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

• Published in: Molecular pharmacology 2008-07, Vol.74 (1), p.154-161
• Main Authors: Medeiros, Rodrigo, Rodrigues, Gustavo Büchele, Figueiredo, Cláudia Pinto, Rodrigues, Eduardo Büchele, Grumman, Astor, Menezes-de-Lima, Octavio, Passos, Giselle Fazzioni, Calixto, João Batista
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.108.046870

Lipoxin A4 (LXA4) is a lipid mediator that plays an important role in inflammation resolution. We assessed the anti-inflammatory effect of LXA4 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 E2 (PGE2), 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 LXA4 (1-10 ng/eye) pretreatment decreased the number of inflammatory cells and the protein leakage into the aqueous humor (AqH). In addition, topical LXA4 (10 ng/eye) inhibited the LPS-induced production of IL-1β, TNF-α, and PGE2, and expression of COX-2 and VEGF. A decreased activation of NF-κB and c-Jun was also found in LXA4-treated eyes. It is very interesting that an anti-inflammatory effect was achieved even when LXA4 (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 LXA4. Together, the present results provide clear evidence that pharmacological activation of LXA4 signaling pathway potently reduces the EIU in rats. Therefore, LXA4 stable analogs could represent promising agents for the management of ocular inflammatory diseases.