@article{harned_ferrell_nagar_goralska_fleisher_mcgahan_2012, title={Ceruloplasmin alters intracellular iron regulated proteins and pathways: Ferritin, transferrin receptor, glutamate and hypoxia-inducible factor-1α}, volume={97}, ISSN={0014-4835}, url={http://dx.doi.org/10.1016/j.exer.2012.02.001}, DOI={10.1016/j.exer.2012.02.001}, abstractNote={Ceruloplasmin (Cp) is a ferroxidase important to the regulation of both systemic and intracellular iron levels. Cp has a critical role in iron metabolism in the brain and retina as shown in patients with aceruloplasminemia and in Cp-/-hep-/y mice where iron accumulates and neural and retinal degeneration ensue. We have previously shown that cultured lens epithelial cells (LEC) secrete Cp. The purpose of the current study was to determine if cultured retinal pigmented epithelial cells (RPE) also secrete Cp. In addition, the effects of exogenously added Cp on iron regulated proteins and pathways, ferritin, transferrin receptor, glutamate secretion and levels of hypoxia-inducible factor-1α in the nucleus were determined. Like LEC, RPE secrete Cp. Cp was found diffusely distributed within both cultured LEC and RPE, but the cell membranes had more intense staining. Exogenously added Cp caused an increase in ferritin levels in both cell types and increased secretion of glutamate. The Cp-induced increase in glutamate secretion was inhibited by both the aconitase inhibitor oxalomalic acid as well as iron chelators. As predicted by the canonical view of the iron regulatory protein (IRP) as the predominant controller of cellular iron status these results indicate that there is an increase in available iron (called the labile iron pool (LIP)) in the cytoplasm. However, both transferrin receptor (TfR) and nuclear levels of HIF-1α were increased and these results point to a decrease in available iron. Such confounding results have been found in other systems and indicate that there is a much more complex regulation of intracellularly available iron (LIP) and its downstream effects on cell metabolism. Importantly, the Cp increased production and secretion of the neurotransmitter, glutamate, is a substantive finding of clinical relevance because of the neural and retinal degeneration found in aceruloplasminemia patients. This finding and Cp-induced nuclear translocation of the hypoxia-inducible factor-1 (HIF1) subunit HIF-1α adds novel information to the list of critical pathways impacted by Cp.}, number={1}, journal={Experimental Eye Research}, publisher={Elsevier BV}, author={Harned, J. and Ferrell, J. and Nagar, S. and Goralska, M. and Fleisher, L.N. and McGahan, M.C.}, year={2012}, month={Apr}, pages={90–97} }
 @article{harned_ferrell_lall_fleisher_nagar_goralska_mcgahan_2010, title={Altered Ferritin Subunit Composition: Change in Iron Metabolism in Lens Epithelial Cells and Downstream Effects on Glutathione Levels and VEGF Secretion}, volume={51}, ISSN={["1552-5783"]}, DOI={10.1167/iovs.09-3861}, abstractNote={PURPOSE
The iron storage protein ferritin is necessary for the safe storage of iron and for protection against the production of iron-catalyzed oxidative damage. Ferritin is composed of 24 subunits of two types: heavy (H) and light (L). The ratio of these subunits is tissue specific, and alteration of this ratio can have profound effects on iron storage and availability. In the present study, siRNA for each of the chains was used to alter the ferritin H:L chain ratio and to determine the effect of these changes on ferritin synthesis, iron metabolism, and downstream effects on iron-responsive pathways in canine lens epithelial cells.


METHODS
Primary cultures of canine lens epithelial cells were used. The cells were transfected with custom-made siRNA for canine ferritin H- and L-chains. De novo ferritin synthesis was determined by labeling newly synthesized ferritin chains with 35S-methionine, immunoprecipitation, and separation by SDS-PAGE. Iron uptake into cells and incorporation into ferritin was measured by incubating the cells with 59Fe-labeled transferrin. Western blot analysis was used to determine the presence of transferrin receptor, and ELISA was used to determine total ferritin concentration. Ferritin localization in the cells was determined by immunofluorescence labeling. VEGF, glutathione secretion levels, and cystine uptake were measured.


RESULTS
FHsiRNA decreased ferritin H-chain synthesis, but doubled ferritin L-chain synthesis. FLsiRNA decreased both ferritin H- and L-chain synthesis. The degradation of ferritin H-chain was blocked by both siRNAs, whereas only FHsiRNA blocked the degradation of ferritin L-chain, which caused significant accumulation of ferritin L-chain in the cells. This excess ferritin L-chain was found in inclusion bodies, some of which were co-localized with lysosomes. Iron storage in ferritin was greatly reduced by FHsiRNA, resulting in increased iron availability, as noted by a decrease in transferrin receptor levels and iron uptake from transferrin. Increased iron availability also increased cystine uptake and glutathione concentration and decreased nuclear translocation of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor (VEGF) accumulation in the cell-conditioned medium.


CONCLUSIONS
Most of the effects of altering the ferritin H:L ratio with the specific siRNAs were due to changes in the availability of iron in a labile pool. They caused significant changes in iron uptake and storage, the rate of ferritin synthesis and degradation, the secretion of VEGF, and the levels of glutathione in cultured lens epithelial cells. These profound effects clearly demonstrate that maintenance of a specific H:L ratio is part of a basic cellular homeostatic mechanism.}, number={9}, journal={INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE}, author={Harned, Jill and Ferrell, Jenny and Lall, Marilyn M. and Fleisher, Lloyd N. and Nagar, Steven and Goralska, Malgorzata and McGahan, M. Christine}, year={2010}, month={Sep}, pages={4437–4446} }
 @article{goralska_ferrell_harned_lall_nagar_fleisher_mcgahan_2009, title={Iron metabolism in the eye: A review}, volume={88}, ISSN={0014-4835}, url={http://dx.doi.org/10.1016/j.exer.2008.10.026}, DOI={10.1016/j.exer.2008.10.026}, abstractNote={This review article covers all aspects of iron metabolism, which include studies of iron levels within the eye and the processes used to maintain normal levels of iron in ocular tissues. In addition, the involvement of iron in ocular pathology is explored. In each section there is a short introduction to a specific metabolic process responsible for iron homeostasis, which for the most part has been studied in non-ocular tissues. This is followed by a summary of our current knowledge of the process in ocular tissues.}, number={2}, journal={Experimental Eye Research}, publisher={Elsevier BV}, author={Goralska, M. and Ferrell, J. and Harned, J. and Lall, M. and Nagar, S. and Fleisher, L.N. and McGahan, M.C.}, year={2009}, month={Feb}, pages={204–215} }
 @article{lall_ferrell_nagar_fleisher_mcgahan_2008, title={Iron regulates L-cystine uptake and glutathione levels in lens epithelial and retinal pigment epithelial cells by its effect on cytosolic aconitase}, volume={49}, ISSN={["1552-5783"]}, DOI={10.1167/iovs.07-1041}, abstractNote={PURPOSE
The authors previously published the novel finding that iron regulates L-glutamate synthesis and accumulation in the cell-conditioned medium (CCM) by increasing cytosolic aconitase activity in cultured lens epithelial cells (LECs), retinal pigment epithelial (RPE) cells, and neurons. The present study was designed to determine whether iron-induced L-glutamate accumulation in the CCM regulates L-cystine uptake and glutathione (GSH) levels through the aconitase pathway in LECs and RPE cells.


METHODS
The presence of xCT, the light chain of X(c)(-), a glutamate/cystine antiporter, was analyzed by RT-PCR, immunoblotting, and immunocytochemistry. Uptake of L-[(35)S]cystine and L-[(3)H]glutamate was measured in the presence or absence of transporter inhibitors. L-cystine uptake and intracellular GSH concentration were measured in the presence or absence of iron-saturated transferrin, the iron chelator dipyridyl (DP), or oxalomalic acid (OMA), an aconitase inhibitor.


RESULTS
LECs and RPE cells express xCT, as evidenced by RT-PCR analysis and immunoblotting. xCT was localized by immunocytochemistry. The authors found that the iron-induced increase in L-glutamate availability increased L-cystine uptake, with subsequent increases in GSH levels. In addition, L-glutamate production, L-cystine uptake, and GSH concentration were inhibited by OMA and DP, indicating a central role for iron-regulated aconitase activity in GSH synthesis in LECs and RPE cells.


CONCLUSIONS
These results demonstrate for the first time that iron regulates L-cystine uptake and the downstream production of GSH in two mammalian cell types. It is possible that the increase in intracellular antioxidant concentration induced by iron serves as a protective mechanism against the well-established capacity of iron to induce oxidative damage.}, number={1}, journal={INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE}, author={Lall, Marilyn M. and Ferrell, Jenny and Nagar, Steve and Fleisher, Lloyd N. and McGahan, M. Christine}, year={2008}, month={Jan}, pages={310–319} }
 @article{mcgahan_harned_mukunnemkeril_goralska_fleisher_ferrell_2005, title={Iron alters glutamate secretion by regulating cytosolic aconitase activity}, volume={288}, ISSN={["1522-1563"]}, DOI={10.1152/ajpcell.00444.2004}, abstractNote={Glutamate has many important physiological functions, including its role as a neurotransmitter in the retina and the central nervous system. We have made the novel observations that retinal pigment epithelial cells underlying and intimately interacting with the retina secrete glutamate and that this secretion is significantly affected by iron. In addition, iron increased secretion of glutamate in cultured lens and neuronal cells, indicating that this may be a common mechanism for the regulation of glutamate production in many cell types. The activity of the iron-dependent enzyme cytosolic aconitase (c-aconitase) is increased by iron. The conversion of citrate to isocitrate by c-aconitase is the first step in a three-step process leading to glutamate formation. In the present study, iron increased c-aconitase activity, and this increase was associated with an increase in glutamate secretion. Inhibition of c-aconitase by oxalomalate decreased glutamate secretion and completely inhibited the iron-induced increase in glutamate secretion. Derangements in both glutamate secretion and iron metabolism have been noted in neurological diseases and retinal degeneration. Our results are the first to provide a functional link between these two physiologically important substances by demonstrating a significant role for iron in the regulation of glutamate production and secretion in mammalian cells resulting from iron regulation of aconitase activity. Glutamatergic systems are found in many nonneuronal tissues. We provide the first evidence that, in addition to secreting glutamate, retinal pigment epithelial cells express the vesicular glutamate transporter VGLUT1 and that regulated vesicular release of glutamate from these cells can be inhibited by riluzole.}, number={5}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY}, author={McGahan, MC and Harned, J and Mukunnemkeril, M and Goralska, M and Fleisher, L and Ferrell, JB}, year={2005}, month={May}, pages={C1117–C1124} }
 @article{fleisher_mcgahan_ferrell_2000, title={Rabbit pigmented ciliary epithelium produces interleukin-6 in response to inflammatory cytokines}, volume={70}, ISSN={["0014-4835"]}, DOI={10.1006/exer.1999.0787}, abstractNote={Interleukin-6 is a multifunctional cytokine that is found in high concentrations in intraocular fluids during the uveitic response. Although monocytic cells are a major source of interleukin-6, resident intraocular cells may also contribute to its accumulation in intraocular fluids during uveitis. The purpose of this study was to determine whether interleukin-6 is produced by pigmented ciliary epithelial cells and whether agents known to stimulate interleukin-6 production, such as interleukin-1beta, tumor necrosis factor-alpha, bacterial endotoxin, and stimulators of the adenylyl cyclase/adenosine 3',5'-cyclic monophosphate system, increase interleukin-6 production by these cells. Primary and first-passage cultures of nontransformed rabbit pigmented ciliary epithelial cells were incubated with the test agents for varying periods of time in serum-free medium and interleukin-6 levels in the cell-conditioned medium were measured by bioassay.Little, if any interleukin-6 was released from pigmented ciliary epithelial cells incubated for up to 18 hr in serum-free medium. Interleukin-1betastimulated interleukin-6 release in a time- and concentration-dependent manner. Tumor necrosis factor-alpha, although ineffective alone, increased interleukin-1beta-induced interleukin-6 release in a concentration-dependent manner when co-incubated with interleukin-1betafor 18 hr. However, tumor necrosis factor-alphadid not enhance interleukin-1beta-induced interleukin-6 release if co-incubated with interleukin-1betafor a shorter time (6 hr). A 6 hr exposure to bacterial endotoxin did not stimulate interleukin-6 release from pigmented ciliary epithelial cells. Co-incubation of pigmented ciliary epithelial cells with interleukin-1betaand agents that stimulate the adenyl cyclase/adenosine 3',5'-cyclic monophosphate system through cell surface G-protein transduced receptors, i.e. isoproterenol, vasoactive intestinal peptide or prostaglandin E(2), significantly enhanced the ability of interleukin-1betato stimulate interleukin-6 release. However, neither the adenyl cyclase activator, forskolin or the adenosine 3', 5'-cyclic monophosphate-mimetic, dibutyryl 3',5'-cyclic monophosphate enhanced interleukin-1beta-induced release of interleukin-6. These results indicate that the pigmented ciliary epithelium is one potential source of interleukin-6 and may contribute to the elevation in intraocular fluid interleukin-6 levels observed during various intraocular inflammatory episodes. Although agents that activate the adenyl cyclase/adenosine 3', 5'-cyclic monophosphate system through cell surface G-protein transduced receptors increased interleukin-1beta-induced release of interleukin-6, the ineffectiveness of forskolin and dibutryl 3', 5'-cyclic monophosphate suggest that simply increasing intracellular 3',5'-cyclic monophosphate is not sufficient to augment interleukin-1beta-induced release of interleukin-6. The significance of interleukin-6 in the intraocular inflammatory response is discussed in terms of its proposed role in an endogenous antiinflammatory system acting through induction of interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, acute-phase proteins and corticosteroids.}, number={3}, journal={EXPERIMENTAL EYE RESEARCH}, author={Fleisher, LN and McGahan, MC and Ferrell, JB}, year={2000}, month={Mar}, pages={271–279} }
 @article{fleisher_mcgahan_ferrell_pagan_1996, title={Interleukin-1 beta increases prostaglandin E(2)-stimulated adenosine 3',5'-cyclic monophosphate production in rabbit pigmented ciliary epithelium}, volume={63}, ISSN={["0014-4835"]}, DOI={10.1006/exer.1996.0095}, abstractNote={This study was designed to determine the effects of interleukin-1 on basal and prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production by primary and first passage cultures of non-transformed rabbit pigmented and non-pigmented ciliary epithelial cells. Confluent cultures of rabbit pigmented and non-pigmented ciliary epithelial cells were incubated for varying periods of time in serum-free medium with or without interleukin-1 beta, tumor necrosis factor-alpha, bacterial lipopolysaccharide, transforming growth factor-beta 2, cycloheximide, indomethacin and combinations of these agents. Cells were then preincubated for 10 min with serum-free medium plus the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (for basal adenosine 3',5'-cyclic monophosphate production) or serum-free medium containing several concentrations of prostaglandin E2 and 3-isobutyl-1-methylxanthine. In certain experiments isoproterenol, vasoactive intestinal peptide, or forskolin was substituted for prostaglandin E2. Adenosine 3',5'-cyclic monophosphate was then extracted into ice-cold absolute ethanol and measured by radioimmunoassay. Prostaglandin E2 stimulated adenosine 3',5'-cyclic monophosphate production in pigmented and non-pigmented ciliary epithelial cells in a dose-dependent manner. Incubation with interleukin-1 beta (150 U ml-1) increased prostaglandin E2-stimulated, but not basal adenosine 3',5'-cyclic monophosphate production in pigmented ciliary epithelial cells. This interleukin-1 beta-induced enhancement of prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production, called the interleukin-1 effect, was not seen with non-pigmented ciliary epithelial cells. The interleukin-1 effect was dependent upon interleukin-1 beta concentration, time and de novo protein synthesis. The interleukin 1 effect could not be reproduced by replacing interleukin-1 beta with tumor necrosis factor-alpha or bacterial lipopolysaccharide and was specific for prostaglandin E2, since interleukin-1 beta did not enhance isoproterenol-, vasoactive intestinal peptide-, or forskolin-induced adenosine 3',5'-cyclic monophosphate production. Chronic exposure to prostaglandin E2 (during the 3 hr incubation period), with or without interleukin-1 beta in the incubation medium, reduced subsequent prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production. Inhibition of de novo prostaglandin synthesis with indomethacin increased the interleukin-1 effect. The interleukin-1 effect was inhibited by the immunosuppressive cytokine, transforming growth factor-beta 2, in a dose-dependent manner. This is the first report of prostaglandin E2-induced stimulation of adenosine 3',5'-cyclic monophosphate production by pigmented ciliary epithelial cells and of the unique ability of interleukin-1 to increase this effect. The results are consistent with interleukin-1-induced upregulation of prostaglandin E receptors. Since transforming growth factor-beta 2 inhibited this interleukin-1 effect, this immunosuppressive cytokine may exert negative feedback and thus regulate the physiological consequences of the interleukin-1 effect.}, number={1}, journal={EXPERIMENTAL EYE RESEARCH}, author={Fleisher, LN and McGahan, MC and Ferrell, JB and Pagan, I}, year={1996}, month={Jul}, pages={91–104} }
 @article{allen_mcgahan_ferrell_adler_fleisher_1996, title={Nitric oxide synthase inhibitors exert differential time-dependent effects on LPS-induced uveitis}, volume={62}, ISSN={["0014-4835"]}, DOI={10.1006/exer.1996.0003}, abstractNote={Nitric oxide (NO) is a highly reactive radical which plays an integral role in physiological and pathophysiological processes. NO is produced endogenously in small amounts by a constitutive NO synthase (cNOS) as a regulator of vascular tone and neurotransmission. NO can also be produced in large amounts by an inducible NOS (iNOS) in response to endotoxin and cytokines, and has been reported to be a mediator of lipopolysaccharide (LPS)-induced uveitis in rats. The purpose of the present study was to investigate the effects of NOS inhibitors with different NOS isoform specificities in the rabbit model of endotoxin-induced ocular inflammation. LPS and/or inhibitors of NOS. NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG), were injected intravitreally and the eyes observed by slit lamp for 24 hr. Coinjection of LPS with L-NAME inhibited anterior inflammation in rabbits. Iridal hyperemia (IH) and aqueous flare (AF) were completely abolished in eight out of nine rabbits in a dose-dependent manner. In addition, total cell counts were significantly suppressed (7393 +/- 697 vs. 325 +/- 188, P < 0.05) and aqueous protein levels were reduced to near control levels (25 +/- 0.75 vs. 1.72 +/- 0.36, P < 0.05). Similar suppression was seen with AG (cell counts = 351 +/- 246 and proteins = 3.1 +/- 1.2). Administration of L-NAME 0.5 hr after LPS injection suppressed inflammation to a lesser extent than coinjection. In contrast, administration of L-NAME 6 hr after LPS injection was not inhibitory, and in fact significantly increased cellular infiltration. However, AG given 6 hr after LPS had a remarkably different effect, since it significantly decreased both protein extravasation and cellular infiltration into the aqueous humor. In fact, our results suggest that cNOS may play a greater role in the earlier stages of this developing inflammatory response. These results extend others' observations that NO is a key mediator in uveitis, that induction of iNOS plays a critical role in experimental uveitis, and suggest that NO has a complex role in the ocular inflammatory process. Inhibitors of NOS can abort the LPS-induced inflammatory response if administered early enough, but could potentially exacerbate an established inflammatory episode.}, number={1}, journal={EXPERIMENTAL EYE RESEARCH}, author={Allen, JB and McGahan, MC and Ferrell, JB and Adler, KB and Fleisher, LN}, year={1996}, month={Jan}, pages={21–28} }
 @article{fleisher_ferrell_mcgahan_1995, title={INFLAMMATION-INDUCED CHANGES IN ADENOSINE 3',5'-CYCLIC-MONOPHOSPHATE PRODUCTION BY CILIARY EPITHELIAL-CELL BILAYERS}, volume={60}, ISSN={["0014-4835"]}, DOI={10.1016/S0014-4835(95)80007-7}, abstractNote={Despite extensive evidence implicating the cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα) in the intraocular inflammatory response, little is known about their effects on signal transduction in anterior uveal tissue. Since these cytokines have been shown to alter the adenylyl cyclase system in nonocular tissues, we tested the hypothesis that IL-1β and TNFα affect the anterior uvea by altering production of the intracellular second messenger adenosine 3′,5′-cyclic monophosphate (cAMP) in ciliary epithelial bilayers. This was accomplished by measuring the levels of cAMP in bilayers ex vivo, following intraocular inflammation induced by intravitreal injection of IL-1β, TNFα or bacterial endotoxin, and in vitro, following exposure to IL-1β, TNFα or bacterial endotoxin. Although cAMP production was enhanced in bilayers from IL-1β-, TNFα- or endotoxin-inflamed eyes, ex vivo, exposure of normal bilayers to IL-1β (15 U ml−1), TNFα (20 U ml−1), or a low concentration of endotoxin (0·01 μg ml−1) for 4 hr, in vitro, had no effect on cAMP production. The inability of IL-1β, TNFα, or the low concentration of endotoxin to increase cAMP production by bilayers, in vitro, suggests that the enhanced cAMP production observed with inflamed bilayers, ex vivo, was not due to a direct action of these inflammatory agonists on the ciliary epithelial bilayer. Although direct exposure to cytokines or endotoxin did not change cAMP production, treatment with IL-1β, TNFα, or a higher concentration of endotoxin (1 μg ml−1) did affect signal transduction mechanisms. For example, exposure to IL-1β, TNFα, or a higher concentration of endotoxin rendered normal bilayers unresponsive to isoproterenol. A similar absence of response to isoproterenol was also seen with bilayers from TNFα-inflamed eyes. This insensitivity to β-receptor stimulation is apparently a consequence of receptor downregulation or functional uncoupling of the receptor from the transducing G protein, since in each case of isoproterenol insensitivity, bilayers exhibited forskolin responses indistinguishable from the appropriate control tissues. Since cAMP production by the epithelial cell bilayer was increased in three different models of intraocular inflammation, augmented production of this second messenger is likely to occur during uveitis of diverse etiology. Enhanced cAMP production by inflamed epithelial bilayers may contribute to some general aspect of the uveitic response such as altered intraocular pressure or possibly serve to enhance efflux of fluid from swollen anterior uveal tissue.}, number={2}, journal={EXPERIMENTAL EYE RESEARCH}, author={FLEISHER, LN and FERRELL, JB and MCGAHAN, MC}, year={1995}, month={Feb}, pages={165–171} }
 @article{fleisher_ferrell_mcgahan_1995, title={MEDIATORS OF THE OCULAR INFLAMMATORY RESPONSE TO INTERLEUKIN-1-BETA PLUS TUMOR-NECROSIS-FACTOR-ALPHA}, volume={233}, ISSN={["0721-832X"]}, DOI={10.1007/BF00241479}, abstractNote={{"Label"=>"BACKGROUND", "NlmCategory"=>"BACKGROUND"} Intravitreal injection of marginally inflammatory doses of interleukin-1 beta and tumor necrosis factor-alpha (IL-1 beta/TNF alpha) has been shown to produce intraocular inflammation distinctly different from that induced by higher intravitreal doses of either IL-1 or TNF alpha. Since cyclooxygenase inhibitors and platelet-activating factor (PAF)-receptor antagonists can reduce IL-1- or TNF alpha-induced uveitis, the present investigation was undertaken to determine whether cyclooxygenase metabolites of arachidonic acid and PAF are important mediators of IL-1 beta/TNF alpha-induced uveitis. {"Label"=>"METHODS", "NlmCategory"=>"METHODS"} The cyclooxygenase inhibitor indomethacin and two structurally dissimilar PAF-receptor antagonists, SRI 63-441 and WEB 2086, were used to investigate the importance of cyclooxygenase metabolites and PAF in IL-1 beta/TNF alpha-induced uveitis. {"Label"=>"RESULTS", "NlmCategory"=>"RESULTS"} Based upon the effectiveness of indomethacin, the anterior uveitis induced by IL-1 beta/TNF alpha could be divided into two phases; a primary phase dependent upon generation of cyclooxygenase metabolites (the first 24 h) and a secondary phase largely independent of cyclooxygenase metabolite production (24-48 h). Posterior uveitis was also apparent at 48 h and was reduced by indomethacin. SRI 63-441 reduced the anterior uveitis at 24 h and to a lesser extent at 48 h; it also reduced the posterior uveitis at 48 h. However, although WEB 2086 was as effective as SRI 63-441 in reducing PAF-induced platelet aggregation, ex vivo, it did not significantly reduce IL-1 beta/TNF alpha-induced uveitis. {"Label"=>"CONCLUSIONS", "NlmCategory"=>"CONCLUSIONS"} Although the findings do not support an important role for PAF in TNF alpha/IL-1 beta-induced uveitis, it cannot be ruled out that more intensive treatment with a specific and long-acting PAF-receptor antagonist might yield more positive results.}, number={2}, journal={GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY}, author={FLEISHER, L and FERRELL, J and MCGAHAN, C}, year={1995}, month={Feb}, pages={94–100} }
 @article{ferrell_fleisher_smith_mcgahan_1992, title={Effects of copper loading and depletion on rabbit superoxide dismutase activity}, volume={9}, journal={Trace Elements in Medicine}, author={Ferrell, J. B. and Fleisher, L. N. and Smith, M. G. and McGahan, M. C.}, year={1992}, pages={55–58} }
 @article{fleisher_ferrell_mcgahan_1992, title={Synergistic uveitic effects of tumor necrosis factor-alpha and interleukin-1 beta}, volume={33}, journal={Investigative Ophthalmology and Visual Science}, author={Fleisher, L. N. and Ferrell, J. B. and McGahan, M. C.}, year={1992}, pages={2120–2127} }
 @article{fleisher_ferrell_mcgahan_1991, title={Lipid mediators of TNF- induced uveitis}, volume={32}, journal={Investigative Ophthalmology and Visual Science}, author={Fleisher, L. N. and Ferrell, J. B. and McGahan, M. C.}, year={1991}, pages={2393–2399} }
 @article{fleisher_ferrell_mcgahan_1990, title={OCULAR INFLAMMATORY EFFECTS OF INTRAVITREALLY INJECTED TUMOR NECROSIS FACTOR-ALPHA AND ENDOTOXIN}, volume={14}, ISSN={["0360-3997"]}, DOI={10.1007/BF00915816}, number={3}, journal={INFLAMMATION}, author={FLEISHER, LN and FERRELL, JB and MCGAHAN, MC}, year={1990}, month={Jun}, pages={325–335} }
 @article{fleisher_ferrell_olson_mcgahan_1989, title={DIMETHYLTHIOUREA INHIBITS THE INFLAMMATORY RESPONSE TO INTRAVITREALLY-INJECTED ENDOTOXIN}, volume={48}, ISSN={["0014-4835"]}, DOI={10.1016/0014-4835(89)90038-9}, abstractNote={Dimethylthiourea, a potent scavenger of toxic oxygen metabolites such as the hydroxyl radical, hypochlorous acid, and hydrogen peroxide, was tested for its ability to inhibit an experimentally induced inflammatory response. Inflammation was induced in one eye of male New Zealand white rabbits by intravitreal injection of 10 ng Escherichia coli endotoxin; the contralateral eye received an equal volume of pyrogen-free saline vehicle. Dimethylthiourea was administered intraperitoneally to these animals at 0, 300, 450 and 600 mg kg−1. At 24 h post-endotoxin injection, all vehicle-injected eyes appeared normal with the exception of a small, but significant increase in aqueous humor protein concentration in the 600 mg kg−1 dimethylthiourea group. In endotoxin-injected eyes, treatment with dimethylthiourea, especially at the highest dose, significantly reduced iridal hyperemia, aqueous humor cell number and protein and prostaglandin-E concentrations, and the ex vivo release of prostaglandin-E from the lens. The ability of dimethylthiourea to significantly inhibit the inflammatory response to intravitreally-injected endotoxin suggests that toxic oxygen metabolites may play an important role in the initiation and/or propagation of this form of acute anterior uveitis. Furthermore, the data are consistent with an important interaction between toxic oxygen and arachidonic acid metabolites.}, number={4}, journal={EXPERIMENTAL EYE RESEARCH}, author={FLEISHER, LN and FERRELL, JB and OLSON, NC and MCGAHAN, MC}, year={1989}, month={Apr}, pages={561–567} }