Lipid mediators are thought to contribute to a wide variety of pathophysiologic effects in the lung. Such molecules include arachidonate derivatives, i.e. the eicosanoids (lipoxygenase and cyclooxygenase pathways: the eicosanoids and the ether phospholipid , platelet activating factor (PAF). It is suggested herein that inflammatory cells and tissue cells of the lung communicate with each other via such mediators and that the progression and outcome of inflammatory and other altered states will depend in part on the synthesis and disposition of these classes of compounds. The overall objective of this Program Project, therefore, is investigation of the synthesis of eicosanoids and PAF in lung cells and inflammatory cells. Specific Objectives include:- Determination of the role that PAF and lyso-PAF play in a proposed alkyl-acyl-glycerophosphocholine cycle in cells leading to release and metabolism of arachidonate as well as reincorporation of arachidonic acid into ether phospholipids. Investigation of the mechanisms determining the specificity of synthesis of PAF from selected ether lipid pools. How does this relate to eicosanoid production? Determination of the enzymatic regulation of the turnover of ether phosphocholines, both as a precursor for PAF and as a source of arachidonate for eicosanoid synthesis. Investigation of the conditions for release of ether lipid mediators from lung and inflammatory cells and pursuit of a role for the large amounts of PAF (and lyso-PAF which may be retained within cells. Do these function in membrane fusion during endocytosis and exocytosis? Examination of eicosanoid and PAF production and release during injury to isolated lung cells and to the whole lung. Do these materials contribute to the injury itself? Might they act on other cells in the lung to induce serious physiologic alterations. The program brings together investigators experienced in cell biology, inflammation, pharmacology, physiology, lipid biochemistry, mass spectometry and clinical pulmonary medicine. This combination of cellular, structural and physiologic approaches to a detailed analysis of the production of eicosanoid and ether lipid mediators in the lung is felt to represent an important step in developing the ability for selected control of this production and also of the pathologic effects of these molecules in vivo.