I propose to do three groups of experiments that investigate lung liquid and protein exchange during the acute inflammatory response to intravascular air emboli and which temporally relate parameters of microvascular function to quantitative structural changes in the pulmonary microcirculation. Acutely-instrumented, anesthetized sheep and chronically-instrumented, awake sheep with lung lymph fistulas will be used to evaluate lung liquid balance and pulmonary microvascular structure. I hypothesize that air embolic acute lung injury begins with pulmonary microvascular obstruction, followed by denaturation of plasma proteins at the air bubble-blood interface, mediator generation and release, neutrophil sequestration, chemotaxis and activation within the pulmonary microcirculation, generation and release of toxic oxygen metabolites, pulmonary microvascular endothelial cell damage, and ends with pulmonary microvascular increased-permeability. The experimental groups are designed to (1) study the development (first hour) of air embolism-induced acute lung injury in anesthetized sheep, (2) assay the generation and release of mediators of inflammation in vivo (sheep) and in vitro (sheep and human serum) and (3) study the efficacy of inhibitors of acute inflammation by testing therapeutic regimens in awake sheep. The first and third groups of experiments are designed to relate lung liquid and protein balance, as well as leukocyte sequestration, to pulmonary microvascular endothelial cell injury and vascular tracer leakage. The second group of experiments, which augment those of groups 1 and 3, will provide in vitro information on the role of leukocytes and the generation and release of mediators of inflammation (complement and toxic oxygen metabolites) in this type of experimental lung injury. The approach of relating function to structure in sheep and to studying functional responses in human serum in vitro will result in greater understanding of the basic mechanisms underlying embolic acute lung injury.
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