The ocular endothelin system: a novel target for the treatment of endotoxin-induced uveitis with bosentan.
OBJECTIVE
We compared the anti-inflammatory effects of bosentan and dexamethasone in endotoxin-induced uveitis (EIU).


METHODS
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.


RESULTS
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).


CONCLUSIONS
Bosentan reduces intraocular inflammation and has similar effects as dexamethasone in a rat model of EIU.
Department of Ophthalmology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Sadullah
S
Keles
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Zekai
Z
Halici
Department of Pathology, Faculty of Veterinary, Kırıkkale University, Kırıkkale, Turkey.
Hasan Tarik
HT
Atmaca
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Muhammed
M
Yayla
Department of Ophthalmology, Igdır Government Hospital, Igdır, Turkey.
Kenan
K
Yildirim
Department of Ophthalmology, Faculty of Medicine, Kafkas University, Kars, Turkey.
Metin
M
Ekinci
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Erol
E
Akpinar
Department of Pharmacology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey.
Durdu
D
Altuner
Department of Ophthalmology, Mugla Sıtkı Kocaman University, Faculty of Medicine, Mugla, Turkey.
Ozgur
O
Cakici
Department of Biochemistry, Regional Research and Education Hospital, Erzurum, Turkey.
Zafer
Z
Bayraktutan
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D000077300:Bosentan; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005938:Glucocorticoids; D017466:Receptors, Endothelin; D013449:Sulfonamides; D012313:RNA; D003907:Dexamethasone; D000077300:Bosentan
TNF-α; bosentan; endothelin-1; endotoxin-induced uveitis; iNOS