New Insights in Treating Ocular Diseases

PAI-1 and Aqueous Outflow

Plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators. These proteases function in fibrinolysis and in controlled extracellular proteolysis. Here, Masos et al. (p. 1006) show that the PAI-1 gene is expressed in the rodent eye specifically in the ciliary processes epithelium, and that PAI-1 inhibitory activity is found in the aqueous humor. This localization implicates PAI-1 in balancing proteolysis and fibrinolysis specifically in the anterior segment of the eye. It is possible that PAI-1 overproduced in the ciliary processes may obstruct aqueous outflow; therefore, the PAI-1 gene could be a target for a novel therapeutic strategy to balance the IOP. 

Eosinophils and Ocular Allergy

Eosinophils are key damage producing cells in allergic eye diseases. Interactions between eosinophils infiltrating the conjunctiva and fibroblasts form the basis for the pathophysiology. Solomon et al. (p. 1038) found that coculturing human peripheral blood eosinophils with conjunctival fibroblasts increases their survival and functional activity and causes their adherence. These actions are mediated through cytokines such as IL-3, IL-5, and GM-CSF. Understanding the mechanisms of eosinophils activation in ocular allergy will contribute to the development of therapies that block the detrimental effects of these cells. 

NGF and Corneal Disease

Nerve growth factor (NGF) is an endogenous mediator produced by several cells including basal corneal epithelial cells. An increase of corneal NGF was observed following mechanical injury. Lambiase et al. (p. 1063) show in vitro and in vivo effects of NGF on human and rat corneal epithelial cells at molecular, biochemical, and cellular levels, demonstrating a modulatory role of NGF on the epithelial healing process. These findings suggest a potential clinical use of NGF in corneal epithelial diseases and an important role of NGF in the crosslink between corneal epithelium and keratocytes. 

A Device for Abnormal Eye Movements

In acquired pendular nystagmus, the eyes oscillate horizontally and/or vertically, causing blurred vision and oscillopsia. Stahl et al. (p. 1084) describe a device that uses electronically controlled prisms to move retinal image in lockstep with the patients’ eyes, thereby improving vision. This device may be useful in treating other ocular motor disorders. 

Immunophilins and Ganglion Cell Death

The immunophilin-agonist FK506 prevents glutamate-induced retinal cell death in culture and prevents glutamate-induced apoptosis in cultured hippocampal neurons. Freeman and Grosskreutz (p. 1111) describe the presence of the immunophilin FKBP12 in retina and retinal ganglion cells (RGCs). In addition, the authors demonstrate the neuroprotective effects of orally-administered FK506 on RGCs after optic nerve crush in the rat. These data raise the possibility that immunophilin-binding agents may have a role in disease conditions characterized by RGC degeneration, including glaucoma. 

Integrins and Diabetic Retinopathy

Leukocyte adhesion to the retinal vasculature is one of the earliest events in experimental diabetes. Barouch et al. (p. 1153) demonstrate that the leukocyte integrins CD18 and CD11b are causal in this process by uncovering a systemic upregulation in the expression and bioactivity of these molecules on diabetic neutrophils. When CD18 blockade is instituted in vivo, the level of diabetic retinal leukostasis is reduced by 62%. Thus, CD18 and CD11b may help trigger the cascade of events leading to diabetic retinopathy. Further definition of the molecules involved in diabetic retinal leukostasis may ultimately lead to the development of novel therapeutic strategies for diabetic retinopathy. 

LEDGF and Photoreceptor Survival

LEDGF is a newly isolated survival and growth factor for many cell types. Nakamura et al. (p. 1168) have studied the effect of LEDGF on the survival of embryonic chick retinal photoreceptor cells in culture under serum starvation and heat stress. In the presence of LEDGF, those cells expressed higher levels of Hsp90 and manifested increased resistance to these stresses. 

Angiotensin II and VEGF Induction

Otani et al. (p. 1192) have investigated the effect of angiotensin II (AII) on vascular endothelial growth factor (VEGF), a potent angiogenic and vasopermeability factor, in bovine retinal microcapillary pericytes. Angiotensin II induced a significant VEGF expression via transcriptional activation of the VEGF gene. This paracrine action of VEGF produced by pericytes might be important in the early stages of diabetic retinopathy. This study suggests that AT₁ blockers, as well as ACE inhibitors, might effectively prevent the progression of diabetic retinopathy in early stages of the disease. 

Carotenoids and AMD

Lutein and zeaxanthin are dietary carotenoids that accumulate in the inner layers of the human fovea and comprise the macular pigment. Rapp et al. (p. 1200) found that these carotenoids are also present in human rod outer segment (ROS) membranes where they may function as antioxidants. ROS concentrations of lutein and zeaxanthin were significantly higher in the perifoveal retina than in periphery. It is possible that an antioxidant function of lutein and zeaxanthin in ROS membranes of the perifoveal retina could be the basis for a protective role in age-related macular degeneration.