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  • 132 6 A number of interesting anti inflammatory molecules

    2024-04-17

    A number of interesting anti-inflammatory molecules have also been identified that are derived from AA or ω−3 fatty acids, including the lipoxins (for “lipoxygenase interaction products”), resolvins, and protectins [18], [19] (Fig. 1). The lipoxins are synthesized from AA by 5-, 12-, and 15-LOX, as well as by COX-2 in the presence of aspirin [18]. These molecules are involved in actively limiting and resolving the inflammatory response. In particular, lipoxins derived from the 15-LOX product 15HETE (termed lipoxin A4 and B4) have been shown to stimulate vasodilation and inhibit neutrophil function [20]. The resolvins are derived from the omega-3 PUFAs docosahexanoic 132 6 (the D-series resolvins) and eicosapentaenoic acid (the E-series resolvins), and their synthesis can involve aspirin and COX-2 (resolvin E1), as well as 5-LOX (resolvin E1) and 15-LOX (D-series resolvins) [19]. E-series resolvins are involved in granulocyte function and clearance, and reduce the release of various pro-inflammatory cytokines [19]. Synthesis of the protectins also involves the action of 15-LOX [19]. These agents appear to be involved in airway/mucosal injury in human asthma, and may also be protective after ischemic renal injury [21], [22]. An interesting class of 12- and 15-LOX-derived lipid products is the esterified eicosanoids formed by direct enzymatic oxidation of membrane phospholipids. First evidence for formation of these products was documented in eosinophils by Brinckmann et al. [23]. Although the 12- and 15-lipoxygenases are regarded as cytosolic enzymes, upon an increase in intracellular calcium they can bind to membrane phospholipids in a reversible fashion [23], [24]. In hematopoietic cells and platelets, 15- and 12-LOX, respectively, have the ability to translocate to cellular membranes in the presence of agonists such as calcium ionophore, thrombin or collagen which increases the fatty acid oxygenase activity of the enzyme [25]. The esterified 15-HETEs are predominant in human peripheral monocytes, while 12-HETEs are predominant in human platelets [25], [26]. The esterified eicosanoids (either phosphatidylethanolamine (PE)- or phosphatidylcoline (PC)-HETEs), are retained in the cells and more recent evidence shows they play important roles as LOX-dependent signaling lipid mediators in the immune cells in inflammation as well as novel pro-thrombotic lipids promoting coagulation [24], [26]. Also, a Th2-dependent production of 12-HETE-PEs in mice and 15-HETE-PEs in humans was recently reported and interesting future studies will help determine the potential anti-inflammatory role of these HETEs in some forms of inflammatory disease in humans [27]. The complex array of metabolites formed as a result of 12- and 15-LOX catalytic activity are tissue and species-specific, and can have both pro- and anti-inflammatory effects. Targeted deletion studies in mouse models have helped identify the potential roles of these pathways. To further clarify the particular role of these products in disease, specific 132 6 pharmacologic inhibitors for each of the LOX isoforms are needed. The development of highly specific pharmacological tools acting as isotype-specific LOX inhibitors is an imperative goal that is currently under intensive investigation [28]. In addition, adequate detection methods for LOX-derived lipid metabolites are crucial to obtaining accurate information on formation and tissue distribution in physiologic and pathologic states. The gold standard methods are liquid chromatography (LC)/electrospray ionization (ESI)/tandom mass spectrometry (MS/MS) and gas chromatography-mass spectrometry (GC/MS), but they represent a significant time and cost investment [29]. Antibody-based methods, such as enzyme-linked immunosorbent assay (ELISA), while much more accessible and cost-effective, should be carefully validated for the particular sample being analyzed. Also, the results should be interpreted with caution, due to the generally low specificity of immunodetection in differentiating structurally close lipid metabolites. An alternative to limit false positive results generated by antibody cross-reactivity would be to use an HPLC separation prior to immunochemical detection. For an excellent review on eicosanoid detection methodology and limitations please see O’Donnell et al. [29].