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Inside IOVS 2001
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February 2001 |
Damaging/Protecting Ocular Tissues
PLA2: Good in Tears?
Using a time-resolved fluoroimmunoassay, Saari et al. (p. 318) observed that the mean concentration of phospholipase A2 (PLA2) in normal tears was 54.5 ± 33.9 µg/ml, which is the highest reported PLA2 content in human secretions. It was highest in young adults and a decrease of PLA2 concentration occurred with an increase of age. There were no significant differences in PLA2 content of tears between the genders. PLA2 plays a substantial antibacterial role in tears which should be investigated in more detail in contact lens wearers and in different eye diseases.
12-HETrE: Bad in Tears?
Mieyal et al. (p. 328) describe the detection of 12-hydroxyeicosatrienoic acid (12-HETrE) in human tear film. Previous observations in animal models have indicated that this cytochrome P450-derived arachidonic acid metabolite is a potent inflammatory mediator and angiogenic factor. The implied contribution of P450-derived metabolites to ocular surface inflammation in humans lends insight to the relative lack of efficacy of non-steroidal anti-inflammatory agents vs. corticosteroids. Moreover, the finding of 12-HETrE in tear film of inflamed eye bridges the findings in animals to humans and provides the impetus for the development of novel treatments for corneal inflammation and neovascularization. Such treatments may apply to acute trauma as well as the prevention of complications associated with contact lens wear.
HLA-DR: Up in Glaucoma
Immunohistochemistry revealed an upregulation of HLA-DR expression in optic nerve head astrocytes in glaucoma. In addition, serum titers of the cytokine IL-10 were found elevated in glaucoma patients compared to age-matched normal subjects. In vitro experiments using cultured lamina cribrosa astrocytes revealed that the expression of HLA-DR and its induction by selective cytokines increase in optic nerve head astrocytes exposed to simulated ischemia. Yang et al. (p. 365) suggest that cytokines and/or ischemia may induce HLA-DR expression in optic nerve head astrocytes. Therefore, optic nerve head astrocytes are likely locus for immunoregulatory events that participate in the pathogenesis of glaucomatous neurodegeneration.
Th1/2: Involved in Keratitis
Herpetic stromal keratitis is thought to be a T cell-dependent immune response to herpes simplex virus (HSV)-1 infection of the cornea, with either T-helper (Th)1 or Th2 immune responses implicated in primary infection. Stumpf et al. (p. 372) now show that the immune response in recurrent HSV-1 infection of the cornea, has features of both Th1 and Th2 responses, with the production of IL-12 and IFN-g as well as IL-6 and IL-10. In addition, it is possible that neutrophils may be involved in some of this cytokine production.
aA: Protecting the Lens?
When aA-crystallin is overexpressed in human lens epithelial cells, an elevation in the levels of the endogenous antioxidant glutathione and protection from UV-A induced cell death is seen. The relationship of GSH to aA expression and molecular mechanisms of GSH elevation were examined in the study by Kannan et al. (p. 409). A positive correlation between aA content and GSH and an upregulation of mRNA and protein for regulatory and catalytic subunits of the rate limiting enzyme for GSH synthesis, g-glutamylcysteine synthetase, were found. In lenses from aA knock out mice, the GSH biosynthetic pathway was significantly impaired prior to cataract formation. Future studies with aA mutants will reveal whether the two phenomena i.e., GSH upregulation and cell protection in aA expressing cells are linked to or are independent of known chaperone function of aA.
ACE Inhibitors: Controlling Angiogenesis
Lonchampt et al. (p. 429) have demonstrated that the Angiotensin-Converting-Enzyme inhibitor (ACEi) perindopril (Coversyl®) (4mg/kg) inhibited (29%, p<0.001) the neovascularization process induced in the retina of neonatal mice exposed to relative hypoxic conditions. Same results (14%, p<0.05) were obtained with losartan (10mg/kg), an angiotensin-1 receptor antagonist. These results in mice confirmed the beneficial effects of lisinopril, another ACE inhibitor, on the progression of human proliferative diabetic retinopathy. These observations suggest that the angiotensin system plays a role in retinal neovascularization and from a therapeutic point of view, inhibition of ACE could be of interest, at least in part, for the prevention or treatment of proliferative retinopathies such as proliferative diabetic retinopathy.
Macular Pigment: Protection from AMD?
Age-related macular degeneration (AMD) is the most common cause of blindness in the Western world, and there is a growing body of evidence suggesting that cumulative blue light damage and/or oxidative stress may be responsible. Consequently, it has been hypothesized that the macular pigment (MP), which screens blue light and acts as an antioxidant, may protect against AMD. In this study, Beatty et al. (p. 439) found a relative lack of MP in elderly subjects, and in eyes predisposed to AMD. Since MP is entirely of dietary origin, the possibility that the course of AMD could be modified by dietary means requires further evaluation.
Halothane: Protecting Photoreceptors
High doses of visible light induce cell death of photoreceptors. Receptor for the damaging light is rhodopsin and a critical determinant for the light damage susceptibility of mice is the rate of rhodopsin regeneration in the visual cycle (Wenzel et al., J. Neurosci., in press). Manipulation of the rhodopsin regeneration kinetics might, therefore, influence light damage susceptibility in mice and rats. Keller et al. (p. 476) used halothane anesthesia to almost completely inhibit rhodopsin regeneration and showed that this treatment protects photoreceptors against damage by white light. This finding corroborates the role of rhodopsin in light damage and supports the observations of other laboratories that halothane may compete with the rhodopsin chromophore 11-cis retinal for the opsin binding site.
Sildenafil: Bad in RP?
Retinitis pigmentosa (RP) is a group of inherited retinal degenerations with many causes, including mutations in the phosphodiesterase-6 (PDE6) genes. Sildenafil (Viagra®) is a specific inhibitor of PDE and is commonly used to treat erectile dysfunction. Behn and Potter (p. 523) investigated the effects of sildenafil on mice that are heterozygous for a PDE mutation. Sildenafil caused a reversible and dose-dependent decrease in retinal function, as measured by electroretinography (ERG). These results could have a bearing on the safety of the use of sildenafil in humans.
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