Roles of eicosanoids in inflammation & asthma
Eicosanoids are a large group of lipid mediators derived from arachidonic acid and related fatty acids. Activation of cells leads to the release of arachidonic acid and its conversion to a variety of biologically active products. The two major pathways for the metabolism of arachidonic acid are initiated by the actions of cyclooxygenase and 5-lipoxygenase. Products of the 5-lipoxygenase pathway, including leuko
trienes and 5-oxo-ETE, are particularly important in inflammation and asthma.
We discovered a 5-lipoxygenase product, 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid), which can be formed by neutrophils, monocytes, and other leukocytes as well as epithelial and endothelial cells (reviewed in Progr Lipid Res, 2005). This compound acts via the highly selective OXE receptor to mobilize calcium, upregulate cell adhesion molecules, and stimulate actin polymerization in eosinophils and neutrophils. It is the most potent human eosinophil chemoattractant known among lipid mediators and has effects similar to peptide chemokines such as eotaxin on these cells. It is also active in vivo, inducing eosinophil infiltration into human skin and Brown Norway rat lungs. Because of its potent effects on eosinophils, 5-oxo-ETE may be an important mediator in asthma.
We are currently investigating the regulation of the synthesis of 5-oxo-ETE and other 5-lipoxygenase products, as well as their effects on inflammatory cells and involvement in asthma. We are particularly interested in the effects of oxidative stress, pyridine nucleotides and glutathione in regulating the formation of 5-oxo-ETE. For these studies we have set up methods to measure GSH and GSSG by postcolumn derivatization-HPLC with fluorescence detection. We have also developed methods for the HPLC analysis of NADP+, NAD+, NADPH, and NADH, as well as various approaches to quantitate eicosanoids by precolumn extraction-HPLC.
We are also investigating the biological effects of 5-oxo-ETE and other eicosanoids. We are trying to define the requirements for activation of the OXE receptor and to develop selective antagonists against this receptor that may be useful in treating eosinophilic inflammation. We are also attempting to identify selective 5-HEDH inhibitors that would prevent the synthesis of 5-oxo-ETE. These and other studies are being done in collaboration with Joshua Rokach of the Florida Institute of Technology.
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Education & Training
BA (hon Biochem), U Sask,1967
PhD (Chem), Dalhousie U, 1972
PDF (Physiol Chem) Karolinska Inst, 1972-75
Methods Biomed Res EXMD 610