The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

Abstract

Diabetic retinopathy is one of the leading causes of blindness in the world with the incidence of disease ever-increasing worldwide. The vitreous humor represents an extensive and complex interactive arena for cytokines in the diabetic eye. In recent decades, there has been significant progress in understanding this environment and its implications in disease pathophysiology. In this review, we investigate the vitreous ecosystem in diabetic retinopathy at the molecular level. Areas of concentration include: the current level of knowledge of growth factors, cytokine and chemokine mediators, and lipid-derived metabolites in the vitreous. We discuss the molecular patho-mechanisms of diabetic retinopathy based upon current vitreous research.

Keywords: cytokine; diabetes; eicosanoid; interleukin; retinopathy; vitreous.

Figure 1

Angiographic evidence of the loss of normal retinal vasculature contributing to the breakdown of the blood–retinal barrier in uncontrolled diabetes mellitus. (A) Right eye of a 29-year-old African American female with peak arterio-venous phase showing neovascularization and no capillary perfusion beyond the posterior pole. (B) Same patient’s left eye showing an enlarged foveal avascular zone, and heavy neovascularization at the border of retinal perfusion and non-perfusion. (C,D) are from a 28-year-old African American female showing global retinal ischemia with little perfusion beyond the peripapillary vasculature. (Images courtesy of Siva S.R. Iyer, MD).

Figure 2

22-year-old Caucasian female type 1 diabetic (diagnosed age 11). Top image (A) shows scattered retro-cortical hemorrhage in the posterior pole from active neovascularization with inadequate laser treatment. Bottom image (B) shows quiescent clinical disease following vitrectomy and endophotocoagulation. Visual acuity improved from count fingers to 20/40. (Images courtesy of Siva S.R. Iyer, MD).

Figure 3

Flow diagram of VEGF dependent and major independent patho-mechanisms in proliferative diabetic retinopathy. Chronic hyperglycemia leads to tissue injury (TI), hypoxia, advanced glycated end products (AGEs), and reactive oxygen species that cause inflammation and endothelial dysfunction with blood–retinal barrier breakdown (BRBB) in a positive feedback loop. VEGF is produced directly by HIF-1 stimulation in hypoxic conditions and directs its action through PKC-β and stimulates ICAM. PEDF and its inhibitory effects on BRBB are suppressed by hypoxia. VEGF independent pathways include IL-6, by acute phase response (APR) with induction of leukocyte (L) accumulation. TI further stimulates MCP-1 and IL-8 through NF-κβ as chemoattractants. TNFα secreted by endothelial cells (EC) and glial cells (GC) and ICAM-1 promote EC and L adhesion to further cause loss of microvascular integrity. TNF-α stimulates MCP-1 (not shown). SDF-1, derived from EC and stromal cells (SC) (bone marrow), is generated in response to endothelial injury and recruits progenitor cells, weakens tight junctions, and may promote neovascularization. Continued microangiopathy results in angiogenesis and culminates in fibrotic extracellular matrix (ECM) remodeling (through TGFβ, CTGF) whose footprint is largely irreversible. The above concepts have been discussed throughout the ongoing PDR vitreous scientific literature [21,35,40,42,64,81,94,99,112,120,123,134,154,163,164,165].

Figure 4

Fibrovascular membrane of a tractional retinal detachment (TRD). A combination of forceps and scissors is used to delaminate and remove the membrane from the retinal surface without injury to the retina. Remnant neovascularization (arrow) can be seen at the base of the white fibrous membrane as the majority has regressed following preoperative treatment with bevacizumab. (Intraoperative image courtesy of Siva S.R. Iyer, MD).