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with neuronal and vascular cells in the retina, these pathological abnormalities likely contribute to diabetes-induced retinal dysfunction.
Retinal microglial are also impacted by diabetes, although further study is required to clarify the causes and effects of microglial activation in diabetic retinopathy. Microglia become hypertrophic in rat retina after 1 month of diabetes, and the number of reactive microglia is significantly increased in the OPL after 4 months, while increases in the outer nuclear and photoreceptor layers occur after 14 months (19). Diabetes upregulates inflammatory cytokines, such as TNF alpha, which activate microglia and induce the production of cytotoxins that may lead to retinal cell death. The activation of microglia after 4 weeks of diabetes, prior to neuronal death, was recently reported to occur in discrete regions of the rodent retina, and likely indicates localized inflammatory responses to diabetic insults on retinal cell populations (21).
NEUROINFLAMMATION IN DIABETIC RETINOPATHY
The pathological alterations in retinal neurons and glial cells in diabetes generally remain below the threshold of detection by ophthalmoscopy. Ophthalmologists have therefore focused on the details of the vascular lesions such as number of microaneurysms, area of macular thickening, quadrants of venous beading or hemorrhages, or degree of neovascularization, to classify and stage diabetic retinopathy. A broader perspective of fundus changes that include increased retinal blood flow and permeability, tissue edema, gliosis, macrophage infiltration and leukostasis, tissue damage (including neuronal apoptosis), and attempts at repair (such as neovascularization) are pathophysiological features that can be considered components of chronic retinal inflammation.
The nature of this chronic activation of the defense mechanisms within the retina, as well as the systemic immune-cell response to inflammatory markers on the vasculature, are still under intense investigation, but clearly includes the release of numerous peptide growth factors (109), activation of the complement pathway (110), increased expression of Fas ligand (111), activation of microglial cells (19), and macrophage infiltration (112). Adaptive inflammation is a normal, highly conserved physiologic response to any type of tissue injury including viral infection, traumas or tumors, and constitutes an attempt to heal the injury and maintain tissue viability. For example, increased expression of interleukins, VEGF or recruitment of macrophages may be designed to remove damaged cells and help maintain the viability of their surviving neighbors. This inflammatory response is turned off when the initial insult subsides. However, when the injury persists, the response continues unabated, and the deleterious effects of proinflammatory cytokineand immune-cell activation may outweigh the benefits. Consideration of the dual roles of the retinal immune response in diabetes is important because, though the targeted inhibition of proinflammatory molecules may provide beneficial effects in the short term, chronic administration may impair the integrity of existing vascular or neuronal cells required for normal retinal function.
HISTORICAL PERSPECTIVE ON DIABETIC RETINOPATHY
The first description of diabetic retinopathy by von Graefe in 1856 (113) discussed the presence of yellow liquid exudates and red hemorrhages in the retina of a patient with diabetes. Over the ensuing 150 years, clinicians have focused on the visually
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detectable appearance of pigmented red lesions in the retina as the primary feature of diabetic retinopathy. This approach is analogous to the finding of pigment clumping as the primary feature of retinitis pigmentosa, whereas modern molecular and genetic studies have confirmed that primary defects reside in the photoreceptors, and pigmentary migration is a secondary hyperplastic response to photoreceptor cell death. There is a long history of anatomical and electrophysiological evidence for alterations in the neurosensory retina as a prominent consequence of diabetes. In 1961 and 1962, Wolter (60) and Bloodworth (61) emphasized the loss of retinal neurons in areas remote from vascular changes as a prominent feature in histopathological studies of postmortem human eyes. Their studies were followed by Simonsen’s discovery in 1969 (114) that patients with diabetic retinopathy had impaired ERG responses. Simonsen’s observations were extended by Bresnick, who found that the b-wave amplitudes, implicit times, and OPs were reduced in patients with diabetic retinopathy. In fact, the ERG changes proved to be better predictors of progression from severe nonproliferative to high-risk proliferative retinopathy than the vascular changes revealed by fundus photographs (115, 116). In 1986, Bresnick (59) proposed that diabetic retinopathy be viewed as a neurosensory disorder. His proposal was supported by numerous reports of impaired contrast sensitivity (42, 117), dark adaptation (40, 118) and color vision (119, 120) in patients with varying degrees of retinopathy. In 1997, Ghirlanda (121) proposed that the initial impact of diabetes on the retina involves the neurosensory retina, and that microvascular abnormalities maybe a secondary development.
During the late 1990s, several reports showing specific cellular defects in the neurosensory retina in human eyes and animal models of diabetes began to provide a mechanistic basis for the functional alterations that had been long observed. These studies included evidence of Müllercell activation in human eyes (95), abnormal glutamate metabolism (87, 89), microglial cell activation (18, 19) and neuronal apoptosis (63, 64, 66). Taken together, these data conclusively demonstrated that diabetes exerts a major impact on the neuroglial parenchyma of the retina. Thus, the term “microvascular disease” fails to adequately describe diabetic retinopathy. We propose that it should be replaced by a more comprehensive understanding of diabetic retinopathy as functional and structural alterations in the retina due to diabetes.
The question arises as to why nearly half a century transpired before the neurovascular concept of diabetic retinopathy began to gain acceptance. Clinical fluorescein angiography was introduced in 1960 (122), and the classic studies of vascular lesions in trypsin-digested retinas were published in 1961 (123). These studies emphasized the same features in the retina observed clinically; that is, microaneurysms, hemorrhages, nonperfused capillaries and neovascularization. During the 1970s and early 1980s, efforts were appropriately applied to treat vision-threatening stages of diabetic retinopathy such as macular edema and proliferative retinopathy. The positive outcomes of the Diabetic Retinopathy Study and Early Treatment Diabetic Retinopathy Study provided promise that lasers and vitrectomy would contain the problem of diabetic retinopathy. In spite of its effectiveness in preventing legal blindness, however, patients and ophthalmologists realized that laser photocoagulation reduced the risk of vision loss only by about 50%, and successfully treated patients often had unsatisfactory vision for seeing fine details and colors, or driving at night. Moreover, numerous clinical trials of potential pharmacotherapeutic compounds have failed to arrest the development or progression
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of vision loss in patients, so there may now be more willingness to consider broader alternative approaches to the treatment of diabetic retinopathy. As of late 2007, no drug which targets retinal blood vessels has been approved for clinical use by the Food and Drug Administration. VEGF inhibitors are under investigation for diabetic macular edema and proliferative diabetic retinopathy (23,124), and while the results of early-stage studies are promising, the long-term effects of blocking VEGF are uncertain. In addition to its role in vascular permeability and neovascularization, VEGF signaling also provides trophic support for neurons (125–127) as well as vascular cells, so prolonged interruption of VEGF action may not only reduce macular edema and vascularization but also compromise the viability of the retinal cells required for vision.
Recent research using rodent models of diabetes has identified a number of compounds with potential antiinflammatory and neuroprotective properties. Growth factors, including nerve growth factor (NGF), insulin-like growth factor (IGF-1) and brain derived neurotrophic factor (BDNF), have been demonstrated to prevent diabetes-related neuroretinal cell death in STZ rats (62,70,82). In 2005, Krady et al. demonstrated the efficacy of minocycline, a semisynthetic tetracycline, as an inhibitor of retinal inflammation, microglial activation and caspase-3 activation in STZ-diabetic rats (21). The prostaglandin F2alpha analogue, latanoprost, is another neuroprotective agent reported to decrease both the number of activated caspase-3-immunoreactive cells, and the number of TUNELpositive cells in STZ rat retina, indicating its effectiveness in the suppression of diabetesinduced apoptosis (128). Cannabidiol, a nonpsychotropic cannabinoid, also possesses neuroprotective and antiinflammatory properties, and is capable of reducing oxidative stress, inflammation, and neurotoxicity in STZ-diabetic rat retina (68). These encouraging findings suggest that retinal neurodegeneration and inflammation, two potentially visionthreatening complications of diabetes, can be diminished in rodent models of diabetes. Further work is required, however, to investigate existing and novel compounds in preclinical testing before clinical trials on targeted pharmacotherapies can be initiated.
NEUROGLIAL DYSFUNCTION IN DIABETIC RETINOPATHY.
The spectrum, interrelationships, and significance of changes in retinal neuroglial cells in diabetes remain incompletely defined at this point. It is clear, however, that the impact of diabetes on the retina includes impaired outer-retina function (delayed dark adaptation) and inner-retina dysfunction (impaired visual fields, impaired contrast sensitivity, and color vision). Likewise, histopathologic studies reveal evidence of retinal pigment epithelial degeneration, as well as atrophy of the ganglion cell layer, and inner nuclear and plexiform layers. The death of retinal neurons appears to be by apoptosis associated with caspase activation. In keeping with the recognition that neurons and glial cells have a linked function, LaNoue et al. (89) observed that retinal conversion of glutamate to glutamine is impaired by diabetes. Thus, glutamate may accumulate in the interstitial fluid, leading to neuronal glutamate excitotoxicity and dysregulation of normal synaptic transmission.
The relationship between neurons and glial cells in the CNS is intimately symbiotic. One class of cells cannot function correctly without the other. The metabolic support provided by Müller cells and astrocytes in the retina is undoubtedly critical to the functional neural output of the retina, and contributes to maintenance of the vasculature.
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Dysfunction in one or more of these elements, therefore, will almost certainly result in altered visual function. Future studies of vision loss in diabetes must consider how neurons and glial cells interact with each other and with elements of the vasculature under both normal and diabetic conditions, in order to create a more comprehensive understanding of retinal function and vision loss in diabetes.
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13 The Role of Inflammation
in the Pathophysiology of Diabetic
Retinopathy
Lauren E. Swenarchuk, Linda E. Whetter,
and Anthony P. Adamis
CONTENTS
INTRODUCTION
PATHOPHYSIOLOGY OF DIABETIC RETINAL VASCULAR INJURY:
THE ROLE OF LEUKOSTASIS
INFLAMMATORY CELLS PROMOTE AND REGULATE THE
DEVELOPMENT OF ISCHEMIC OCULAR
NEOVASCULARIZATION
GROWTH FACTORS AS MEDIATORS OF INFLAMMATION
IN DIABETIC RETINOPATHY
TUMOR NECROSIS FACTOR-α
STUDIES WITH ANTI-INFLAMMATORY AGENTS LINK DIABETIC
RETINOPATHY AND INFLAMMATION
CONCLUSIONS
REFERENCES
ABSTRACT
The inflammatory nature of diabetic retinopathy (DR) was first suggested by the finding that it occurred less frequently among diabetic patients taking salicylates for rheumatoid arthritis. Subsequent work has identified many features that are characteristic of inflammation, including increased blood flow, vascular permeability, and edema, as well as the influx of cells that are associated with inflammatory responses. While DR involves defects in many retinal cell types, the retinal vasculature appears to be the principal locus of the inflammation-linked damage.
From: Contemporary Diabetes: Diabetic Retinopathy
Edited by: E. Duh © Humana Press, Totowa, NJ
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