Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities.

Purpose: To determine the levels of the neutrophil chemoattractants CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8, the T helper 1 chemoattractants CXCL9, CXCL10 and CXCL11, the lymphoid chemokines CXCL12 and CXCL13 and the soluble form of the transmembrane chemokines CXCL16 and CX3CL1, in aqueous humor samples from patients with specific uveitic entities. Methods: Aqueous humor samples from patients with active uveitis associated with Behçet's disease (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt-Koyanagi-Harada (VKH) disease (n = 12), and healthy controls (n = 9) were assayed with the use of a multiplex assay. Results: All chemoattractant levels were significantly higher in all patients than in the controls. The levels of all neutrophil chemoattractants and CXCL10, CXCL16, and CX3CL1 were significantly higher in nongranulomatous uveitis (Behçet's disease and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease), whereas the levels of the B cell chemoattractant CXCL13 were significantly higher in granulomatous uveitis than in nongranulomatous uveitis. CXCL13 levels were highest in the patients with VKH disease. CXCL9, CXCL11, and CXCL12 levels did not differ significantly. Conclusions: Inflammation in nongranulomatous uveitis appears to be driven by neutrophils and T helper 1 lymphocytes, whereas B lymphocytes may contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease.

Role of inflammation in the pathogenesis of diabetic retinopathy.

Diabetic retinopathy (DR) remains a major cause of worldwide preventable blindness. The microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, including activation of protein kinase C, increased advanced glycation end products formation, polyol pathway, and oxidative stress, and activation of the renin angiotensin system (RAS). There is an accumulating body of evidence that inflammation plays a prominent role in the pathogenesis of DR.

High-mobility group box-1 and biomarkers of inflammation in the vitreous from patients with proliferative diabetic retinopathy.

PURPOSE: To measure levels of high-mobility group box -1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR) and to correlate their levels with clinical disease activity and the levels of the inflammatory biomarkers monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-1ß (IL-1ß), and granulocyte macrophage colony-stimulating factor (GM-CSF). In addition, we examined the expression of HMGB1 in the retinas of diabetic mice. METHODS: Vitreous samples from 29 PDR and 17 nondiabetic patients were studied by enzyme-linked immunosorbent assay. Retinas of mice were examined by immunofluorescence analysis and western blotting. RESULTS: HMGB1 was detected in all vitreous samples and sRAGE was detected in 5 PDR samples. IL-1ß was detected in 3PDR samples and GM-CSF was not detected. Mean HMGB1 levels in PDR with active neovascularization were twofold and threefold higher than that in inactive PDR and nondiabetic patients, respectively. Mean HMGB1 levels in PDR patients with hemorrhage were significantly higher than those in PDR patients without hemorrhage and nondiabetic patients (p=0.0111). There were significant correlations between levels of HMGB1 and levels of MCP-1 (r=0.333, p=0.025) and sICAM-1 (r=0.548, p<0.001). HMGB1 expression was also upregulated in the retinas of diabetic mice. CONCLUSIONS: Subclinical chronic inflammation might contribute to the progression of PDR.

CXC chemokine expression profiles in aqueous humor of patients with different clinical entities of endogenous uveitis.

Aqueous humor (AH) samples from patients with Behçet's disease (BD) (n=29), Vogt-Koyanagi-Harada (VKH) disease (n=21), and HLA-B27-associated uveitis (n=8), and 42 control patients were assayed for the neutrophil chemoattractants CXCL1/GRO-α and CXCL8/IL-8 and the lymphocyte chemoattractants CXCL9/MIG, CXCL10/IP-10 and CXCL12/SDF-1 with the use of a multiplex chemokine assay. Chemokine levels except SDF-1 were significantly higher in the 3 disease groups than in normal controls. Considering all patients, mean GRO-α levels were 15-fold higher than IL-8 levels and mean IP-10 levels were 22-fold higher than MIG levels. In patients with the same disease activity, AH levels of GRO-α and IP-10 were significantly higher in patients with BD than in patients with VKH disease and HLA-B27-associated uveitis (p=0.0474; p<0.001, respectively). These data suggest that GRO-α and IP-10 are the predominant CXC chemokines involved in neutrophil and activated T lymphocyte chemoattraction in endogenous uveitis, particularly in BD.

Expression of high-mobility groups box-1/receptor for advanced glycation end products/osteopontin/early growth response-1 pathway in proliferative vitreoretinal epiretinal membranes.

PURPOSE: The high-mobility group box -1 (HMGB1)/receptor for advanced glycation end products (RAGE)/osteopontin (OPN)/early growth response-1 (Egr-1) pathway is involved in inflammation, angiogenesis, and fibrosis. We investigated the expression of the components of this pathway in proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR) epiretinal membranes. METHODS: Nine active and 13 inactive membranes from patients with PDR and 21 membranes from patients with PVR were studied by immunohistochemistry. RESULTS: In PDR membranes, vascular endothelial cells expressed HMGB1, RAGE, OPN, and Egr-1 in 21, 15, 20, and 16 membranes, respectively. Stromal cells expressed HMGB1, RAGE, OPN, and Egr-1 in 21, 20, 20, and 16 membranes, respectively. Significant correlations were detected between the number of blood vessels expressing the panendothelial cell marker CD34 and the number of blood vessels and stromal cells expressing HMGB1, RAGE, and OPN. The numbers of blood vessels and stromal cells expressing CD34, HMGB1, RAGE, and OPN and stromal cells expressing Egr-1 were significantly higher in active membranes than in inactive membranes. In PVR membranes, spindle-shaped myofibroblasts expressing α-smooth muscle actin coexpressed HMGB1, RAGE, OPN, and Egr-1. CONCLUSIONS: The HMGB1/RAGE/OPN/Egr-1 pathway may be involved in inflammatory, angiogenic and fibrotic responses in proliferative vitreoretinal disorders.

Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis.

We assayed aqueous humor (AH) samples from patients with Behçet's disease (BD), Vogt-Koyanagi-Harada (VKH) disease, and HLA-B27-associated uveitis and control patients for the proinflammatory cytokines IL-15, IL-17, interferon-γ and tumor necrosis factor-α and the immunosuppressive cytokine IL-10. Cytokine levels were significantly higher in the three disease groups than in controls. In patients with similar disease activity, levels of IL-15 and IFN-γ were significantly higher in BD patients than in VKH and HLA-B27-associated uveitis groups. Logistic regression identified a significant negative correlation between BD and high levels of IL-10 and a significant positive correlation between VKH disease and high levels of IL-10. The proinflammatory cytokines versus IL-10 ratios were significantly higher in BD compared with other groups. These data suggest that both T helper (Th) 1 and Th17 cells are involved in endogenous uveitis immunopathogenesis. BD is characterized by extensive Th1 polarization, severe proinflammatory conditions and a low immunosuppressive status.

Pharmacologic vitreolysis in diabetic retinopathy.

Diabetic retinopathy remains a major cause of worldwide preventable blindness. The vitreo-retinal interface plays a critical role in the pathogenesis of diabetic retinopathy. The term pharmacologic vitreolysis refers to the use of enzymes to liquefy the vitreous gel, and to induce posterior vitreous detachment (PVD). Intravitreal ovine hyaluronidase injection was effective in clearing vitreous hemorrhage. Several human case series demonstrated that intravitreal injection of autologous plasmin enzyme was a safe and effective adjunct to vitreous surgery for the treatment of diabetic macular edema and proliferative diabetic retinopathy. Recently, it was shown that intravitreal injection of plasmin enzyme without the performance of vitrectomy induced complete PVD and reduced macular thickening due to refractory diabetic macular edema.

A clinical approach to the diagnosis of retinal vasculitis.

Retinal vasculitis is a sight-threatening inflammatory eye condition that involves the retinal vessels. Detection of retinal vasculitis is made clinically, and is confirmed with the help of fundus fluorescein angiography. Active vascular disease is characterized by exudates around retinal vessels resulting in white sheathing or cuffing of the affected vessels. In this review, a practical approach to the diagnosis of retinal vasculitis is discussed based on ophthalmoscopic and fundus fluorescein angiographic findings.

Changing paradigms in the treatment of diabetic retinopathy.

PURPOSE OF REVIEW: To review current treatment approaches in diabetic retinopathy. RECENT FINDINGS: Diabetic retinopathy remains one of the leading causes of blindness worldwide. Strict metabolic control, tight blood pressure control, laser photocoagulation, and vitrectomy remain the standard care for diabetic retinopathy. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with diabetic macular edema. The current evidence suggests that intravitreal triamcinolone acetonide or antivascular endothelial growth factor agents are effective adjunctive treatment to laser photocoagulation or vitrectomy. However, triamcinolone is associated with risks of elevated intraocular pressure and cataract. Vitrectomy with removal of the posterior hyaloid without internal limiting membrane peeling seems to be effective in eyes with persistent diffuse diabetic macular edema, particularly in eyes with associated vitreomacular traction. Emerging therapies include islet cell transplantation, fenofibrate, ruboxistaurin, and intravitreal hyaluronidase. SUMMARY: A variety of promising new medical and surgical therapies are emerging, but more randomized controlled clinical trials are required to clarify their role alone or in combination.