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

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina. Florianópolis, Brazil

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- (TNF-), 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-B (NF-B) 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-, and PGE₂, and expression of COX-2 and VEGF. A decreased activation of NF-B 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.

Address correspondence to: Dr. J. B. Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco D, CCB, Caixa Postal 476, CEP 88049-900, Florianópolis, SC, Brazil. E-mail: calixto{at}farmaco.ufsc.br