cynomolgus and rhesus monkeys synthesized detectable amounts of cyclo-oxygenase and lipoxygenase products, indicating the presence of cyclo-oxygenase and 5- and 12-lipoxygenase activities in these tissues. In comparison, cynomolgus anterior uvea synthesized a considerably lesser amount of cyclo-oxygenase products. The cyclo-oxygenase activity was considerably greater than the lipoxygenase activity in cynomolgus and rhesus conjunctiva and eyelids.
Transport of timolol and befunolol in the anterior uvea of the albino rabbit was studied in vitro. Also, the mode of timolol elimination from the living eye was investigated. The isolated iris-ciliary body incubated at 37 degrees C accumulated 14C-timolol and 14C-befunolol against the concentration gradient, and the tissue-to-medium ratio was 5.45 +/- 0.29 and 5.46 +/- 0.44, respectively. The accumulation of both drugs was significantly suppressed by incubation at 0 degrees C and also by pretreatment with ouabain or cyanine but not with probenecid. The relationship between the initial velocities of accumulation and medium drug concentrations conformed with saturation kinetics, indicating the presence of mediated transport of these drugs. The apparent Km was 1.08 X 10(-6) mole per liter for timolol and 8.00 X 10(-7) for befunolol, and the Vmax was 5.46 X 10(-9) mole per g per hour for timolol and 1.52 X 10(-8) for befunolol. A mixture of 14C-timolol and 3H-sucrose was injected into the center of the vitreous cavity of the living rabbit. Timolol was lost from the vitreous at a rapid rate of about 36% per hour, while sucrose was lost very slowly, at about 5% per hour. Thus it was thought that an energy-requiring carrier-mediated transport system is operative in the anterior uvea of the albino rabbit, and that this would account for the rapid removal of the beta-blockers out of the eye.
A murine model has been developed to study the role of immunoglobulin charge in the regulation of the intraocular distribution of circulating IgG antibodies. Intravenously injected cationic antibodies to the tracer enzyme horseradish peroxidase bind within the ciliary body and choroid (CB/Ch). These cationic antibodies can selectively entrap and bind circulating antigens forming immune complexes (IC) within the uveal tissues. The structure of the uvea with its fenestrated CB/Ch capillaries and fixed anionic sites (within Bruch's membrane and the stroma of the CB and processes) may predispose the CB/Ch to in situ IC formation. Local IC formation mediated initially by deposition of cationic antibodies within the uvea may play an important role in the immunopathogenesis of some forms of uveitis.
In the present study, the presence and localization of mast cells and the intraocular effects of compound 48/80 have been studied in detail in the rabbit eye using histochemical and physiological methods. In histochemical studies mast cells were localized in the anterior uvea, especially in the ciliary and iridial processes. Intracamerally injected, compound 48/80 caused an increase in the intraocular pressure, disruption of the blood-aqueous barrier and an increase in the cAMP content in the aqueous humour. Miosis was observed only after higher doses of compound 48/80 (greater than 100 micrograms) and even then only one-half of the eyes responded. The intraocular effects, excluding miosis, of compound 48/80 resembled an on/off-type of response, where 20 micrograms caused only minor changes, if any, and 50 micrograms gave a maximal response. The ocular hypertensive reaction developed a tachyphylaxis so that the second and third consecutive dose of compound 48/80 (100 micrograms) produced no significant change in IOP. The results indicate that mast cells, which are present in the anterior uvea in an extent not known previously, might be involved in certain inflammatory reactions in the rabbit eye. The inconsistent and slight miosis after the intracameral application of compound 48/80 indicates that the mechanism is different from that caused by sensory nerve stimulation. The rapid development of tachyphylaxis after consecutive application of compound 48/80 suggests that mast cells are easily depleted which might be useful for further studies to evaluate the functional role of mast cells in different pathophysiological conditions in the rabbit eye.
Although metastatic cancer to the uvea is reported to be the most common intraocular malignancy, most ophthalmologists have had little experience with its diagnosis and treatment. This report describes our experience with the diagnosis and management of 70 patients with metastatic cancer to the uvea. Many patients were evaluated with modern diagnostic modalities such as fluorescein angiography, ultrasonography, and the 32P test when indicated. Thirty-one percent of patients had no history of previous malignancy, and the ocular complaints represented the first symptoms of systemic cancer. The ocular malignancy often simulated better-known ophthalmic entities, and the referring diagnosis was correct in only 38% of cases. This series, therefore, reflects the clinical problem confronting the practicing ophthalmologist. About one-half of the patients were treated with external beam irradiation to the involved eye(s), which often resulted in dramatic resolution of the tumor and visual return. Other patients had either no treatment, chemotherapy, or enucleation in selected instances.
Between 1983 and 1986, six eyes with diffuse malignant melanomas of the anterior uvea were enucleated at the Eye Hospital of the University of Erlangen-Nürnberg. The characteristic clinical findings were a monolateral open-angle glaucoma in the same eye and a diffuse spreading of malignant melanocytes on the inner walls of the anterior chamber. These cells can be differentiated biomicroscopically (40 x magnification, Zeiss slit-lamp) from melanin granula and benign melanocytes. Findings in two patients show that individual cells can be biocytologically classified in this way. Malignant cells are characterized by large, prominent nuclei and long cytoplasmic processes. Biocytological evaluation of individual melanocytic cells can be helpful in the differential diagnosis of melanocytic processes of the anterior uvea.
A 76-year-old patient developed cystic exudative retinal detachment with many yellowish subretinal precipitates and a large retinal pigment epithelial (RPE) tear in midperiphery of the right eye in the course of polyclonal hypergammaglobulinemia. The left eye showed localized RPE detachment in the posterior pole which gradually extended. Systemic steroid administration reduced the subretinal precipitates to some extent, but suspicion of malignancy led to enucleation of the right eye after unsuccessful diagnostic vitrectomy. A histopathological study revealed massive infiltration of the uvea with plasma cells and small lymphocytes but no abnormal cells. This is the first report to show the association of an RPE tear with reactive lymphoid hyperplasia of the uvea.
The management of malignant melanomas of the posterior uvea recently has become a topic of great controversy. The traditional treatment by enucleation of the tumor-containing eye has recently been challenged by a number of authorities, and clinicians more frequently are using alternative methods of management when possible. Current management can range from periodic observation and fundus photography of selected small lesions that appear dormant, to photocoagulation, radiotherapy, or local resection in the case of growing tumors in eyes with useful or salvageable vision. In cases where the tumor is far advanced and there is no hope of useful vision, enucleation is often inevitable. The choice of therapy is a complex issue and each case must be individualized. In selecting a therapeutic approach certain factors must be carefully weighed. These include the size of the melanoma, its extent and location, its apparent activity, the condition of the opposite eye and the age, general health, and psychological status of the patient. Based on personal experience with approximately 3000 cases, the authors discuss their current indications for the various therapeutic techniques for posterior uvea melanomas.
A patient with Prader-Willi syndrome and unilateral congenital ectropion uveae with glaucoma was found to have factor XI deficiency and reduced levels of serum luteinizing hormone, follicle-stimulating hormone, and testosterone. Administration of gonadorelin (LH-RH) increased serum levels of luteinizing hormone and follicle-stimulating hormone, while clomiphene citrate had no effect, suggesting a primary hypothalamic defect. Patients with congenital ectropion uveae should be followed up for the development of both glaucoma and neural crest disorders.
The uveal tract of the eyes of monkeys was examined by electron microscopy using both thin sections and freeze-fracture replicas. The ultrastructural features of the lamina fusca in the monkey resembled those previously described for rabbit. The lamina fusca was composed of numerous interleaved processes of fibroblastic and pigmented cells and contained tight junctions between fibroblastic cell processes that were predominantly discontinuous, as well as numerous fenestrations through the attenuated cell processes. There was no regional compaction of cellular processes traversing the entire uvea at the level of the ora serrata as reported previously in hamster eyes.