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Inside IOVS 2001
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August 2001 |
Therapeutic Management of Ocular Diseases: Diagnosis and Treatments
MMP-7: A Role in Pterygium?
The involvement of the matrix metalloproteinases (MMPs) in the pathogenesis of pterygia has recently received ample attention. Di Girolamo et al. (p. 1963) describe the abundant expression of active and latent MMP-7 in pterygia versus normal conjunctiva. Both forms of MMP-7 were localized to the pterygium epithelium, vascular endothelium and infiltrating leukocytes, as well as detected in the supernatants of organ cultured pterygia. MMP-7 is a multifunctional enzyme that potentiates apoptosis, amplifies inflammation, mediates wound healing, and participates in vascular and cellular invasion. The authors propose that MMP-7 is a key component in developing pterygia and targeting its activity may be of therapeutic benefit.
Naked DNA Gene Therapy
Stechschulte et al. (p. 1975) show that naked plasmid DNA injected into the corneal stroma results in the efficient transfection of corneal keratocytes and epithelium. Biologically relevant levels of VEGF and its soluble receptor are shown to promote and inhibit, respectively, corneal neovascularization. Gene products are expressed within an hour of DNA expression and persist for at least ten days. As protein-based therapeutics become increasingly common, naked DNA gene therapy should prove useful in the treatment of corneal disease.
a1-PI: A Role in Keratoconus?
In corneas of keratoconus, a disease that thins and scars the stroma, levels of acid phosphatase and cathepsin B are elevated and those of a1-proteinase inhibitor (a1-PI) and a2-macroglobulin are reduced, especially in the epithelium. Transcription factor Sp1 was also found increased. Maruyama et al (p. 1980) demonstrated that in corneal epithelial cells, as in stromal cells, the a1-PI promoter activity was suppressed by Sp1 overexpression. Sp1 did not affect the promoter activities of other above-mentioned genes. These results support the theory that the corneal epithelium, along with stroma, is involved in keratoconus. The Sp1-mediated downregulation of the a1-PI gene may be a key event in the disease development.
Fiber Gene and Adenovirus Identification
Adenoviral ocular infection is the leading worldwide cause of viral conjunctivitis. Many serotypes of subgenus D are associated with highly contagious, epidemic keratoconjunctivitis and acute follicular conjunctivitis. Fiber protein mediate cellular attachment and hemagglutination with hexon gene, provides for serotype specificity of adenoviruses. Combined use of polymerase chain reaction and restriction enzyme analysis of the fiber gene has been found useful in the molecular discrimination of subgenus D adenoviruses. The accuracy and rapidity of this new detection method by Adhikary et al. (p. 2010) is supportive of further use of fiber-based methodology for the rapid identification of important adenoviruses from other subgenera.
IL-13: A Role in Uveitis?
One injection into the anterior chamber of recombinant human interleukin (IL)-13 performed simultaneously with a single footpad injection of lipopolysaccharide induced a significant clinical and histopathological inhibition of endotoxin-induced uveitis in Lewis rat. High levels of IL-13 were detected in the aqueous humor up to 18 hours, whereas IL-13 was not detected in the corresponding serums. A decreased expression of proinflammatory cytokine and chemokine mRNAs was observed in the iris ciliary body and the retina from IL-13-treated rats. In human pathology, systemic therapies (steroids and immunosuppressors) induce side effects that explain the increasing interest for local therapy in animal models of uveitis. The present study by Lemaitre et al. (p. 2022) could be a promising therapeutical alternative to systemic steroids in human uveitis.
Inhibition of EAAU by CTAL4-Fc
Anterior uveitis is a leading cause of eye blindness. So far, the treatment of uveitis and, especially, recurrent uveitis has been limited and difficult. Shao et al. (p. 2016) have demonstrated that CTLA4-Fc, a fusion protein which blocks CD28-B7 costimulatory pathways for complete T cell activation, prevents the development of experimental autoimmune anterior uveitis (EAAU), an animal model for anterior uveitis. These results provide an important clue that the CD28-B7 costimulatory signals are required for T cells to initiate immune response in the eye and may serve as a potential target for immunotherapeutic strategies designed to regulate autoimmune diseases, including eye inflammation.
11b-HSD: Controlling IOP?
The isozymes of 11b-hydroxysteroid dehydrogenase (11b-HSD) underpin corticosteroid hormone action, principally through the interconversion of hormonally active cortisol to inactive cortisone. A known association between corticosteroids and ocular diseases such as glaucoma exists. The expression of 11b-HSD type 1 in the human nonpigmented ciliary epithelium, cortisol concentrations in excess of cortisone in the aqueous humor, and the systemic inhibition of the 11b-HSD isozymes resulting in a fall in intraocular pressure, suggest a locally generating cortisol system, which may contribute to aqueous humor production and drainage. These observations by Rauz et al. (p. 2037) could potentially have ramifications for the future therapeutic management of patients with glaucoma.
A2B Receptor: Controlling Neovascularization?
Purine nucleosides can modulate numerous cellular functions. Adenosine is released in response to hypoxia and can modulate endothelial cell gene expression. Grant et al. (p. 2068) demonstrate that an adenosine analogue increases proliferation and migration of cultured human retinal endothelial cells, and stabilizes endothelial tube formation. These effects are inhibited using antagonists selective for a specific adenosine receptor subtype. The signal transduction molecules ERK and CREB are activated in adenosine-stimulated endothelial cells, and activation of these kinases can be partially inhibited by specific adenosine receptor antagonists. These findings raise the possibility of targeting specific adenosine receptors as a therapeutic approach to modulating aberrant retinal neovascular responses.
a2SA: Controlling Ischemia?
Ischemia leads to irreversible retinal damage including the massive loss of retinal ganglion cells (RGC). Lafuente et al. (p. 2074) document that 90 minutes of retinal ischemia induce the loss of approximately half of the RGC population by 7 days. Moreover, ischemia-induced RGC loss continues in the following 2 weeks. RGC loss may be prevented fully with a2-selective adrenergic agonists (a2SA) pretreatment and partially when a2SA are administered shortly after ischemia. This indicates a potent neuroprotective effect for a2SA against retinal ischemia and supports a potential therapeutic role in retinal diseases associated with ischemia.
Genistein: Controlling Macular Edema?
Genistein, a safe tyrosine kinase pathway inhibitor naturally found in soy, significantly reduced retinal vascular permeability in the streptozotocin diabetic rat in a dose response fashion. The results by Nakajima et al. (p. 2110) suggest that genistein may be beneficial in the treatment and prevention of clinical diabetic macular edema. As the current therapy for diabetic macular edema has side effects, and is not beneficial for all patients, the public health implications of a safe pharmacologic preventive therapy are profound.
Müller Glia: Cone Progenitor Cells?
The possibility that neural stem cells might persist in the adult mammalian retina has galvanized vision researchers to adopt a more optimistic perspective when considering the possibility that ‘regenerative medicine’ might one day be available as a therapeutic treatment for retinal disease. It is now accepted that neural stem cells exist in the adult mammalian brain, and some researchers believe that they derive from specialized populations of glial cells. In adult teleost fish, regeneration of retinal neurons, including photoreceptors, is a robust phenomenon. Wu et al. (p. 2115) show that retinal Müller glia in goldfish are a potential source of progenitors that can replace cone photoreceptors destroyed by laser lesions.
Improved VEP Diagnosis
A high level of inter-subject variability has long been recognized as one of the major factors limiting clinical use of the visual evoked potential (VEP) in diagnosing ocular disease. Recent advances in multifocal recording techniques have extended the possible applications of the VEP to objective perimetry. In this issue, Klistorner and Graham (p. 2145) describe a method that dramatically reduces intersubject variability by scaling the subject’s VEP responses based on underlying electroencephalogram signal levels. This will significantly increase the sensitivity of the test when utilizing a normal database and facilitate the objective detection of defects in early glaucoma.
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