Molecular Mechanisms of Topical Anti-Inflammatory Effects of Lipoxin A4 in Endotoxin-Induced Uveitis

• Published in: Molecular pharmacology 2008-07, Vol.74 (1), p.154
• Main Authors: Rodrigo Medeiros, Gustavo Büchele Rodrigues, Cláudia Pinto Figueiredo, Eduardo Büchele Rodrigues, Astor Grumman, Jr, Octavio Menezes-de-Lima, Jr, Giselle Fazzioni Passos, João Batista Calixto
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.108.046870

Lipoxin A 4 (LXA 4 ) is a lipid mediator that plays an important role in inflammation resolution. We assessed the anti-inflammatory effect of LXA 4 on endotoxin-induced uveitis (EIU) in rats. The inflammatory cell number and levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), prostaglandin E 2 (PGE 2 ), and protein, as well as expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), in the anterior chamber of the eye were determined 24 h after lipopolysaccharide (LPS; 200 μg/paw) intradermal injection. The immunohistochemical reactivities of nuclear factor-κB (NF-κB) and c-Jun were also examined. Topical LXA 4 (1-10 ng/eye) pretreatment decreased the number of inflammatory cells and the protein leakage into the aqueous humor (AqH). In addition, topical LXA 4 (10 ng/eye) inhibited the LPS-induced production of IL-1β, TNF-α, and PGE 2 , and expression of COX-2 and VEGF. A decreased activation of NF-κB and c-Jun was also found in LXA 4 -treated eyes. It is very interesting that an anti-inflammatory effect was achieved even when LXA 4 (10 ng/eye) was applied topically after LPS challenge, as indicated by the reduction in the cellular and protein extravasations into the AqH. Moreover, topical treatment of corticosteroid prednisolone (200 μg/eye) beginning before or after LPS injection reduced all of the molecular and biochemical alterations promoted on EIU rats in an efficacy similar to that of LXA 4 . Together, the present results provide clear evidence that pharmacological activation of LXA 4 signaling pathway potently reduces the EIU in rats. Therefore, LXA 4 stable analogs could represent promising agents for the management of ocular inflammatory diseases.