However, no significant changes have been detected in LX biosynthesis in other chronic inflammatory diseases such as COPD [38, 39]; thus, general conclusions cannot be drawn and lipoxin receptor levels may be specific for each disease condition. Although the well-documented beneficial actions reported for LXs are suggested to involve FPR2/ALX-triggered signalling, the
specific associated pathways responsible for in-vivo lipoxin activity remain to be elucidated. In addition, data supporting a role for LXs in modulating human neutrophil function check details in an IL-8 environment is missing, although moderate efficacy has been shown on human neutrophil transmigration across the intestinal epithelium and on the blockade of the release of human neutrophil azurophilic granules [40, 41]. The reported binding data indicate that FPR2/ALX is a high-affinity receptor for LXs and its analogues , but in our study the signalling activated by LXs– FPR2/ALX interactions are not the
classical G-protein-activated pathways involving an increase in GTPγ binding response, a decrease in cAMP or enhancement Z-IETD-FMK purchase of the intracellular calcium flux. However, in the same FPR2/ALX recombinant cells the peptide ligand WKYMVm and the small molecule FPR2/ALX agonist compound 43 induced GTPγ binding and calcium influx, suggesting that proinflammatory peptides and synthetic FPR2/ALX compounds present agonist properties whereas, in principle, 15-epi-LXA4 binds but not acts as an FPR2/ALX agonist. Similarly, recent
work from an independent group has shown lack of signalling induced by 15-epi-LXA4 through enhancement in intracellular Tenoxicam calcium in FPR2/ALX over-expressing cells . Conversely, a novel lipid-mediated downstream FPR2/ALX signalling has been described, involving intracellular polyisoprenyl phosphate remodelling. Interaction of these endogenous lipids with FPR2/ALX block agonist-induced presqualene diphosphate (PSDP) turnover to presqualene monophosphate (PSMP) and an increase in PSDP accentuates anti-inflammatory actions through inhibition of PLD and PI3K in human neutrophils [42, 43]. Nevertheless, the role for these pathways in FPR2/ALX-associated functions in vivo remains to be elucidated. In addition to reducing acute inflammation induced by the potent neutrophil chemoattractant LTB4, LXs are able to modulate neutrophil functions induced by proinflammatory FPR2/ALX peptides. It has been reported that LXs reverse both neutrophil chemotaxis induced by MHC- and MMK-1-derived peptides  and neutrophil apoptosis arrest mediated by SAA .