Effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep.

Abstract

We tested the effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep in order to evaluate the role of thromboxane (Tx) in this injury. Escherichia coli endotoxin (1 microgram/kg) infusion produced a biphasic response. The early period (Phase 1) was a transient pulmonary hypertension. The late period (Phase 2) was a more prolonged period characterized by a marked high flow of lung lymph with a high concentration of protein, suggesting increased pulmonary vascular permeability. During Phase 1, there were remarkable increases in TxB2 and 6-keto-PGF1 alpha concentrations in lung lymph and in plasma samples obtained from the pulmonary artery (PA) and the left atrium (LA). The increase in plasma TxB2 level of the LA was greater than that of the PA. During Phase 2, TxB2 levels returned to the baseline values, whereas 6-keto-PGF1 alpha levels remained elevated. Pretreatment with OKY-046 prevented the pulmonary hypertension and increases in TxB2 levels during Phase 1. However, OKY-046 had little effect on lung lymph balance during Phase 2. We conclude that the early pulmonary hypertension induced by endotoxin is mediated mainly by release of TxA2 from the lungs, and TxA2 is not attributed to the increased pulmonary permeability during the late period.