Overview

Diabetic retinopathy (DR) is a major cause of blindness worldwide. For many patients the few preventable measures, strict blood glucose and blood pressure control, poorly predict or prevent the disease. There is increasing scientific evidence that inflammation plays a pathogenic role. In diabetic patients leukocytes, for example, inundate the retinal vasculature. And in patients with advanced DR and diabetic macular edema (DME), inflammatory cytokine levels increase in the aqueous and vitreous. Such observations provide strong rationale for anti-inflammatory based therapies. Our lab recently showed that levels of the inflammation mediator PGE2 elevate in the vitreous of patients with advanced DR. Further, these PGE2 levels correlate with VEGF and other cytokines. Several experimental systems show PGE2 inhibition prevents or slows progression of DR.  Our central hypothesis is that PGE2 plays a prominent role in the underlying inflammatory-mediated vascular damage that results in vascular leakage, capillary non-perfusion, and retinal ischemia in DR. Our major objectives are to: 1) analyze intraocular PGE2 and cytokine levels in diabetic patients over time to define their relationship with progression of DR, 2) investigate the long-term effect of pharmacologic inhibition of retinal PGE2 by topical ketorolac (Acuvail) on intraocular cytokine levels and on progression of DR and incidence of DME. Our long-term goal is to prevent, slow and/or reverse DR and DME that otherwise would result in visual impairment and blindness.   

Investigations

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Putative Pathway for the role of PGE2 and inflammatory cytokines in the pathogenesis of DR1

 

 

 

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Cyclooxygenase mediated biosynthesis of prostaglandins (adapted from Kim et al.)2

 

 

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Elevated Inflammatory Mediators in the vitreous of eyes with Proliferative Diabetic Retinopathy (PDR) compared to eyes without diabetes (Control)3

 

 

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Reduction of inflammatory cytokines in eyes with PDR after 3 days of topical ketorolac treatment versus placebo4

 

 

 

1.    Kim, S. J. Novel Approaches for Retinal Drug and Gene Delivery. Transl. Vis. Sci. Technol. 3, 7 (2014).

2.    Kim, S. J., Flach, A. J. & Jampol, L. M. Nonsteroidal Anti-inflammatory Drugs in Ophthalmology. Surv. Ophthalmol. 55, 108–133 (2010).

3.    Schoenberger, S. D., Kim, S. J., Sheng, J., Rezaei, K. A., Lalezary, M. & Cherney, E. Increased prostaglandin E2 (PGE2) levels in proliferative diabetic retinopathy, and correlation with VEGF and inflammatory cytokines. Investig. Ophthalmol. Vis. Sci. 53, 5906–5911 (2012).

4.    Schoenberger, S., Kim, S., Shah, R., Sheng, J. & Cherney, E. Reduction of interleukin 8 and platelet-derived growth factor levels by topical ketorolac, 0.45%, in patients with diabetic retinopathy. JAMA Ophthalmol. 132, 32–37 (2014).

5.    Schoenberger, S. D. & Kim, S. J. Nonsteroidal anti-inflammatory drugs for retinal disease. Int. J. Inflam. 2013, (2013).