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

Invest Ophthalmol Vis Sci. 2014 May 15;55(6):3517-24. doi: 10.1167/iovs.14-14193.


Purpose: 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.

Keywords: TNF-α; bosentan; endothelin-1; endotoxin-induced uveitis; iNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aqueous Humor / metabolism*
  • Bosentan
  • 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
  • RNA / genetics*
  • Rats
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • Receptors, Endothelin / biosynthesis
  • Receptors, Endothelin / genetics
  • Sulfonamides / administration & dosage
  • Sulfonamides / therapeutic use*
  • Treatment Outcome
  • Uveitis / chemically induced
  • Uveitis / drug therapy*
  • Uveitis / metabolism


  • Endothelin Receptor Antagonists
  • Endothelins
  • Glucocorticoids
  • Receptors, Endothelin
  • Sulfonamides
  • RNA
  • Dexamethasone
  • Bosentan