Molecular Mechanisms of Topical Anti-Inflammatory Effects of Lipoxin A sub(4) in Endotoxin-Induced Uveitis

Lipoxin A sub(4) (LXA sub(4)) is a lipid mediator that plays an important role in inflammation resolution. We assessed the anti-inflammatory effect of LXA sub(4) on endotoxin-induced uveitis (EIU) in rats. The inflammatory cell number and levels of tumor necrosis factor- alpha (TNF- alpha ), interleukin-1 beta (IL-1 beta ), prostaglandin E sub(2) (PGE sub(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 mu g/paw) intradermal injection. The immunohistochemical reactivities of nuclear factor- Kappa B (NF- Kappa B) and c-Jun were also examined. Topical LXA sub(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 sub(4) (10 ng/eye) inhibited the LPS-induced production of IL-1 beta , TNF- alpha , and PGE sub(2), and expression of COX-2 and VEGF. A decreased activation of NF- Kappa B and c-Jun was also found in LXA sub(4)-treated eyes. It is very interesting that an anti-inflammatory effect was achieved even when LXA sub(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 mu g/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 sub(4). Together, the present results provide clear evidence that pharmacological activation of LXA sub(4) signaling pathway potently reduces the EIU in rats. Therefore, LXA sub(4) stable analogs could represent promising agents for the management of ocular inflammatory diseases.