Roles of Arachidonic Acid Metabolites in Endotoxin-Induced Pulmonary Edema

Abstract

Pulmonary edema develops after insults that increase lung vascular permeability (primary pulmonary edema) and/or increase lung vascular pressures (secondary pulmonary edema). Secondary pulmonary edema often results from high vascular pressures during left heart failure. The causes of primary pulmonary edema are less well understood. For example, abrupt, severe pulmonary hypertension may injure lung capillaries causing focal increases in capillary permeability. Other possible sources of increased lung vascular permeability include complement activation, release of histamine or lysosomal enzymes, and synthesis of leukotrienes (formerly slow reacting substances) or toxic oxygen radicals, such as superoxide and hydroxyl radicals. At Vanderbilt's Pulmonary Circulation Center, we are studying the pathogenesis of primary pulmonary edema in chronically instrumented, unanesthetized sheep prepared for continuous measurement of vascular pressures and collection of lung lymph. We can elicit primary pulmonary edema by infusing small amounts of E. coli endotoxin, which consistently causes a reaction characterized by an early period of severe pulmonary hypertension lasting less than one hour (phase I), followed by a period of increased lung vascular permeability from three to five hours after endotoxemia. We and others have measured concentrations of various potential mediators and metabolites in lung lymph and blood plasma" during the pulmonary vascular response to endotoxin. Several metabolites of arachidonic acid have endured as potential mediators of both pulmonary hypertension (such as thromboxane [Tx] A2) and increased lung vascular permeability (such as SRSA or leukotrienes). Since several aspects of the pulmonary vascular response to endotoxemia are reproducible in the same animal, we have also investigated the influences of numerous pharmacologic interventions on the endotoxin reaction. This article will summarize our current understanding of the involvement of metabolites of arachidonic acid in the pathogenesis of pulmonary edema after endotoxemia.