Suppression of Ocular Inflammation in Endotoxin–induced Uveitis by Blocking Angiotensin II Type 1 Receptor

Abstract

Abstract: : Purpose: To investigate the anti–inflammatory effects of telmisartan, an angiotensin II type 1 receptor (AT1–R) antagonist, on ocular inflammation in endotoxin–induced uveitis (EIU). Methods: EIU was induced in C57BL/6 mice by a single intraperitoneal injection of lipopolysaccharide (LPS) from Escherichia coli in phosphate–buffered saline solution (PBS). Angiotensin II type 1 receptor antagonist (telmisartan) or PBS was administered intraperitoneanlly every 5 days before the injection of LPS. Twenty–four hours after LPS administration, leukocyte adhesion to the retinal vasculature was evaluated with concanavalin A lectin staining. Retinal mRNA and protein levels of intercellular adhesion molecule–1 (ICAM–1) were examined by reverse transcription–polymerase chain reaction (RT–PCR) and enzyme–linked immunosorbent assay (ELISA). Protein concentration and inflammatory cells in the aqueous humor were also measured. Results: Twenty–four hours after the LPS injection, significant increases in leukocyte adhesion and retinal ICAM–1 levels were observed. The number of adherent leukocytes in non–treated EIU mice was significantly (P < 0.01) higher than that of normal mice. Leukocyte counts showed a significant (P < 0.01) decrease in telmisartan–treated EIU mice, compared with vehicle–treated EIU mice or non–treated EIU mice. Retinal ICAM–1 levels in telmisartan–treated EIU mice were significantly (P < 0.05) lower than in vehicle–treated EIU mice. The number of aqueous–humor cells in non–treated EIU mice was significantly (P < 0.01) higher than in normal mice. The number of aqueous–humor cells showed a significant (P < 0.01) decrease in telmisartan–treated EIU mice, compared with vehicle–treated or non–treated EIU mice. Protein concentration in the aqueous humor of telmisartan–treated EIU mice tended to be lower than that of vehicle–treated or non–treated EIU mice, but the difference was not statistically significant. Conclusions: AT1–R signaling blockade suppressed the LPS–induced increases in leukocyte adhesion to the retinal vessels, retinal ICAM–1 m–RNA and protein levels, and infiltrating cells in the aqueous humor in the murine model of uveitis. These results suggest the potential use of AT1–R antagonists as a therapeutic agent to reduce ocular inflammation.

Keywords: drug toxicity/drug effects • inflammation • uveitis-clinical/animal model