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Steve Louie, Karen Anderson, Hui Li, Debby Long, Sha-Mei Liao, Bruce D Jaffee, Michael Stefanidakis; Systemic Inhibition of the EGF Receptor Reduces Leukostasis and Retinal Vascular Leakage in Streptozotocin Induced-Diabetic Rats. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4700.
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Diabetic macular edema (DME) is a major cause of poor vision in patients with non-proliferative diabetic retinopathy. Despite new treatments for DME, such as focal laser administration and agents targeting the VEGF receptor pathway, it remains a disease of substantial unmet medical need. The purpose of this study is to assess the effect of epidermal growth factor receptor (EGFR) inhibitors on leukocyte adherence (leukostasis) and retinal vascular leakage.
Eight-week-old Brown Norway rats were purchased from Harlan Laboratories. Diabetes was induced by a single intraperitoneal dose of STZ (65 mg/kg). Age-matched, non-diabetic control rats received citrate buffer. Baseline blood glucose and body weight were measured prior to the study. Only diabetic rats with a blood glucose level over 250 mg/dL were considered diabetic and included in the study. Inflammatory cytokine and adhesion molecule mRNA levels were measured by RT-PCR at different time points. EGFR inhibitors (X, Y and Z) were dosed orally, once a day, 4 days prior to the end of the study. FITC-labeled concanavalin A and FITC-dextran were used to determine leukostasis (retinal flat mount) at week 2 and retinal vascular leakage (retinal lysate) at week 6 post-injection, respectively. The number of leukocytes adhering to the retinal vasculature were counted using Axiovision software.
Systemic administration of STZ to induce diabetes led to increased expression of inflammatory cytokines and adhesion molecules, such as ICAM-1, in ocular tissues compared to vehicle-treated controls. Upregulation of proinflammatory molecules in diabetic rats correlated well with increased leukostasis and retinal vascular leakage at week 2 and week 6 post-injection, respectively. In diabetic rats, the EGFR inhibitor X inhibited retinal leukostasis in a dose-dependent manner and reduced retinal leakage by 82% (at 30 mg/kg; p < 0.05). Inhibitor Y (at 10 mg/kg; p > 0.05) and inhibitor Z (at 30 mg/kg; p > 0.05) only partially reduced retinal leakage by 49% and 54%, respectively.
These findings suggest that regulating the EGF receptor pathway reduces leukostasis and retinal vascular permeability. Results shown may provide insight into potential therapeutic approaches to treat DME.
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