Pulmonary endothelium expresses a variety of transporter and enzyme proteins which are known or suspected modulators of cardiovascular homeostasis, and which are selectively susceptible to injury. The long-term goal of our laboratory is the elucidation of the properties and functions of pulmonary endothelial enzymes, in vivo, under normal and toxicant-altered environments. The proposed studies will utilize the anesthetized rabbit heart bypass model, developed in our laboratory, to continue searching for optimum probes (substrates, inhibitors) of endothelial ectoenzyme (angiotensin converting enzyme, 5' -nucleotidase) function. We will apply our acquired knowledge to the study of induction, as well as (for the first time) reversal of endothelial ectoenzyme dysfunction by three clinically relevant models of endothelial toxicity, in vivo; diabetes (and its reversal by insulin), phorbol ester-activated neutrophils (and their antagonism by free radical scavengers and proteinase inhibitors), and microembolization. We will compare and contrast possible mechanisms of, and relative susceptibility to, injury of pulmonary endothelial ectoenzymes vs. a newly discovered cytoplasmic enzyme (endothelium derived relaxing factor, EDRF-generating nitric oxide synthase), in cultured pulmonary endothelial cells. We will begin in vivo assays of pulmonary endothelial ACE activity, in man. These investigations should advance our understanding of pulmonary endothelial function in health and disease and aid in the development of a clinically useful diagnostic procedure for the early detection of lung microvascular injury, such as that produced by the adult respiratory distress syndrome (ARDS).
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