The proposed studies are designed to investigate the relationships between pulmonary microvascular hemodynamics and pulmonary microvascular metabolism. Pulmonary microvascular endothelial cells are responsible for the bioconversion of many compounds, and recently the extent of this bioconversion has been considered an indicator of microvascular injury. These studies will investigate the effect of altered microvascular hemodynamics on pulmonary angiotensin converting enzyme (ACE) activity and on pulmonary inactivation of 5-hydroxytryptamine (5-HT). Preliminary studies in isolated rabbit lungs have demonstrated that hydrolysis of a synthetic ACE substrate (3H-benzoylphenylalanyl-alanyl-proline, 3H-BPAP) can be altered by changing pulmonary perfusion patterns as well as by vascular injury. ACE is of significant interest because it is located on the luminal surface of microvascular endothelial cells. At this location, pulmonary ACE activity reflects not only the biochemical health of the cell but also the ability of the pulmonary vascular system to deliver substrate to enzyme sites. Thus physiological and pathophysiological events that alter ACE activity may operate by either altering ACE biochemistry or substrate delivery. Substrate delivery or enzyme accessibility is a function of the number of available enzyme sites or the kinetic variable Vmax. Substrate delivery also reflects perfusion phenomena such as flow or perfused surface area. Thus Vmax may serve as an index of surface area in the pulmonary circulation. This concept will be studied by subjecting normal isolated perfused rabbit lungs to maneuvers that alter pulmonary vascular surface area and simultaneously assessing 5-HT removal and ACE activity. Pulmonary metabolic activity can be measured by indicator dilution techniques and apparent enzyme kinetics can be calculated from indicator dilution data. These techniques will be applied to existing models of pulmonary injury, including microembolization, endotoxemia, hyperoxia and bleomycin in isolated lungs to assess the relative contribution of perfusion changes to altered metabolic function in these models. Additionally, enzyme kinetic studies will be repeated in intact anesthetized rabbits in which pulmonary hemodynamics can be experimentally controlled.
| Williams, J J; Moalli, R; Calista, C et al. (1990) Pulmonary endothelial injury and altered fibrinolysis after femur fracture in rabbits. J Orthop Trauma 4:303-8 |
| Mansell, A L; Moalli, R R; Calista, C L et al. (1989) Elastic moduli of lungs during postnatal development in the piglet. J Appl Physiol 67:1422-7 |
| Moalli, R; Warburton, S; Hasan, F M et al. (1987) Effects of antiplatelet drugs on pulmonary responses to thrombin in anesthetized rabbits. Thromb Res 48:519-33 |
| Moalli, R; Saldeen, K; Saldeen, T (1987) Effect of a fibrin-derived vasoactive peptide on pulmonary angiotensin converting enzyme activity and on pressure responses to bradykinin. J Pharmacol Exp Ther 243:897-900 |
