Pulmonary dysfunction caused by diffuse lung inflammation. Roles of metabolites of arachidonic acid.

Abstract

Gram-negative endotoxemia in chronically instrumented sheep causes diffuse lung inflammation. Pathophysiologic responses of the lung include marked changes in lung mechanics, pulmonary vasoconstriction, increased lung vascular permeability, and capillary endothelial injury. Over the course of the response to endotoxemia, cyclooxygenase and lipoxygenase products of arachidonic acid are released into lung lymph and the time course of the two classes of compounds is different. Thromboxane concentrations in lung lymph increase early, coincident with the most marked changes in lung mechanics and the most severe pulmonary hypertension. Concentrations of a prostacyclin metabolite also increase during this early phase of the endotoxin response but peak levels in lung lymph appear slightly later than that for thromboxane. Concentrations of these cyclooxygenase products subside as the later phase of increased vascular permeability develops. Lung lymph concentrations of two lipoxygenase products, 5- and 12-HETE, increase late in the endotoxin reaction, approximately coincident with physiologic evidence of increased lung vascular permeability. Neutrophil chemotactic activity appears in lung lymph early after endotoxin infusion and persists for several hours. Drugs which inhibit cyclooxygenase attenuate the early changes in lung mechanics and the early pulmonary hypertension after endotoxemia, but do not prevent the late phase increase in vascular permeability, suggesting that the net effect of endogenous generation of cyclooxygenase products explains the early constrictor phase of the reaction, but not the later capillary injury. However, neutrophil depletion prevents the early changes in lung mechanics without preventing the coincident pulmonary hypertension or the increase in lung lymph thromboxane concentrations which may indicate that the cell source of constrictor cyclooxygenase products mediating changes in lung mechanics is different than that for products causing pulmonary vasoconstriction. The specific role of prostacyclin in the lungs' response to endotoxemia is not clear. The temporal course of prostacyclin release suggests that it may play a role in moderating the pulmonary hypertension and changes in lung mechanics. The fact that neutrophil depletion, corticosteroids, and the antioxidant n-acetylcysteine diminish both the endotoxin-induced increase in lung vascular permeability and lung prostacyclin release may indicate that the release of prostacyclin is a response to endothelial injury.(ABSTRACT TRUNCATED AT 400 WORDS)