ETHER LIPIDS, EICOSANOIDS AND LUNG CELL PATHOPHYSIOLOGY

National Jewish Health, Denver CO

Investigators

Linked publications & trials

Abstract

Lipid mediators include a wide variety of enzymatic and non- enzymatically derived oxidation products from phospholipids and unsaturated fatty acids. Here we will focus particularly on a newer arena of action for such molecules, namely suppression and resolution of pulmonary inflammation. Specific objectives include: Characterization of the nature and mechanism of action of oxidized phospholipids and PAF suppressing pro-inflammatory mediator production from macrophages in vitro and during resolution of pulmonary inflammation. Structural and functional investigation of the products resulting from oxidation of phospholipids along with a determination of the chemical mechanisms of oxidant action. The production of oxidized phospholipids in human pulmonary disease will be investigated by mass spectrometric analysis of materials exhaled from patients. Detailed study of cPLA2, an enzyme critically involved in the first step of lipid mediator production. Emphasis will be placed signal pathways leading to its phosphorylation, activation and translocation to the membrane. Analysis of the role played by a family of phospholipid scramblases in transbilayer movement of phospholipids across the cell membrane. Investigation of integration signaling via chemoattractant G protein-liked receptors and tyrosine phosphorylated membrane receptors such as FcgammaRIIa. In particular the studies will address the role of scaffold proteins and a possible central role in neutrophil signaling for the FcR gamma chain. The program brings together investigators experienced in cell biology, signal transduction, inflammation, pharmacology, physiology, lipid biochemistry, analytical chemistry, and clinical pulmonary medicine. This combination of structural, cellular, and physiologic approaches to a detailed analysis of the effects of lipid mediators in the lung is felt to represent an important step in developing the ability to selectively control pro- and anti-inflammatory lipid mediators, and thereby, influence the outcome of pulmonary inflammation.