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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.
PURPOSE: The effects of endothelium-related substances such as acetylcholine, a stimulator of endogenous NO-production, the NO-synthesis inhibitor L-NMMA, the exogenous NO-donor sodium nitroprusside and the endothelin (ET)A-receptor antagonist BQ123, on uveal blood flow were investigated in normotensive and hypertensive SHR rats. METHOD: The radioactively-labelled microsphere method was applied for the measurement of regional blood flow in the uvea. RESULTS: Under resting conditions, local blood flow was lower in the hypertensive animals. The increase in choroidal blood flow (145 +/- 50%; P < 0.01) and reduction in vascular resistance (-58 +/- 7%; P < 0.01) observed in the WKY after i.v. infusion of acetylcholine, 2 micrograms x kg bw-1 x min-1, were significantly less pronounced in animals pretreated with L-NMMA, indicating local formation of NO as a vasodilator mechanism. In contrast, acetylcholine did not induce significant vasodilation in the choroid of SHR rats. In the anterior uvea of both strains, acetylcholine did not affect local blood flow. L-NMMA, 20 mg x kg bw-1, alone reduced blood flow in the entire uvea of both strains. Intravenous injection of BQ123, 1 mg x kg bw-1, did not affect regional blood flow in the uvea of WKY or SHR animals. Infusion of acetylcholine following ETA-receptor blockade induced vasodilation in both the choroid and anterior uvea in the WKY but not in the SHR. CONCLUSIONS: Acetylcholine-stimulated NO-mediated vasodilation, but not basal NO-formation, was impaired in the choroid of the SHR. Furthermore, an interaction between vasoconstricting ET and acetylcholine was found in the anterior uvea of normotensive but not hypertensive rats.
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.
The expression of MHC Class I and Class II antigens was investigated in the human uvea using monoclonal antibodies in an indirect immunofluorescence technique. The anterior border layer of the iris, the non-pigmented and pigmented epithelium of the ciliary body, the external basement membrane of the ciliary body and the vascular endothelium in the uvea showed a positive staining for Class I antigens. The endothelium lining the bloodvessels in the uvea expressed the highest density of Class I antigens. Class II antigens were found only on single cells spread throughout the entire uvea. These cells did not seem to relate to any anatomical entity. No staining for Class II antigens was detected in the uveal blood vessel endothelium. The expression of HLA-antigens in the uvea may provide insight in the pathogenesis of certain HLA associated uveitis entities.
The ability of rabbit conjunctiva and anterior uvea to synthesize lipoxygenase products was assessed. Using autoradiographic techniques, we demonstrate that rabbit anterior uvea synthesizes 5 and 12 lipoxygenase products such as 12-HETE, 5-HETE and 5,12-DiHETE and cyclooxygenase product HHT from 14C-arachidonic acid. Indomethacin pretreated conjunctiva and anterior uvea generated slow reacting substance (SRS)-like activity from arachidonic acid in the presence of reduced glutathione and A23187. This SRS-like activity contracted guinea pig ileum. Specific SRS-like activity antagonist FPL-55712 inhibited the contractions of guinea pig ileum induced by SRS-like substance generated by either conjunctiva or anterior uvea. The activity was still present in the sample following extraction with organic solvents. SRS-like activity was destroyed by arylsulfatase and its generation was prevented by either boiling or pretreatment with cyclooxygenase/lipoxygenase inhibitors, BW755 and nordihydroguaiacetic acid. These results indicate that following cyclooxygenase inhibition by indomethacin rabbit conjunctiva and anterior uvea generate SRS-like activity from arachidonic acid via lipoxygenase pathways.
The neuropeptide galanin has not been localized previously in the primate uvea, and the neuropeptide somatostatin has not been localized in the uvea of any mammal. Here, the distribution of galanin-like and somatostatin-like immunoreactive axons in the iris, ciliary body and choroid of macaques and baboons using double and triple immunofluorescence labeling techniques and confocal microscopy was reported. In the ciliary body, galanin-like immunoreactive axons innervated blood vessels and the ciliary processes, particularly at their bases. In the iris, the majority of these axons was associated with the loose connective tissue in the stroma. Somatostatin-like immunoreactive axons were found in many of the same areas of the uvea supplied by cholinergic nerves. In the ciliary body, there were labelled axons within the ciliary processes and ciliary muscle. They were also found alongside blood vessels in the ciliary stroma. In the iris, somatostatin-like immunoreactive axons were abundant in the sphincter muscle and less so in the dilator muscle. A unilateral sympathectomy had no effect on the distribution of somatostatin-like or galanin-like immunoreactive axons, and these axons did not contain the sympathetic marker tyrosine hydroxylase. They did not contain the parasympathetic marker choline acetyltransferase, either. The galanin-like immunoreactive axons contained other neuropeptides found in sensory nerves, including calcitonin gene-related peptide, substance P and cholecystokinin. Somatostatin-like immunoreactive axons did not contain any of these sensory neuropeptides or galanin-like immunoreactivity, and they were neither labelled with an antibody to 200kDa neurofilament protein, nor did they bind isolectin-IB(4). Nevertheless, they are likely to be of sensory origin because somatostatin-like immunoreactive perikarya have previously been localized in the trigeminal ganglion of primates. Taken together, these findings indicate galanin and somatostatin are present in two different subsets of sensory axons in primate uvea.
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.
PURPOSE: Ample evidence is available demonstrating that cytokines play a pivotal role in the pathogenesis of uveitis. Because little is known concerning the site of cytokine synthesis in the eye, cytokine mRNA expression was analyzed in the uvea, retina, and cornea during endotoxin-induced uveitis (EIU) in the rat. METHODS: RNA was isolated from the iris, ciliary body, choroid-sclera, retina, and cornea at different points in time after foot-pad injection of 200 micrograms lipopolysaccharide (LPS) in Lewis rats. Reverse-transcription polymerase chain reaction analysis was used to determine tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), IL-6, IL-10, interferon gamma (IFN-gamma), monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and IL-1 receptor antagonist (IL-1RA) mRNA expression. RESULTS: Maximal mRNA expression of all cytokines examined already was observed in the uvea 4 hours after systemic LPS injection, before the onset of clinical uveitis. Elevated expression of TNF-alpha, IL-1 beta, IL-6, IFN-gamma, MCP-1, and MIP-2 was also observed concomitant with maximal uveitis, at 22 to 24 hours. Except for IL-10 and IFN-gamma, all cytokines investigated were induced in the retina, with maximal expression at 22 to 24 hours. Expression of IL-1RA was detected in the uvea and retina at 4 hours and remained elevated up to 48 hours, when the clinical uveitis started to decline. LPS did not induce cytokine expression in the cornea. Strikingly, a considerable expression of IL-1RA was found in normal corneas, suggesting an inherent control mechanism for IL-1-mediated responses. CONCLUSIONS: Systemic LPS injection induces elevated mRNA expression of multiple cytokines and IL-1RA in the uvea and retina during various stages of EIU. This suggests that these mediators may contribute to the development and recovery of this intraocular inflammation.
OBJECTIVE: To report on frequency, time of occurrence, treatment, and final outcome of rhegmatogenous retinal detachment after block excision, combined with corneoscleral tectonic grafts, of intraocular epithelial implantation cysts and tumors of the anterior uvea involving the anterior chamber angle. DESIGN: Noncomparative case series. PARTICIPANTS: The study included 144 patients who had consecutively undergone scleral full-thickness block excision of tumors of the anterior uvea (n = 87) or intraocular epithelial implantation cysts (n = 57). Diameter of the block excision ranged between 5.5 and 20 mm. In 39 patients, the tumor extended posterior to the ora serrata. INTERVENTIONS: Retinal detachment surgery. MAIN OUTCOME MEASURES: Retinal detachment rate, visual acuity, risk factors. RESULTS: Retinal detachment occurred in 10 (6.9%) of 144 patients (2 of 57, or 3.5% of patients with cysts; 8 of 87 or 9.2% of patients with tumors) 3 to 12 months after block excision. Six patients underwent primary pars plana vitrectomy with temporary endotamponade by silicone oil, which was removed 3 to 9 months later. In four patients, a scleral buckling procedure only was performed. After a mean follow-up of 31 months after silicone oil removal or the buckling procedure (median, 30 months; range, 13-42 months), the retina has remained attached in all patients operated on. Visual acuity increased from 2/20 (median; range, light perception-6/20) to 8/20 (median; range, 2/20-12/20). In the eyes with retinal detachment compared to the eyes without retinal detachment, the block excision was significantly larger (13.75+/-4.86 mm vs. 9.41+/-3.02; P = 0.01) and was located significantly more posteriorly (limbus distance of posterior excision margin: 6.75+/-2.87 vs. 4.35+/-3.24 mm; P = 0.01). CONCLUSIONS: Scleral buckling procedures and primary pars plana vitrectomy with temporary ocular endotamponade can give acceptable results in eyes with rhegmatogenous retinal detachment occurring after block excision of epithelial implantation cysts or tumors of the anterior uvea. Despite intraoperative vitreous prolapse or tumor extension posterior to the ciliary body, rhegmatogenous retinal detachment occurs in fewer than 10% of patients undergoing block excision of cysts or tumors of the anterior uvea. Size and posterior location of the block excision are the main risk factors for rhegmatogenous retinal detachment, which becomes unlikely later than 12 months after surgery.
In vitro accumulation of radioactive para-aminohippuric acid (3H-PAH) and rubidium (86Rb+) by the anterior uvea, ciliary processes, and the choroid plexus was evaluated in tissues from newborn and various aged rabbits. Accumulation of PAH was present in the anterior uvea at 1 day of age (tissue to media ratio, T/M, of 2.1 +/- 0.2) and remained at this level for the first 14 days of life. Accumulation did not rise to adult levels until 21 days of age (T/M 5.5 +/- 0.6). Rubidium accumulation in the anterior uvea, a measure of Na+, K+-pump activity, was higher than adult values 6 hr after birth (T/M25.2 +/- 0.9). Activity remained elevated through day 28 and did not fall to adult levels until day 60 (T/M 13.4 +/- 0.6). Accumulation studies on isolated ciliary processes were similar to those obtained from anterior uveal tissue. Daily subcutaneous injections of penicillin (300,000 units/kg/day) for 1 week had no effect on anterior uvea PAH accumulation (penicillin T/M was 1.7 +/- 0.1 and saline control T/M was 2.0 +/- 0.2). Accumulation of either 3H-PAH or 86Rb+ by the choroid plexus was present 1 day after birth in amounts that were similar to adult values and did not change during the 90 days of testing.
We present nine patients with unilateral congenital ectropion uveae (hyperplasia of the iris pigment border), iris hypoplasia, characteristic gonioscopic findings, and glaucoma. A majority of these patients also demonstrated mild ptosis. In none of these patients were there any associated systemic abnormalities. The apparent ectropion uveae results from spread of the iris pigment epithelium beyond the iris ruff and onto the anterior surface of the iris. In two patients with this abnormality, histopathologic and electron microscopic findings are presented. All patients with congenital ectropion uveae should be carefully examined periodically to detect glaucoma.
The presence of vasoactive intestinal polypeptide (VIP)-like immunoreactivity, especially in the anterior part of the guinea pig uvea, was studied using an indirect immunofluorescence technique. In the ciliary body, thin varicose VIP fibers displaying VIP immunoreactivity were observed in the ciliary muscle and in the ciliary processes. The iris was virtually free of VIP fibers. In the choroid, VIP-immunoreactive fibers were seen mainly in close association with the choroidal blood vessels. The histochemical localization of VIP-immunoreactive fibers in the anterior uvea suggests that the physiological role of neuronal VIP in the uvea is not only associated with the regulation of the blood flow of the choroid but also with the functions of ciliary muscle and ciliary epithelium.
Arachidonic acid is metabolized into biologically active prostaglandins, thromboxanes, and lipoxygenase products, leukotrienes. In the present study, the ability of human anterior uvea to synthesize lipoxygenase products from 14C-radiolabelled arachidonic acid is assessed. Following cyclooxygenase inhibition by indomethacin, human anterior uvea, similar to rabbit conjunctiva and anterior uvea, synthesizes chemotactic products 12-hydroxyeicosatetraenoic acid (HETE) and 5,12-DiHETE, indicating the presence of both 5- and 12-lipoxygenase enzyme activities.
Primary congenital ectropion uveae is an extremely rare ocular malformation frequently associated with unilateral glaucoma. We report on a 15-year-old boy with unilateral congenital ectropion uveae, glaucoma and transvitreal strands in an optically empty vitreous. Dark adaptation was normal, but scotopic ERG showed subnormal b-wave amplitudes in the affected eye, which is a typical finding in hereditary vitreoretinal degenerations. The coincidence of primary congenital ectropion uveae and unilateral vitreoretinal degeneration without a family history seems to be sporadic and very extraordinary but could be due to a common defect of maturation.
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 article details a previously undescribed complication of trabeculotomy occurring in a patient with congenital ectropion uvea and discusses its possible association with an anterior chamber membrane. A 6-year-old boy with congenital ectropion uvea underwent trabeculotomy. After the trabeculotome was swept into the anterior chamber, multiple ovoid and round endothelial and posterior stromal opacities developed in the cornea, and new areas of iris surface irregularities appeared. This is the first reported case of corneal endothelial and iris changes occurring in a patient with congenital ectropion uvea after trabeculotomy without direct endothelial or iris contact from the trabeculotome. The exact cause of these changes is unknown.
The inflammatory cell reaction within the vitreous and uvea of a human eye with atypical sympathetic ophthalmia was studied immunohistologically and with the fluorescence-activated cell sorter. The uveal infiltrate consisted predominantly of T cells of the helper/inducer subset, with less than 5% of the cells characterized as B cells, plasma cells, or monocytes. These results suggest that T cells perform an important role in atypical human sympathetic ophthalmia. A similar population of mononuclear cells was observed in the vitreous inflammatory infiltrate, in marked contrast to the peripheral blood, where there was a significant depression of circulating T cells. The similarity between the inflammatory cell populations within the vitreous cavity and uvea, in contrast to the peripheral blood, underlines the importance of studying the intraocular inflammatory reaction in uveitis to gain further insight into the mechanism of this disease.