Adhesion molecules in experimental phacoanaphylactic endophthalmitis.

Intraocular accumulation of inflammatory neutrophils is an important feature of experimental phacoanaphylactic endophthalmitis (EPE). Increasing evidence suggests that localization of neutrophils to the site of inflammation requires the participation of neutrophil and endothelial adhesion molecules. These studies were undertaken to determine if blocking of adhesion molecules on neutrophils (CD18) or endothelium (ELAM-1) could attenuate EPE in Lewis rats. Treatment of experimental animals with anti-CD18 or anti-ELAM-1 significantly suppressed intraocular neutrophil accumulation, retinal hemorrhage, and vasculitis, and attenuated retinal edema formation by 48% and 70%, respectively. These observations demonstrate that antibodies directed against adhesion molecules on the neutrophil (CD18) or the vascular endothelial cell (ELAM-1) exhibit potent anti-inflammatory effects, resulting in a striking amelioration of injury in EPE in rats.

Protection by dimethylthiourea against retinal light damage in rats.

The protective effect of dimethylthiourea (DMTU) against retinal light damage was determined in albino rats reared in darkness or in weak cyclic light. Rats maintained under these conditions were treated with DMTU at different concentrations and dosing schedules and then exposed for various times to intense visible light, either intermittently (1 hr light and 2 hr dark) or continuously. The extent of retinal light damage was determined 2 weeks after light exposure by comparing rhodopsin levels in experimental rats with those in unexposed control animals. To determine the effect of DMTU on rod outer segment (ROS) membrane fatty acids, ROS were isolated immediately after intermittent light exposure, and fatty acid compositions were measured. The time course for DMTU uptake and its distribution in serum, retina, and the retinal pigment epithelium (RPE)/choroid complex was determined in other rats not exposed to intense light. After intraperitoneal injection of the drug (500 mg/kg body weight), DMTU appeared rapidly in the serum, retina, and the RPE and choroid. In the ocular tissues, it was distributed 70-80% in the retina and 20-30% in the RPE and choroid. This antioxidant appears to have a long half-life because it was present in these same tissues 72 hr after a second intraperitoneal injection. For rats reared in the weak cyclic light environment, DMTU (two injections) provided complete protection against rhodopsin loss after intense light exposures of up to 16 hr. Only 15% rhodopsin loss was found in cyclic-light DMTU-treated rats after 24 hr of intermittent or continuous light. For rats reared in darkness, DMTU treatment resulted in a rhodopsin loss of less than 20% after 8-16 hr of continuous light and approximately 40% after similar exposure to intermittent light. Irrespective of the type of light exposure, rhodopsin loss in the dark-reared DMTU-treated rats was nearly identical to that found in uninjected cyclic light-reared animals. In rats from both light-rearing environments, DMTU treatment prevented the light-induced loss of docosahexaenoic acid from ROS membranes. As measured by rhodopsin levels 2 weeks later, DMTU was most effective when given as two doses administered 24 hr before and just before intense light exposure. As a single dose given during continuous light exposure, DMTU protected cyclic light-reared rats for at least 4 hr after the start of exposure but was ineffective in dark-reared animals if injected 1 hr after the start of light. It was also ineffective in both types of rats when given after light exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Phacoanaphylactic endophthalmitis.

Phacoanaphylactic endophthalmitis is a rare disease that develops infrequently after lens injury. The recent popularity of extracapsular cataract extraction with intraocular lens implants and the recently described possible association of low-grade infections have stimulated renewed interest in phacoanaphylactic endophthalmitis. It was formerly believed that this disease was due to the rejection of a lens protein that had been sequestered prior to lens injury. Recent observations indicate that this concept is incorrect and that phacoanaphylactic endophthalmitis represents altered tolerance to lens proteins. Clinical and histopathologic features as well as controversies in clinical management are discussed. Recent evidence concerning mechanisms of pathogenesis is reviewed [corrected].

Anti-inflammatory effects of vitamin E on experimental lens-induced uveitis.

The anti-phlogistic effect of dietary vitamin E supplementation on the acute inflammation observed in experimental lens-induced uveitis in Brown Norway rats was studied. The effects of vitamin E were examined using histopathologic parameters as well as by measuring the levels of arachidonic acid metabolites. Histologic examination of the eyes revealed that the vitamin E-deficient animals had the most severe destruction of the retina, while those animals receiving the vitamin E-supplemented diet exhibited the best preservation of the retinal architecture. Levels of arachidonic acid metabolites, as determined by radioimmunoassay, were significantly higher in vitamin E deficient rats as compared with rats on a normal diet.

Phacoanaphylactic endophthalmitis: a clinicopathologic review.

Lens-induced uveitis or phacoanaphylactic endophthalmitis (PE) is a chronic endophthalmitis with a zonal granulomatous inflammation surrounding a ruptured lens. One hundred forty four cases of PE were retrospectively evaluated clinically and histopathologically. The disease was not well recognized clinically as only six of the cases were given the clinical diagnosis of PE. Most cases (80%) occurred after trauma, surgical or non-surgical. The time after injury varied from two days to fifty nine years. Of those individuals less than 55 years of age who had no history of trauma. 29% were noted by clinical history to have microphthalmia. Although classically the inflammation of PE has been described as being confined to the anterior aspect of the eye, the choroid was involved with an inflammatory reaction in 76% of the cases.

Xanthine oxidase generation of toxic oxygen metabolites in acute uveitis.

Lodoxamide, a xanthine oxidase inhibitor, has antiphlogistic effects in the treatment of acute uveitis. The role of xanthine oxidase generated free radicals is discussed.

Pharmacologic modulation of acute uveitis with aminonicotinamide.

The hexose monophosphate shunt inhibitor 6-aminonicotinamide was observed to have an anti-inflammatory effect in the treatment of experimental uveitis. The electrons required for the reduction of molecular oxygen to superoxide radicals are generated by the pentose phosphate pathway in acute inflammatory cells. The inhibition of superoxide production is discussed as one of the potential antiphlogistic mechanisms.

Free radicals and antioxidants in the pathogenesis of eye diseases.

There is fairly convincing evidence that free radical mechanisms are involved in the pathogenesis of cataracts and uveitis and that antioxidants may be protective. Studies on retinal degeneration are almost entirely limited to dietary manipulation of vitamins C and D. Unfortunately, antioxidant properties are not easily isolated from other metabolic effects of vitamins. Cataracts, uveitis, and retinal degeneration cause nearly one-third of all blindness. The evidence that free radical mechanisms are important in the pathogenesis of these diseases is compelling incentive to encourage more extensive and detailed investigation.

Effect of antioxidant enzymes on experimental uveitis in rats.

The antioxidant enzymes superoxide dismutase and glutathione peroxidase have been observed to be effective antiphlogistic agents in severe experimental allergic uveitis induced by retinal S antigen in rats. The role that the high concentration of antioxidants found in the eye may play in modulating acute inflammation is discussed.

Pharmacologic modulation of acute ocular inflammation with quercetin.

Anti-inflammatory potentials of a safe, common dietary component, quercetin, were investigated in suppression of intraocular inflammation induced by retinal S antigen. Lewis rats sensitized to S antigen were treated daily with intraperitoneal injections of quercetin. Control rats with S-antigen-induced uveitis were similarly treated with diluent. When compared with controls the treated group showed marked reduction in uveal and retinal inflammation and in vasculitis and perivasculitis. Morphometric analysis revealed a significant reduction (p less than 0.005) in choroidal thickness when compared with that of control animals. These results clearly show the antiphlogistic effects of quercetin in experimental uveitis.

Anti-inflammatory effect of glutathione peroxidase on experimental lens-induced uveitis.

An acute lens-induced necrotizing intraocular inflammation was produced in Lewis rats. Treatment of these animals by intraperitoneal injection of glutathione peroxidase resulted in marked decrease in uveal inflammation, retinal edema, hemorrhage and vasculitis. Intraperitoneal injection of glutathione peroxidase resulted in increased levels of this enzyme in ocular tissue. These findings suggest that glutathione peroxidase can modulate acute lens-induced ocular inflammation by serving as a potent anti-inflammatory agent.

Pharmacologic modulation of acute ocular inflammation. I. Adenosine.

Modulation of signal transduction at the surface of inflammatory cells appears to influence acute inflammation. Adenosine, a well-known chemical messenger, inhibits the production of superoxide by stimulated neutrophils. In experimental allergic uveitis induced by sensitization with retinal 's' antigen, treatment with adenosine produced a marked reduction in the expected inflammation.

Effects of mydriatic agents on neutrophil migration.

We have investigated the effects of various mydriatic agents on the locomotion of polymorphonuclear leukocytes in vitro. Human as well as rat neutrophils showed a dose-dependent increase of migration into micropore filters when tested against cyclopentolate hydrochloride at a dose range between 16 and 63 micrograms/ml. At higher doses (250 micrograms/ml), a complete inhibition of neutrophil migration was observed. A commercially available cyclopentolate hydrochloride preparation showed identical effects. Little or no changes in neutrophil locomotion were seen with atropine, homatropine, scopolamine or tropicamide when tested at the same concentration range. Since addition of cyclopentolate to either the lower or upper compartment of the multiwell chemotaxis chamber gave virtually the same results, it is assumed that the drug most likely induces a chemokinetic neutrophil response. However, an additional chemotactic effect cannot be excluded. These in vitro observations may help to explain an accidental observation in a patient with severe anterior uveitis who showed a massive, localized leukocyte accumulation on the corneal endothelium after contact with a cyclopentolate-soaked cotton pledget.

Treatment of experimental lens-induced uveitis by dimethyl thiourea.

Dimethyl thiourea is a highly specific hydroxyl radical scavenger. The antiinflammatory potential of this hydroxyl radical scavenger was studied in Lewis rats sensitized with soluble lens protein. Intraperitoneal injection of dimethyl thiourea into the experimental animals at the onset of the disease resulted in marked reduction of intraocular inflammation, hemorrhage and edema, and eliminated the retinal and choroidal necrotizing vasculitis that was characteristic in untreated animals. These findings indicate that dimethyl thiourea may act as a potent antiphlogistic agent in the treatment of experimental lens-induced uveitis.

Role of free radicals in uveitis.

In acute inflammation, the tissue damage is generally mediated through polymorphonuclear leukocytes and macrophages. Recent studies on the mechanism of this leukocyte-mediated cytolysis have demonstrated that these cells, on stimulation, release a variety of reactive products. These metabolic products consist of superoxide and hydrogen peroxide, which in turn can form highly reactive species such as hydroxyl radicals. It is believed that these oxygen products play an important role in the tissue damage that occurs in inflammations such as uveitis. The ocular structures contain various antioxidant enzymes that normally protect against free radical mediated injury. In experimental animal models of uveitis, it has been shown that antioxidants and free radical scavengers can function as antiinflammatory agents and can protect the eye from inflammation-mediated tissue damage.

Role of oxygen radicals in experimental allergic uveitis.

The experimental autoimmune disease elicited by a large dose of retinal S antigen in guinea pigs is characterized by massive necrotizing uveitis and retinitis. Treatment of these animals with the antioxidants superoxide dismutase, catalase, and sodium benzoate resulted in marked reduction of uveal inflammation. The attenuated inflammation was characterized by a relatively well-preserved retina and retinal pigment epithelium along with a reduction of subretinal exudate and vitreous inflammation. These findings suggest that reactive oxygen metabolites may play a role in the destruction of ocular tissue and amplification of the inflammatory process in experimental uveitis.

Treatment of experimental granulomatous uveitis by lipoxygenase and cyclo-oxygenase inhibitors.

Lens-induced granulomatous uveitis was produced in brown Norway rats. To determine the role of the lipoxygenase and cyclo-oxygenase products of arachidonic acid in the modulation of granulomatous uveitis, one group of experimental animals was treated with nafazatrom, while another group was treated with nordihydroguaiaretic acid (lipoxygenase inhibitors). Both resulted in significant attenuation of granulomatous inflammation, with reduced giant-cell infiltration into the choroid. In contrast, indomethacin (a cyclo-oxygenase inhibitor) therapy resulted in increased giant-cell formation. These findings suggest that the lipoxygenase and cyclo-oxygenase products of arachidonic acid play a role in the development of granulomatous uveitis and that such inflammation can be selectively suppressed by lipoxygenase inhibitors.

Modulation of experimental phacoanaphylactic endophthalmitis with the antioxidants sodium benzoate, and 2,3-dihydroxybenzoic acid.

The antioxidants sodium benzoate and 2,3-dihydroxybenzoic acid reduced the inflammatory response in experimental phacoanaphylactic endophthalmitis. The 2,3-dihydroxybenzoic acid was by far the more effective antiphlogistic agent. The molecular mechanisms that may have contributed to the observed difference in antiphlogistic activity are discussed.