Pulmonary edema, the most immediate consequence of acute injury to the pulmonary endothelium, is the principal cause of hypoxemia, respiratory distress, and the need for mechanical ventilatory support during the acute respiratory distress syndrome (ARDS). Recently, we reported that specific thromboxane receptor blockade could reduce experimental pulmonary edema accumulation. The severity of hypoxemia in ARDS is off-set by a redistribution of pulmonary blood flow away from edematous lung units. We also found recently, using the quantitative imaging technique of positron emission tomography, that perfusion redistribution could be prevented by pretreatment with low-dose endotoxin, which resulted in markedly increased endogenous prostacyclin production by a cyclooxygenase (COX)-2 dependent mechanism. The result was systemic hypotension as well as pulmonary vasodilation with severe hypoxemia. The dramatic increases in prostacyclin production after low-dose endotoxin were dependent on the presence of lung injury, implying a synergistic effect. Thus, we propose the following specific aims:
Specific Aim 1 : to determine the mechanisms responsible for the physiologic and biochemical synergistic effects of low-dose endotoxin with experimentally-induced acute lung injury.
Specific Aim 2 : to determine the relationship between changes in lung COX-2 expression and lung arachidonic acid utilization, and increased prostacyclin production, in patients with ARDS.
Specific Aim 3 : to determine the impact of specific thromboxane receptor blockade on pulmonary capillary pressures and extravascular lung water accumulation in patients with ARDS. To accomplish these specific aims, we will employ novel radiopharmaceuticals and highly specific inhibitors of key putative pathways in studies which will evaluate the role of neutrophils, tumor necrosis factor, platelet activating factor, phospholipase A2 activation, COX-2 expression, pulmonary venoconstriction, and altered arachidonic acid kinetics, in both experimental animals and patients with ARDS. These studies will help determine how changes in pulmonary perfusion affect the physiologic expression of acute lung injury. They will also extend previous work targeted toward improving outcomes associated with ARDS by limiting pulmonary edema accumulation.
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