The resolution of inflammation is a dynamically regulated process that may be subverted in many pathological conditions. Macrophage (

Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native lipoxins LXA4 and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA4 and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA4 analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PMN) by macrophages, with comparable efficacy to the effect of native LXA4, albeit greater potency, while the LXB4 analogue also stimulated phagocytosis with a maximum effect observed at 10-11 M. LX-stimulated phagocytosis was associated with rearrangement of the actin cytoskeleton consistent with that reported for native lipoxins. Using zymosan-induced peritonitis as a murine model of acute inflammation (1R)-3a significantly reduced PMN accumulation.

Lipoxins (LX) are a class of eicosanoid that possesses a wide spectrum of antiinflammatory and proresolution bioactions. Here we have investigated the impact of the endogenously produced eicosanoid LXA4 on endothelial cell inflammatory, proliferative, and antigenic responses. Using HUVECs we demonstrate that LXA4 inhibits vascular endothelial growth factor (VEGF)-stimulated inflammatory responses including IL-6, TNF-α, IFN-γ and IL-8 secretion, as well as endothelial ICAM-1 expression. Interestingly, LXA4 up-regulated IL-10 production from HUVECs. Consistent with these antiinflammatory and proresolution responses to LXA4, we demonstrate that LXA4 inhibited leukotriene D4 and VEGF-stimulated proliferation and angiogenesis as determined by tube formation of HUVECs. We have explored the underlying molecular mechanisms and demonstrate that LXA4 pretreatment is associated with the decrease of VEGF-stimulated VEGF receptor 2 (KDR/FLK-1) phosphorylation and downstream signaling events including activation of phospholipase C-γ, ERK1/2, and Akt.

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