Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression

FASEB J. 2002 Mar;16(3):438-40. doi: 10.1096/fj.01-0707fje. Epub 2002 Jan 30.

Abstract

Leukocyte adhesion to the diabetic retinal vasculature results in blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Intercellular adhesion molecule-1 (ICAM-1) and the leukocyte integrin CD18 are required for these processes. Diabetes was induced in Long Evans rats, resulting in a two- to threefold increase in retinal leukocyte adhesion. Following one week of diabetes, neutrophil CD11a, CD11b, and CD18 expression was increased significantly, as were retinal ICAM-1 levels. Animals were treated with aspirin, a cyclooxygenase 2 (COX-2) inhibitor (meloxicam), or a soluble tumor necrosis factor alpha (TNF-alpha) receptor/Fc construct (TNFR-Fc, etanercept). High-dose aspirin, etanercept, and high-dose meloxicam each reduced leukocyte adhesion and suppressed blood-retinal barrier breakdown. High-dose aspirin also reduced the expression of CD11a, CD11b, and CD18, whereas meloxicam and etanercept did not. High-dose aspirin, etanercept, and high-dose meloxicam each reduced retinal ICAM-1 expression. Aspirin and meloxicam both lowered retinal TNF-alpha levels. Notably, aspirin, meloxicam, and etanercept did not change retinal vascular endothelial growth factor levels. High-dose aspirin, etanercept and high-dose meloxicam, each suppressed the retinal expression of eNOS and the DNA-binding capacity of retinal nuclear factor-kappaB. High-dose aspirin also suppressed Erk kinase activity, which is involved in CD18 up-regulation. Taken together, these data identify COX-2 and TNF-alpha as operative in the early signature pathologies of diabetic retinopathy, a newly recognized inflammatory disease.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Aspirin / pharmacology
  • Blood-Retinal Barrier / drug effects
  • Cell Adhesion / drug effects
  • Cyclooxygenase Inhibitors / pharmacology
  • Diabetic Retinopathy / blood
  • Diabetic Retinopathy / immunology
  • Diabetic Retinopathy / prevention & control*
  • Etanercept
  • Immunoglobulin G / pharmacology
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kinetics
  • Meloxicam
  • Models, Biological
  • NF-kappa B / metabolism
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Rats
  • Rats, Long-Evans
  • Receptors, Leukocyte-Adhesion / metabolism
  • Receptors, Tumor Necrosis Factor
  • Retina / drug effects
  • Retina / immunology
  • Thiazines / administration & dosage
  • Thiazines / pharmacology
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Immunoglobulin G
  • NF-kappa B
  • Receptors, Leukocyte-Adhesion
  • Receptors, Tumor Necrosis Factor
  • Thiazines
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Etanercept
  • Aspirin
  • Meloxicam