The pulmonary endothelium has the capacity for removing and/or metabolizing certain monoamines, prostaglandins and peptides carried in the mixed venous blood. Thus, the lungs influence the arterial concentration of these substrates. In addition, it has been suggested that changes in these endothelial functions may portend more serious damage and that if these functions could be monitored, they might provide a sensitive indicator of impending lung damage or failure. When a bolus containing a nonpermeating reference tracer and a radiolabeled substrate which is removed and/or metabolozed by the endothelial cells is injected into the pulmonary artery, the pulmonary venous concentration versus time curves contain information about the kinetics of the endothelial cell uptake and/or metabolism, as well as about pulmonary hemodynamic factors which also influence the whole organ endothelial function. In the proposed study, we will quantify this information using mathematical models in which the endothelial uptake or metabolism is represented by the Michaelis-Menten equation and convective transport is considered. The models will be used to calculate the kinetic parameters, Vmax and Km, for endothelial uptake or metabolism. We will determine the influence of various physiologic factors and experimental variables on the model parameters when H3 or C14-labeled serotonin, norepinephrine, prostaglandin E1, or a synthetic substrate for angiotensin-converting enzyme, benzoyl-Phe-Ala-Pro, are injected into the pulmonary artery of isolated dog lung lobes, isolated rabbit lungs, and intact anesthetized dogs. The experiments will be designed to provide insight into the meaning of changes in the model parameters, particularly in regard to separation of changes in endothelial cell function from changes in hemodynamics. In addition, we will use changes in the model parameters to evaluate the changes in lung uptake and metabolism of these substrates induced by embolism and toxic agents. We will continue to develop and theoretically evaluate the mathematical models used in the analysis as indicated by the experimental results. The basis of the approach is that if endothelial transport or metabolism kinetic parameters which are independent of convective transport can be calculated from the substrate extraction data, changes in endothelial cell function can be separated from changes in lung perfusion. If this objective is accomplished, this project will provide the rationale for the clinical use of indicator dilution approach to evaluating pulmonary endothelial cell function in vivo.
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