Abstract
Lipoxins and their 15 epimers, aspirin triggered lipoxins (ATL), are eicosanoids derived from sequential lipoxygenase (LO) metabolism of arachidonic acid. The main routes of lipoxin biosynthesis involve cooperation between 15- and 5-LO, and between 12- and 5-LO. ATL are generated by interactions between 5-LO and aspirin-acetylated cyclooxygenase-2. Cellular models recapitulating these interactions involve leukocytes, platelets, vascular endothelium, and epithelium. To circumvent rapid lipoxin and ATL metabolism and inactivation, stable analogs, bearing potent and long-lasting biological activity, have been synthesized. Some of these analogs displayed therapeutic potential by showing strong anti-inflammatory activity in a number of animal models of disease, including reperfusion injury; arthritis; gastrointestinal, renal, respiratory, and vascular inflammatory disorders; eye damage; periodontitis; and selected infectious diseases. Counter-regulatory signaling by lipoxin A4 and 15-epi-lipoxin A4 is triggered by the activation of a seven-transmembrane domain receptor, termed FPR2/ALX, which is highly expressed in myeloid cells and has been recognized as a main anti-inflammatory receptor.
Highlights
The presence of polar compounds carrying a conjugated tetraene chromophore was first revealed in incubations of human leukocytes with arachidonic acid or 15S-hydroperoxy-5,8,11,13-eicosatetraenoic acid (HpETE)[1,2]
This pathway was initially characterized in mixed polymorphonuclear neutrophils (PMNs)-platelet incubations[12,13,14] and further elucidated with megakaryocytes[15], 12-LO–transfected cells[15], platelets exposed to leukotriene A4 (LTA4)[16], and human platelet recombinant 12-LO incubated with LTA4 in a cell-free system[17]
The formation of epi-lipoxins was first detected in mixed incubations of aspirin-treated human umbilical endothelial cells with PMNs[21], which were done on the basis of previous observation that aspirin did not completely suppress COX-2 catalytic activity, but rather redirected it to the transformation of arachidonic acid into 15R-hydroxy eicosatetreanoic acid (HETE)[22]
Summary
In vivo evidence of the 5-/12-LO route of lipoxin generation has been obtained in patients with cardiovascular disease, during coronary angioplasty[18], and in healthy subjects undergoing strenuous physical exercise[19] In both conditions, enhanced transcellular exchanges between PMNs and platelets have been documented. The formation of epi-lipoxins was first detected in mixed incubations of aspirin-treated human umbilical endothelial cells with PMNs[21], which were done on the basis of previous observation that aspirin did not completely suppress COX-2 catalytic activity, but rather redirected it to the transformation of arachidonic acid into 15R-HETE[22]. Fifteen-epi-lipoxins were collectively termed aspirin-triggered lipoxins (ATL) Their biosynthesis proceeds through the conversion of 15R-HETE by 5-LO to an epoxide intermediate, which, to what occurs during lipoxin formation by 5-/15-LO interactions, is enzymatically converted into 15-epi-lipoxin A4 (ATLa) and 15-epi-lipoxin B4 (Fig. 4).
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