The overall goal of this project is to establish correlates of pulmonary endothelial injury that will aid in the diagnosis and management of alveolar-capillary injury. We will use human pulmonary endothelial cells in culture and isolated perfused lungs of laboratory animals to achieve several specific goals. First, we will identify potential enzymatic markers from the endothelium or subendothelial tissues that are altered or released with injury. These enzymes include several peptidases that metabolize biologically active peptides: angiotensin I converting enzyme, a neural metalloendopeptidase, carboxypeptidase N and aminopeptidase A. Next, we will determine how these enzymes relate to normal structure and function of the lung and how their activities change in pathological conditions. Our studies will include compare serum enzymes with those bound to cell membranes with regard to substrate specificities and molecular characteristics. Our project includes the identification and quantification of metabolites of arachidonic acid (AA), with particular emphasis upon the lipoxygenase and epoxygenase pathways. We will see if endothelial injury shifts the metabolism of AA from the cyclooxygenase pathway to these pathways. The objective is to determine how AA metabolites influence the behavior of leukocytes and platelets. Studies of cellular interactions between these formed elements and normal or damaged endothelium will provide us with an in vitro model for diseases, such as ARDS.
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