The ocular endothelin system: a novel target for the treatment of endotoxin-induced uveitis with bosentan

• Published in: Investigative ophthalmology & visual science 2014-05, Vol.55 (6), p.3517-3524
• Main Authors: Keles, Sadullah, Halici, Zekai, Atmaca, Hasan Tarik, Yayla, Muhammed, Yildirim, Kenan, Ekinci, Metin, Akpinar, Erol, Altuner, Durdu, Cakici, Ozgur, Bayraktutan, Zafer
• Format: Article
• Language: English
• Subjects: Animals; Aqueous Humor - metabolism; Dexamethasone - administration & dosage; Dexamethasone - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelins - biosynthesis; Endothelins - drug effects; Endothelins - genetics; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glucocorticoids - administration & dosage; Glucocorticoids - therapeutic use; Male; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Endothelin - biosynthesis; Receptors, Endothelin - genetics; RNA - genetics; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use; Treatment Outcome; Uveitis - chemically induced; Uveitis - drug therapy; Uveitis - metabolism
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.14-14193

We compared the anti-inflammatory effects of bosentan and dexamethasone in endotoxin-induced uveitis (EIU). Endotoxin-induced uveitis was induced by subcutaneous injection of lipopolysaccharide (LPS, 200 μg) in Wistar rats. Rats were divided randomly into 10 groups (n = 6). Bosentan at doses of 50 and 100 mg/kg were administered orally 1 hour before and 12 hours after LPS injection, and dexamethasone was administered by intraperitoneally 30 minutes before and 30 minutes after LPS injection at a dose of 1 mg/kg. Data were collected at two time points for each control and treatment; animals were killed at either 3 or 24 hours after LPS injection. Histopathologic evaluation and aqueous humour measurements of TNF-α level were performed, and endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS), and endothelin receptor A and B (EDNRA and B) expression were analyzed. The group treated with 100 mg/kg bosentan at 24 hours displayed significantly milder uveitis and fewer inflammatory cells compared to LPS-injected animals, and there were similar findings in the dexamethasone-treated group at 24 hours. The TNF-α levels in the dexamethasone treatment group were lower than those in the LPS-induced uveitis control group (P < 0.05); however, there was no difference between the dexamethasone and bosentan treatment groups at 3 and 24 hours after LPS administration. Bosentan treatment at doses of 50 and 100 mg/kg significantly decreased iNOS expression compared to LPS-injected animals (P < 0.001). The ET-1 expression was suppressed significantly by bosentan and dexamethasone at 3 and 24 hours after LPS administration (P < 0.001). The EDNRA expression in the bosentan treatment groups was statistically significantly lower than that in the LPS-induced uveitis control group at 3 and 24 hours after LPS administration (P < 0.05). Bosentan reduces intraocular inflammation and has similar effects as dexamethasone in a rat model of EIU.