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J R Polansky

Publications and source records attributed to J R Polansky.

At least 55 records · Page 3Linked to original sources

Proteins secreted by human trabecular cells. Glucocorticoid and other effects.

The capacity of cultured human trabecular meshwork (HTM) cells to secrete an extracellular matrix was studied by indirect immunofluorescence. Synthesis of nine extracellular matrix (ECM) proteins known to be present in the normal trabecular meshwork was assessed in three HTM cell lines. Fourteen primary antibodies were used and cultures were labeled two and four weeks after confluence. The HTM cell lines showed consistent labelling patterns for the normal extracellular connective tissue constituents including collagens (types I, III, IV, V and VI), glycoproteins (laminin and fibronectin) and a basement membrane-associated proteoglycan. These antigens were localized to the basal cell surface in an extracellular reticular pattern corresponding to cell margins. Dextran addition at confluence helped to intensify the staining of these components, but ascorbate had no apparent effect. Interestingly, elastin, another normal component of the trabecular meshwork, was not identified under standard conditions, or after addition of ascorbate or dextran. However, elastin could be detected intracellularly following dexamethasone treatment for three days, and extracellularly in punctate deposits when this treatment was used for 1 or 2 weeks. Our findings indicate that HTM cells may be responsible for the secretion and maintenance of all the major ECM constituents of the trabecular meshwork. The elastin results suggest a possible mechanism contributing to obstruction of outflow in steroid glaucoma if increased amounts of elastin are also produced in vivo. This approach can also serve as a useful baseline for comparison with HTM cell lines treated with glaucoma medications or obtained from patients with glaucoma.

Antibodies↗

Tissue plasminogen activator in cultured human trabecular meshwork cells. Predominance of enzyme over plasminogen activator inhibitor.

Maintenance of patency of the trabecular meshwork, the major outflow channel of the anterior chamber of the eye, is necessary to prevent an excessive rise in intraocular pressure. Obstruction of flow due to clot formation results in severe glaucoma and damage to the optic nerve. We have found that human trabecular meshwork cells which have been passaged in tissue culture synthesize large amounts of tissue plasminogen activator (t-PA), based on functional, immunologic and molecular weight analysis. Trabecular cells express substantially more t-PA activity than vascular endothelium which produces t-PA for clot dissolution in the systemic circulation. Vascular cells produce excess t-PA inhibitor while trabecular cells make comparatively little. Trabecular meshwork cells are the first normal cell type reported in which the balance between t-PA and inhibitor is weighted towards the activator, indicating that fibrinolysis may be more important than clotting in the anterior chamber of the eye.

Cells, Cultured↗

Arachidonic acid metabolism in human trabecular meshwork cells.

Prostaglandins and other eicosanoids in the trabecular meshwork may play important physiological and pharmacological roles in the aqueous outflow pathway. In the present studies, we employed [14C]-arachidonic acid to explore potentially important pathways for the production of eicosanoids in cultured human trabecular meshwork cells (HTM). In these cells, we demonstrated that prostaglandin E2 (PGE2) and PGF2 alpha are major cyclooxygenase products, with some 6-keto-PGF1 alpha also detected. The amount of radiolabelled PGE2 formed was substantially higher than the PGF2 alpha formed in the early time periods. The amount of PGF2 alpha in the culture media increased at a time when the amount of PGE2 was declining, suggesting a possible metabolic conversion between the prostaglandins. HTM produced a range of products of the lipoxygenase pathway. Products co-eluting with 5, 12, and 15-hydroxyeicosatetraenoic acids (HETEs) were detected, with 12 and 15-HETEs predominating. A large amount of radiolabelled product was detected also in peaks co-eluting with leukotriene B4 (LTB4) and an LTB4 degradation product. Biosynthesis of lipoxygenase products was markedly inhibited by BW 755c and partially inhibited by dexamethasone. These data emphasize that HTM cells are capable of converting arachidonic acid into a wider variety of biologically active products than previously recognized.

Arachidonic Acid↗

Trabecular meshwork cells grown on filters. Conductivity and cytochalasin effects.

A system was developed to measure the hydraulic conductivity of cultured monolayers of human trabecular meshwork (HTM) cells. By optimizing the cell growth conditions and evaluating a number of filter supports, confluent HTM cells in single layers were obtained for measurement of hydraulic conductivity. The HTM monolayers had hydraulic conductivities of 0.3-2.0 microliters/min/mm Hg/cm2 measured at near-physiological flow rates. Evaluations of cytochalasin B (CB) effects on the hydraulic conductivity of our HTM monolayers revealed that CB (10(-6) to 10(-5) M) caused a dramatic dose-related increase in conductivity within 10 to 30 min, which parallels CB effects on outflow facility in vivo. Morphologic observations show that the increase in hydraulic conductivity was accompanied by a retraction of the trabecular cells and widening of the intercellular spaces. Our findings suggest that growth of HTM cells on filter supports can provide a useful in vitro system to study the regulation of aqueous outflow.

Adult↗

Dissociation of cholinergic supersensitivity from receptor number in ciliary muscle.

Ciliary ganglionectomy in the cynomolgus monkey produced loss of the accommodative response to electrical stimulation of the Edinger-Westphal nucleus and to topical eserine, concurrent with enhanced responsiveness to topical and systemic pilocarpine. This supersensitivity produced by parasympathetic denervation was not associated with an increase in muscarinic receptor number or affinity measured using specific QNB binding sites in ciliary muscle homogenates. In seven of ten cases, ciliary muscle muscarinic receptors were decreased by 60-84%, while in the remaining three cases, the decrease ranged from 12-37%. In no case was supersensitivity accompanied by an increased number of receptors. Six or more months after ganglionectomy, accommodative responses to central electrical stimulation and topical eserine returned to normal in most animals, indicating parasympathetic reinnervation of the ciliary muscle. Ciliary muscle sensitivity to pilocarpine returned to normal with reinnervation and was associated with recovery of normal receptor number and with normal binding affinity.

Accommodation, Ocular↗

Cholinergic drugs alter ciliary muscle response and receptor content.

Topical echothiophate administration to the cynomolgus monkey eye for 5-6.5 months produced marked subsensitivity of the accommodative response to pilocarpine and a 65% decrease in specific high affinity 3H-QNB binding sites (ostensibly indicating muscarinic receptors) in the ciliary muscle. The decrease in 3H-QNB binding sites was quantitatively similar in surgically untouched, totally iridectomized, and ciliary muscle disinserted eyes. Following a 5-month off treatment recovery period, 3H-QNB binding sites increased to more than twice the number in untreated control eyes. In echothiophate-treated eyes whose contralateral eyes had previously received atropine+echothiophate, 3H-QNB binding sites were three to six times more numerous than in other long-term echothiophate-treated eyes, and one to two times more numerous than in untreated controls. Topical pilocarpine administration for 1 day to 7 months reduced ciliary muscle 3H-QNB binding sites by approximately 25%. Alterations in muscarinic receptors during and following cholinergic drug therapy may in part explain the observed subsensitization and recovery of ciliary muscle physiological responses.

Accommodation, Ocular↗

Isopilocarpine binding to muscarinic cholinergic receptors.

Isopilocarpine coexists with pilocarpine in nature, and it is present in varying degrees in commercial pilocarpine preparations. Using muscarinic cholinergic receptors from bovine ciliary muscle tissue, we measured the relative binding affinity of isopilocarpine and pilocarpine. The binding affinity of isopilocarpine was approximately one-tenth that of pilocarpine. Because of the relatively low concentration of isopilocarpine found in commercial pilocarpine preparations, and the low binding affinity of isopilocarpine for the muscarinic receptors, the practical effect of isopilocarpine contamination is small.

Animals↗

The cytoskeleton of the cynomolgus monkey trabecular cell. II. Influence of cytoskeleton-active drugs.

The effects of cytochalasin B (10(-6) M and 10(-5) M), taxol (10(-5) M), and colchicine (10(-5) M) on the cytoskeleton of cynomolgus monkey trabecular cells were examined with Nomarski observations, fluorescent labeling as well as extraction, S-1 labeling, and critical-point drying. Changes in actin, microtubules, and intermediate filaments, the three major cytoskeletal systems, were correlated with changes in the overall shape and organization of the monkey trabecular cell. Incubation with cytochalasin B caused a marked alteration on actin filament structure, as well as cell shape and cytoskeletal organization. Effects on microtubule structure were noted with taxol, nocodozole, or colchicine; however, no marked changes in overall cell shape or other cytoskeletal structures were observed. These studies demonstrate the importance of actin filaments in regulating the shape and cytoskeletal organization of cynomolgus monkey trabecular cells.

Actins↗

Isolation and evaluation of target cells in glaucoma research: hormone receptors and drug responses.

To investigate the actions of drugs and hormones which influence intraocular pressure (IOP), we have been measuring receptor binding characteristics and dose-response effects using individual target cells from the anterior segment. Similar methods have also permitted us to develop sensitive radio-receptor assays for glucocorticoids and beta adrenergic antagonists. These methods provide a means to obtain new and potentially useful information regarding the efficacy and specificity of ocular drug therapy.

Animals↗

Adrenergic and cholinergic receptors in isolated non-pigmented ciliary epithelial cells.

Methods were developed to isolate non-pigmented ciliary epithelium from bovine eyes (BCBE) free from other cell types in the ciliary process. Once background binding due to pigment was minimized, it was possible to assay specific beta adrenergic receptors in these preparations. The BCBE beta adrenergic receptors showed appropriate stereospecificity and an order of binding affinities compatible with a beta 2 adrenergic selectivity. Interestingly, specific high affinity muscarinic cholinergic receptors were detected in both BCBE and primate non-pigmented ciliary epithelium. These muscarinic receptors showed an appropriate affinity and selectivity for agonists and antagonists. Further evaluations of the receptors and responses of non-pigmented ciliary epithelial cells may prove useful in understanding the effects of adrenergic and cholinergic agents on aqueous humor inflow.

Animals↗

Acute effects of dexamethasone on intraocular pressure in glaucoma.

The effects of 3 mg orally administered dexamethasone on the intraocular pressure (IOP) were examined in four patients with primary open-angle glaucoma hospitalized for this study. Plasma-free glucocorticoid activity was measured by a radioreceptor assay. Diurnal rhythms of IOP and plasma-free glucocorticoid activity were detected prior to administration of dexamethasone. The plasma-free glucocorticoid activity rose two- to threefold in the 30-min period following steroid administration and then declined throughout the rest of the day. IOP was approximately 2 mmHg higher in the 0-4-hr period and approximately 5.5 mmHg higher in the 4-8-hr period following the pharmacologic doses of dexamethasone compared with similar periods on control days. The increase in the IOP was highly significant (P less than 0.006) in the latter time period. These findings suggest that the glucocorticoids may have a greater role in regulating IOP than generally has been appreciated.

Adult↗

Trabecular meshwork cell culture in glaucoma research: evaluation of biological activity and structural properties of human trabecular cells in vitro.

The propagation of human trabecular cells in culture allows the study of the structural and functional properties of this distinct cell type under reproducible experimental conditions. Human trabecular cells can be effectively grown from dissected explants of trabecullar tissue, and the cultured cells can maintain the distinctive ultrastructural features of uncultured trabecular cells through at least five passages in vitro. The trabecular cell possesses a wide range of biochemical and structural properties that may be important for the maintenance of the aqueous outflow pathway. These properties include the growth of trabecular cells as an endothelial monolayer with a nonthrombogenic cell surface, the production of plasminogen activator, avid phagocytosis, and the ability to synthesize glycosaminoglycans, collagen, fibronectin, and other connective tissue elements. The presence of hyaluronidase and other lysosomal enzymes emphasizes that human trabecular cells are capable of metabolizing hyaluronic acid and other extracellular materials. Potential mechanisms of trabecular cell damage in vitro are examined by evaluating the effects of extended passage, peroxide exposure, and laser treatment on cellular morphology.

Adolescent↗

Prostaglandin production by human trabecular cells: in vitro inhibition by dexamethasone.

In addition to the well-known ability of prostaglandins (PGs) to raise intraocular pressure (IOP), it recently has been reported that moderate and low doses of PGE2 and PGF2 alpha significantly reduce IOP in a variety of experimental animals. These studies suggested to us that PGs might serve as endogenous regulators of outflow facility in the meshwork if these autacoids were produced and secreted by human trabecular cells. To examine this possibility, media from well-defined trabecular cell material were assayed using specific radioimmunoassays. Morphologically differentiated human trabecular cells produced high levels of PGE2, and somewhat lower levels of PGF2 alpha and 6KF1 alpha in the presence and absence of serum. In a typical experiment, the following PG levels were detected in the cell culture media after 24 hours: PGE2; 225; PGF2 alpha, 33.5; 6KF1 alpha, 12.7 ng/ml with the presence of 10% fetal calf serum; and PGE2, 30.0; PGF2 alpha, 4.8; 6KF1 alpha, 3.6 ng/ml in serum-free media. Since glucocorticoids are known to inhibit PG pathways in other tissues, this effect was examined in the cultured trabecular cells. Moderate concentrations of dexamethasone (DEX) produced a marked inhibition in the levels of all three PGs. For PGE2 production, 10(-8) M DEX inhibited approximately 75%, and 10(-7) M DEX inhibited approximately 90%. More detailed dose-response studies revealed that the I50 for inhibition of PG production by dexamethasone was less than 10 nM, thus indicating that the steroid effect probably involved high affinity glucocorticoid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

Human trabecular cells. II. Growth pattern and ultrastructural characteristics.

The morphologic features of third-passage human trabecular cells were examined in multiple experiments by light and electron microscopy. Evaluation of the cellular growth pattern, fibronectin immunofluorescence, and specific ultrastructural features have helped to establish the identity of the trabecular cell type. Comparison of the cultured trabecular cells with cultured keratocytes and scleral fibrocytes grown under identical conditions emphasized the specialized morphologic features of trabecular cells in vitro. The characteristics of trabecular cells in vitro closely resemble those described for trabecular cells in vivo, including the presence of similar cell surface features and cell junctions, cytoplasmic organelle composition, and nuclear chromatin pattern. Since many of the differentiated features of the trabecular cells are retained after passage in culture, it is possible that study of these cells will provide a means to understand the biochemical and morphologic properties of this important cell type.

Adolescent↗

Detection of glucocorticoid receptors in cultured human trabecular cells.

To evaluate potential direct effects of glucocorticoids on the aqueous outflow pathway, the cellular binding of steroids to cultured human trabecular cells was examined. After incubation of cells with 5 to 40 nM [3H]dexamethasone, specific binding (i.e., binding that could be blocked by an excess of nonlabeled steroid) was detected by measuring the total cell-associated labeled hormone. A binding affinity of 5 nM and 60,000 receptor sites/cell were demonstrated with labeled dexamethasone. Incubation of human trabecular cells with 40 nM [3H]dexamethasone for 60 min revealed that 62% +/- 7 of the specific binding was found in the nuclear fraction and 38% +/- 3 was in the cytoplasmic fraction. In competition studies, dexamethasone had a higher affinity for these sites than cortisol, which in turn had a higher affinity than progesterone. These studies suggest that functional glucocorticoid receptors are present in human trabecular cell cultures. Therefore it is possible that a direct action of glucocorticoids on trabecular cells could contribute to the decreased outflow facility observed in steroid glaucoma.

Cells, Cultured↗

Human trabecular cells. I. Establishment in tissue culture and growth characteristics.

After a careful dissection of trabecular tissue from recent postmortem specimens, human trabecular cells were established in tissue culture with 250 ng/ml fibroblast growth factor (FGF), Dulbecco's modified Eagle's medium (DME), and 10% human serum. These conditions have allowed propagation of human trabecular cells for a number of passages at high density without apparent cellular degeneration. FGF increased the rate of cell division and the plating efficiency for trabecular cells but was not needed after cells had achieved confluency. Human trabecular cells had a pattern of growth which differed from human corneal keratocytes and human corneal endothelial cells compared at a similar passage. Propagation of human trabecular cells in vitro may provide a valuable source of experimental material to study the functional aspects of these cells which line the trabecular meshwork.

Adolescent↗