title: Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression.
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.
authors.affiliation: Retina Research Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Joussen
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Poulaki
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Bernd
authors.initials: B
authors.lastname: Kirchhof
authors.forename: Kan
authors.initials: K
authors.lastname: Koizumi
authors.forename: Sven
authors.initials: S
authors.lastname: Döhmen
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Adamis
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003930:Diabetic Retinopathy / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007700:Kinetics; D000077239:Meloxicam; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D020318:Rats, Long-Evans; D016028:Receptors, Leukocyte-Adhesion / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012160:Retina / Q000187:drug effects / Q000276:immunology; D013843:Thiazines / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007074:Immunoglobulin G; D016328:NF-kappa B; D016028:Receptors, Leukocyte-Adhesion; D018124:Receptors, Tumor Necrosis Factor; D013843:Thiazines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000068800:Etanercept; D001241:Aspirin; D000077239:Meloxicam