Secondary Events and Sequelae: Importance in Ocular Pathology and Treatment

Abstract

Diabetic Corneas and AGE

Corneal complications occur frequently in diabetic patients and may be related to nonenzymatic glycation of matrix proteins and the formation of advanced glycation end products (AGEs). Kaji et al. (p. 362) identified increased AGE formation in corneas from diabetic human subjects vs. suitable controls. The authors also found that when immortalized human corneal epithelial cells were cultured on nonenzymatically glycated laminin, cell adhesion was attenuated and epithelial spreading was reduced. If glycation of laminin was prevented by adding aminoguanidine, inhibition of epithelial cell adhesion and reduction of cell spreading were prevented in a dose-dependent manner, suggesting that AGE formation may be important in the corneal abnormalities of diabetes. 

LASIK and Keratocyte Activation

Using in vivo confocal microscopy, Vesaluoma et al. (p. 369) showed that post-interface keratocyte activation was greatest on day 3 postoperatively and lasted up to 2 weeks. This confirmed the profound differences between LASIK and PRK in the extent and duration of the initial keratocyte response. The results, however, suggested that a thin flap predisposed prolonged keratocyte activation and production of abnormal extracellular matrix at the interface. 

Conjunctivochalasis (CC) and MMPs

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are implicated in connective tissue degradation and remodeling. The looseness of redundant conjunctiva suggests that MMPs may contribute to the pathogenesis of CC. The present study by Li et al. (p. 404) shows that the expression and activity of MMP-1 and MMP-3, but not MMP-2 or MMP-9, are significantly increased in CC fibroblasts while the expression of TIMP-1 and TIMP-2 is not changed vs. normal conjunctival fibroblasts. Collectively, these data help explain how CC manifests excessive degradation of the conjunctival matrix. 

IOP and Neurotrophins

The hypothesis that retinal ganglion cell loss in glaucoma results from neurotrophin withdrawal was tested in rats by determining the coordinated responses of several retinal and optic nerve head proteins to elevated IOP. Although neurotrophin labeling in the nerve head and retina was lost, Johnson et al. (p. 431) found that the earliest protein alteration was a reduction in nerve head gap junctions, indicating reduced glial buffering capacity. Also, eyes with prolonged pressure elevation demonstrated endogenous neurotrophin expression in nerve head glia and retinal ganglion cells. Neurotrophin withdrawal may be one of several mechanisms contributing to optic nerve damage. 

Trabeculoplasty (TP) and Cytokines

Laser TP, a common treatment for glaucoma, induces sustained matrix MMP expression within the juxtacanalicular region of the aqueous humor outflow pathway. Since these MMPs increase aqueous humor outflow facility, this can explain the efficacy of this treatment for glaucoma. Bradley et al. (p. 422) found that, within 8 hours following laser treatment, trabecular IL-1α, IL-1β, and TNFα are increased, and that the latter two are secreted. These cytokines are strong stimulators of trabecular MMP expression. Furthermore, adding the IL-1 receptor antagonist or TNFα-blocking antibodies to culture medium from laser-treated anterior segments eliminates the MMP induction. Thus, secreted IL-1β and TNFα may mediate the MMP response and the efficacy of laser TP in glaucoma. 

AMD, Drusen, and Lipofuscin

Delori et al. (p. 496) investigated RPE lipofuscin distribution over drusen in ARM/AMD using autofluorescence (AF) imaging. The authors found that a distinct AF pattern was frequently spatially associated with hard and soft drusen. This pattern consists of a center with low AF surrounded, in some cases, by an annulus of high AF. For most drusen, the AF distribution is consistent with a peripheral displacement of the overlying RPE cytoplasm and/or lipofuscin granules without an actual loss of the RPE. However, focal decreases in RPE lipofuscin correspond with some drusen and may mark sites where drusen have regressed. 

Müller Cells and Tractional Forces

Tractional forces of the type that cause retinal detachment are generated by Müller cells in response to stimulation by certain growth factors. The study by Mamballikalathil et al. (p. 529) describes a paracrine relationship between RPE and Müller cells in which RPE-secreted growth factors stimulate extracellular matrix contraction by Müller cells. RPE-secreted contraction-stimulating activity was detected throughout RPE dedifferentiation from epithelial to fibroblastic cells, was highest in the fibroblastic cells, and could be attributed to IGF-1 and PDGF. Thus, RPE cells have the capacity to induce fibrocontractive responses in Müller cells through local secretion of contraction-promoting growth factors. 

RD and the Vascular Plexus

In the rd mouse, photoreceptor loss is followed by atrophy of the deep vascular plexus. Wang et al. (p. 537) found that, with time, RPE cells invade the retina and become associated with vascular foci at the outer retina border. The vessels, arising from the superficial plexus that supply these foci, exert tension on axon bundles of the optic fiber layer, resulting in axonal distortion and contributing to the loss of retina ganglion cells. The loss of both the deep vascular plexus and the reduction in retinal ganglion cells may impede repair strategies at the photoreceptor layer.