We will study the nature, mechanisms and consequences of impaired lung metabolic functions and, with such knowledge, develop a reliable means for early detection of acute lung injury. Pulmonary microvascular endothelial cells are metabolically active and synthesize and degrade many circulating vasoactive and other compounds. We found previously that alterated magnitude of these processes can reflect the presence of lung microvascular injury. We also found that the magnitude of change is influenced both by intrinsic endothelial dysfunction and by hemodynamic factors, including blood flow rate and its distribution relative to endothelial surface area. We propose, therefore, to apply a new non-linear analysis of multiple indicator dilution data to estimate the apparent kinetic parameters of selected lung metabolic functions. We believe that Kmapp will reflect endothelial metabolic function and Vmaxapp, indirectly, will be related to endothelial surface area. Kinetic parameters will be determined with isolated perfused lungs where the influence of altered flow, vascular surface area, transpulmonary pressure will be controlled. Kinetic data derived by bolus injection or steady state infusion of Benz-phe-ala-pro (BPAP) or prostaglandins will be compared. Kmapp and Vmaxapp will also be determined in intact, anesthetized or conscious rabbits under control conditions and after injury by hyperoxia, endotoxin, live organisms, embolization, used alone or in combination. This approach will allow us to unravel the complex interaction of endothelial cell damage and accompanying hemodynamic influences. With such knowledge we will then use kinetic measurements to follow (a) the development of injury; (b) the appearance of potential eicosanoid mediators of injury; and (c) the effectiveness of three reportedly specific inhibitors of eicosanoid biosynthesis - nafazatrom, BW775c and U-60257 - in preventing or ameliorating effects of acute lung injury. Finally, we will use photon-emitting isotopes to develop virtually """"""""on-line"""""""" methods for determination of Kmapp and Vmaxapp of lung metabolic events in perfused lung and intact animal.
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