Dimethylthiourea inhibits the inflammatory response to intravitreally-injected endotoxin

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.     

Immunohistochemical study of the local inflammatory response to chlamydial ocular infection

Immunohistochemical staining of conjunctival biopsies from cynomolgus monkeys (Macaca fascicularis) was performed after they received a single primary ocular infection, a single secondary challenge infection, or repeated ocular inoculations with Chlamydia trachomatis. T cells of the suppressor/cytotoxic (OKT8F) phenotype predominated regardless of the infection protocol, and perifollicular T lymphocytes of both the suppressor/cytotoxic and helper (OKT4A) phenotypes appeared in large numbers during the peak inflammatory reaction. In repeatedly inoculated monkeys, T cells and follicles persisted until cessation of reinfection. IgM-bearing B lymphocytes comprised the majority of cells within follicles, with smaller numbers of IgG- or IgA-positive B cells. The major difference in the response to the various infection protocols was the increased number and persistence of follicles with repeated reinoculation. The finding of large numbers of T-suppressor/cytotoxic and T-helper cells in the infected conjunctiva supports a role for cell-mediated immunity in the local response to C. trachomatis ocular infection.     

Ferroxidase activity increases in the aqueous humor during the ocular inflammatory response

Ferroxidase activity was increased in the aqueous humor from inflamed eyes compared to their uninflamed contralateral controls 24 h after intravitreal injection of 10 ng of endotoxin. Changes in ferroxidase activity and copper concentration paralleled each other indicating that the plasma copper transport protein ceruloplasmin (plasma ferroxidase) entered the inflamed aqueous humor from plasma through disrupted blood ocular barriers. The presence of ferroxidase activity would facilitate the removal of potentially damaging, free radical generating Fe+2. Therefore, plasma proteins may perform important protective functions in the inflamed intraocular fluids.     

Mediation of the ocular response to cyclocryocoagulation

The possible roles of prostaglandins and a neural pathway in the disruption of the blood-aqueous barrier in the rabbit eye after cyclocryocoagulation were studied. Both the preoperative IV administration of the prostaglandin inhibitor acetylsalicylic acid and the application of retrobulbar and topical anesthesia reduced IOP and decreased breakdown of the blood-aqueous barrier, as measured by protein in the aqueous humour. These results imply that the acute response of the animal eye to cyclocryocoagulation is mediated partly by prostaglandins and partly by a neural component resistent to an inhibitor of prostaglandin synthesis. When administered together, acetylsalicylic acid and ocular anesthesia yielded a further reduction in postoperative reactions and protein concentrations in the aqueous humour, but were unable to abolish the ocular response completely. The dual ocular mediation to cyclocryocoagulation is apparently due to the combined thermal and mechanical injury caused to ocular structures which synthesize prostaglandins and receive sensory innervation from the trigeminal nerve. The considerable breakdown of the blood-aqueous barrier in cyclocryocoagulation allows leakage of different molecular weight proteins, in equal ratio, into the aqueous humour.

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Zusammenfassung In dieser Studie wird der Einfluß der Prostaglandine und der neuralen Reaktion auf den Zusammenbruch der Blut-Kammerwasser-Schranke nach Cyclokryokoagulation im Kaninchenauge untersucht. Sowohl die präoperative Gabe eines Prostaglandin-Inhibitors, Acetylsalicylsäure, als auch eine retrobulbäre und Oberflächenanaesthesie verminderten den intraokulären Druckanstieg und den Zusammenbruch der Blut-Kammerwasser-Schranke, gemessen an der Konzentration verschiedener Proteine im Kammerwasser. Diese Ergebnisse scheinen darauf hinzudeuten, daß die Sofortreaktion in diesem Experiment teils durch Prostaglandine und teils durch eine neurale Komponente hervorgerufen wird, wobei letztere durch einen Prostaglandinsynthetase-Inhibitor nicht beeinflußt wird. Bei gleichzeitiger Anwendung von Salicylsäure und Lokalanaesthesie kam es zu einer weiteren Verminderung der postoperativen Reaktionen, einschließlich eines geringeren Proteinanstieges, ohne daß jedoch die Reaktion zur Gänze unterdrückt werden konnte. Die zweifache Reaktion des Auges auf Cyclokryokoagulation ist offensichtlich auf eine kombinierte Schädigung des betroffenen Uveagewebes, einerseits durch Temperaturwirkung, andererseits durch mechanische Zerstörung zurückzuführen. Die beträchtliche Störung der Blut-Kammerwasser-Schranke nach Cyclokryokoagulation führt dazu, daß Proteine von verschiedenem Molekulargewicht (Albumin und IgG) im gleichen Verhältnis in das Kammerwasser einströmen.

     

Sterile ocular inflammatory reactions to monofilament suture material

Objective : To report six cases of sterile inflammatory reactions to fine monofilament suture materials, which is exceedingly rare in ophthalmology. Methods : We report six patients (four underwent penetrating keratoplasty and two underwent cataract surgery) with unusually severe local inflammatory reactions to suture material. Results : Patients developed multiple focal inflammatory infiltrates and corneal oedema related to 10/0 monofilament nylon sutures. Four patients had evidence of either atopy or raised serum IgE and one had an autoimmune disorder (systemic lupus erythematosis). Onset was four to 11 days in five cases and six weeks in one. Allograft reaction occurred in two of the four corneal grafts, and three grafts failed. One of the cataract patients developed significant against-the-rule astigmatism. Microbial cultures of corneal scrapings, donor corneal rims, and suture material were generally negative. Polymorphonuclear leucocytes were noted on Gram stain in four cases, and cytology of corneal scrapings demonstrated eosinophils in one case. Conclusions : Sterile inflammatory reactions to monofilament suture material are an uncommon complication of ocular surgery which may lead to corneal graft failure, and which is more common in atopic individuals. Systemic steroid therapy may be required.     

Quantitative studies of the ocular response to norepinephrine

The responses of the iris and intraocular pressure of conscious rabbits to norepinephrine (NE) given either topically or intravitreally have been determined. The dose-response curves for pupil dilatation and for decreased intraocular pressure occurring within 6 hr of the intravitreal administration of NE were similar and could be antagonized by prior intravenous injections of the α-adrenergic antagonists phenoxybenzamine or phentolamine. There were, however, marked differences in the time of onset and in the duration of the pupillary and pressure responses. A prolonged decrease in intraocular pressure, lasting more than 5 days, followed the intravitreal injection of NE. This prolonged pressure response could not be reversed by either phenoxybenzamine or phentolamine.     

The effect of naproxen on the ocular inflammatory response following extracapsular lens extraction in rabbits

Naproxen effects on the ocular inflammatory response following extracapsular lens extraction were studied in rabbits. Twelve hours before surgery, rabbits were given 20 mg of a 5 mg/ml naproxen suspension by gavage. A maintenance dose of 10 mg naproxen 3 times per day was started on the day of lensectomy and continued throughout the entire observation period. Phakic and aphakic control rabbits received no drug suspension. Central corneal thickness and intraocular pressure measurements were determined pre-operatively, at 4 and 24 h post-operatively and every 24 h thereafter. Four groups of rabbits, sacrificed at 24, 48, 72, and 168 h after lensectomy, had anterior chamber paracentesis performed for PMN (polymorphonuclear leucocyte) counts and determination of protein content. A 5th group had both paracentesis and iris-ciliary body excision for PGE2 assay at 24 h. No parameter was significantly altered by the naproxen regimen compared to untreated rabbits.     

Contrasting ocular effects of local versus systemic endotoxin

PURPOSE. A marked cellular infiltrate has been observed when endotoxin (lipopolysaccharide [LPS]) is injected into the mouse eye, but systemically injected LPS does not produce a comparable effect. Several hypotheses were tested to reconcile this discordance. METHODS. BALB/c mice were injected intravitreally (ivt) or intraperitoneally (ip) with Escherichia coli LPS. Uveitis was assessed by traditional and intravital microscopy. Cytokine levels in the eye, plasma, or spleen were measured by single or multiplex ELISA assays. RESULTS. The eye's higher sensitivity was confirmed to local LPS exposure, as 250 ng ivt LPS produced a brisk leukocytic infiltrate whereas ip injection of 100 μg LPS did not. The hypothesis was tested that the lack of a cellular infiltrate after ip LPS is explained by less induction of cytokines in the eye, but surprisingly, ip LPS resulted in comparable cytokine levels to ivt LPS. The hypothesis was disproved that the eye's sensitivity to local LPS is due to lack of expression of intracellular inhibitors of LPS such as A20, IRAK-M, or SARM. Finally, the hypothesis that systemic LPS inhibits diapedesis was tested by injection of LPS ip and ivt simultaneously, a strategy that did not significantly reduce leukocyte rolling or sticking in iris vessels but blocked the cellular infiltrate normally seen with ivt LPS. CONCLUSIONS. Systemic and local LPS exposures produce discordant effects within the murine eye. The hypothesis that systemic LPS desensitizes leukocytes to the stimuli responsible for transmigration offers a plausible explanation for this discordance.     

Sensory mediation of the ocular response to neutral formaldehyde

Topical application of 100 or 250 μg neutral formaldehyde to the rabbit eye elicits an acute inflammatory response consisting of a raised intraocular pressure (IOP), anterior uveal vasodilation, miosis and an increase in protein in the aqueous humour. Prior treatment with 0·4% benoxinate (12 drops over 30 min) inhibited these ocular changes whereas systemic indomethacin or atropine pretreatment had no notable effect. No raised levels of prostaglandin-like activity were observed in any samples of aqueous humour withdrawn 15 min after stimulation with formaldehyde. The major site of breakdown of the blood-aqueous barrier was shown by fluorescein angiography and colloidal carbon vascular “labelling” to occur in the ciliary processes.The IOP response to 6–50 μg formaldehyde administered intracamerally during closed circuit perfusion was greatly reduced by benoxinate or intracamerally infused tetrodotoxin. Furthermore the response was essentially abolished in eyes in which the ipsilateral sensory nerve supply had been destroyed by diathermic coagulation of the ophthalmic branch of the trigeminal nerve. The response to submaximal doses of formaldehyde was greater in the unilaterally sympathectomized eye than in the fellow control eye.These observations indicate that the ocular response to this form of chemical irritation is dependent largely, if not entirely, upon a non-prostaglandinergic and non-cholinergic excitatory pathway most likely occurring in sensory nervous elements.     

Intravitreal bevacizumab in inflammatory ocular neovascularization

PURPOSE: To assess the role of bevacizumab in inflammatory ocular neovascularization. DESIGN: Retrospective, multicenter, consecutive case series of inflammatory ocular neovascularization. METHODS: Patients with inflammatory ocular neovascularization of varying causes for whom standard therapy failed were treated with intravitreal injection of bevacizumab. Main outcome measures included improvement of best-corrected visual acuity (BCVA) expressed in logarithm of minimum angle of resolution units, response of inflammatory ocular neovascularization by funduscopy and angiography, and decrease in central foveal thickness as measured by optical coherence tomography at the three-month follow-up. RESULTS: At the three-month follow-up, 84 eyes of 79 patients had been treated with a mean of 1.3 injections (range, one to three). Thirty-four eyes showed juxtafoveal choroidal neovascularization (CNV), 34 eyes showed subfoveal CNV, eight eyes showed peripapillary CNV, and 11 eyes showed neovascularization of the disc (NVD) or neovascularization elsewhere (NVE). BCVA improved 2.4 lines from 0.68 (6/28 or 20/94) to 0.44 (6/17 or 20/55) (P < .001). BCVA improved by one to three lines in 34.5% of the eyes, by four to six lines in 16.7% of the eyes, and by more than six lines in 14.2% of the eyes. Function was unchanged in 23.8% of the eyes. BCVA worsened in 10.7% (zero to three lines in 7.1%, more than four lines in 3.6%). Central foveal thickness decreased from baseline 346 to 252 microm (P < .001). For CNV, 32 eyes (43.2%) had complete regression after the injection, 27 (36.5%) had partial regression, five (6.8%) had no response, and 10 eyes (13.5%) were not evaluated by the contributors. For NVD or NVE, seven eyes (63.6%) had complete regression of new vessels and four eyes (36.4%) had partial regression after the injection. CONCLUSIONS: Intravitreal bevacizumab led to short-term significant visual improvement and regression of inflammatory ocular neovascularization in a wide variety of inflammatory ocular diseases.     

Experimental models of autoimmune inflammatory ocular diseases

Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin). Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.     

Glaucoma in patients with ocular inflammatory disease

Uveitic glaucoma can pose some of the most challenging management problems faced by the ophthalmologist. A better understanding of the pathogenesis of glaucoma associated with ocular inflammatory disease is an important key to making appropriate therapeutic decisions. This article provides an update on recent advances in understanding the epidemiology and pathogenesis of uveitic glaucoma, as well as developments in the diagnosis and management of this condition.