Access Type

Open Access Dissertation

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Anatomy and Cell Biology

First Advisor

Elizabeth Berger

Abstract

The general purpose of these studies is to investigate inflammation in diabetic retinopathy in an effort to identify key intervention points to develop as treatments. Firstly, we showed that the neuropeptide VIP displayed protective immunoregulatory effects on retinal endothelial cells cultured under high glucose conditions. This effect was carried out, in part through the VPAC2 receptor.

Next, we studied the β-adrenergic receptor agonist, Compound 49b, and its effect on the pro-resolving RvD1 pathway. Compound 49b was previously shown to suppress both inflammatory and apoptotic responses in DR. We demonstrated that Compound 49b rescued the high glucose-induced decrese in RvD1 and its receptors in diabetic animals and retinal endothelial cell culture, by upregulating 15-LOX enzyme expression.

We also studied the phosphorylation of NF-κB p65 in two retinal cell types exposed to high glucose. High glucose conditions stimulated phosphorylation of NF-κB p65 at Thr-254, Ser-276, Ser-468, Ser-529, Thr-435 in retinal endothelial cells and Thr-254, Ser-281, Ser-311, Ser-468, Thr-435 in Müller cells. IL-4, an anti-inflammatory cytokine, suppressed phosphorylation at Thr-254, Ser-311, Thr-435 in retinal endothelial cells and Thr-254, Ser-276, Ser-281, Thr-435 in Müller cells. Futhermore, IL-4 also reduced related downstream NF-κB regulated molecules IL-8, TNF-α, and upregulated IL-10.

The influence of type 1 vs type 2 immune backgrounds on DR-related damage using a model of retinal ischemia-reperfusion was studied in C57BL/6 and BALB/c mice. Notably, both neuronal and vascular degeneration were significantly less in BALB/c compared to B6 mice. Furthermore, key inflammatory molecules IL-1β, TNF-α, NF-κB, ICAM-1 and VEGF were downregulated in BLAB/c mice, as well.

Collectively, we have shown the extensive role that inflammation plays in diabetic retinopathy pathogenesis. More importantly, the innate type 1/type 2 paradigm suggests that the potential of anti-inflammatory treamtents and pro-resolving lipid mediators in suppressing pathogenesis of DR. We expect our findings in pathogenesis of inflammation to contibute to development of anti-inflammatory and pro-resolving treatments for diabetic retinopathy.

Download

Share

COinS