Novel Extracellular Biosignals From Lipids Pathways Of Inflammationresolution

It is now appreciated that inflammation plays an important role in many prevalent diseases in the Western world. In addition to the chronic inflammatory diseases, such as arthritis, psoriasis, and periodontitis, as noted above, it is now increasingly apparent that diseases such as asthma, Alzheimer's disease, and even cancer have an inflammatory component associated with the disease process. Therefore, it is important for us to gain more detailed information on the molecules and mechanisms controlling inflammation and its resolution. Toward this end, we recently identified new families of lipid mediators generated from fatty acids during resolution of inflammation; termed resolvins and docosatrienes. Using systematic analysis of resolving inflammatory exudates, we sampled exudates during resolution as leukocytic infiltrates were declining to determine whether there were indeed new mediators generated. Figure 12.5 schematically represents our functional mediator-lipi-domics approach using LC tandem MS (LC-MS/MS-based analyses) to evaluate and profile temporal production of compounds at defined points during experimental inflammation and its resolution. We constructed libraries of physical properties for known mediators, i.e., prostaglandins, epoxyeicosatetraenoic acids (EETs), leukot-rienes, and lipoxins (Figure 12.1C), as well as theoretical compounds and potential diagnostic fragments as signatures for specific enzymatic pathways. When novel compounds were pinpointed within chromatographic profiles, we carried out complete structural elucidation as well as retrograde chemical analyses that involve both biogenic and total organic synthesis, which permitted scaling up of the compound of interest and its evaluation in vitro and in vivo. These in vivo models include the murine air pouch model of inflammation as well as peritonitis. In vitro cell assays focused on regulation of cytokines and leukocyte migration across transepithelial or

Pmn Cytokines
Establish Actions -Cells: PMN transmigration -Cytokine gene regulation -In vivo: air pouch & peritonitis models

Figure 12.5 Elucidation of the cycle of mediator-lipidomics.

transendothelial monolayers. This full cycle of events defines mediator-lipidomics because it is important to establish both the structure and function of bioactive molecules. With this new lipidomics-based approach that combined LC-PDA-MS/MS, a novel array of endogenous lipid mediators were identified410 during the multicellular events that occur during resolution of inflammation. The novel biosyn-thetic pathways uncovered use omega-3 fatty acids, eicosapentanoic acid and docosa-hexanoic acid, as precursors to new families of protective molecules, termed resolvins. These include resolvin E (18^ series from EPA) and resolvin D (17-series from DHA).12 In humans, the vasculature — particularly endothelial cells during cross-talk with leukocytes — generate these products via transcellular biosynthesis pathways.4 In this novel cell-cell interaction, endothelial cells generate the first biochemical step and then pass this intermediate 18^-HEPE to leukocytes, which transform this to a potent molecule termed resolvin E1 (RvE1), as depicted in Figure 12.6. RvE1 is ~100 to 1000 times more potent than native EPA as a down-regulator of neutrophils and stops their migration into inflammatory loci.410 DHA, which is enriched in neural systems, is also released and transformed to potent bioactive molecules denoted 10,17-docosatriene (neuroprotectin D1) and resolvins of the D series (Figure 12.1C). Human brain, synapses, and retina are rich with DHA, a major omega-3 fatty acid. Deficiencies in DHA are associated with altered neural functions, cancer, and inflammation in experimental animals.13 Employing our mediator-lipi-domics approach, we learned that on activation neural systems release DHA to produce neuroprotectin D1, which in addition to stopping leukocyte-mediated tissue

Resolvin E1 RvE 1

Resolvin E1 RvE 1

Figure 12.6 Biosynthesis of resolvin E1 derived from EPA.

damage in stroke also maintains retinal integrity.14 Figure 12.7 gives an example of resolvin PDA profiles and MS/MS spectra.

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