Received for publication March 6, 2008.
Revised April 12, 2008.
Accepted for publication April 14, 2008.

Molecular mechanisms of topical antiinflammatory effects of lipoxin A₄ in endotoxin-induced uveitis

Abstract

Lipoxin A₄ (LXA₄) is a lipid mediator that plays an important role in inflammation resolution. We assessed the antiinflammatory effect of LXA₄ on endotoxin-induced uveitis (EIU) in rats. The inflammatory cell number and levels of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), 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 humour (AqH). In addition, topical LXA₄ (10 ng/eye) inhibited the LPS-induced production of IL-1, 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. Of high interest, an antiinflammatory 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 pre- and post-treatment of corticosteroid prednisolone (200 µg/eye) reduced all of the molecular and biochemical alterations promoted on EIU rats in a similar efficacy to LXA₄. Together, 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.

Key words: Interleukins, Tumor necrosis factor, AP-1, NFkappaB, Immunocytochemistry, Cyclooxygenases, Lipoxygenases