STUDIES ON THE ROLE OF THROMBOXANE IN THROMBIN-INDUCED PULMONARY INSUFFICIENCY IN THE RAT

The pathophysiology of the acute pulmonary damage that may occur in association with sepsis, hemorrhagic shock and microembolism seems to involve the activity of cyclooxygenase derived arachidonate metabolites. In the rat, pulmonary microembolism due to infusion of thrombin together with inhibition of fibrinolysis has been found to induce pulmonary insufficiency with similarities to the clinical adult respiratory distress syndrome. The infusion of thrombin results in systemic hypotension, pulmonary hypertension and platelet aggregation, and subsequently, with a certain dealy in time, to increased pulmonary vascular permeability. The main purposes of this investigation were to study the release of TxA2 and PGI2 following thrcmbin-induced pulmonary microembolizaticn in the rat and to examine the effects of a thromboxane synthetase inhibitor (DazoxibenR) on pulmonary arterial and systemic mean arterial pressure and vascular permeability. During infusion of thrcmbin in rats pulmonary arterial pressure rose from 15 ± 2 to 35 ± 3 rmHg and mean arterial pressure fell from 120 ± 6 to 49 ± 27 mmHg. Plasma thromboxane B2 (TxB2) increased from 0.3 ± 0.004 to 3.6 ± 0.5 ng/ml. Ninety minutes later the lung weight and albunin concentration in the lung were increased (2.21 ± 0.13 g and 22.7 ± 4.7 mg/g) compared with controls (1.12 ± 0.14 g and 8.5 ± 0.9 mg/g). Dazoxiben reduced the elevated pulmonary arterial pressure and the elevated plasma TxB2 concentration following infusion of thrombin. Ninety minutes after infusion of thrcmbin, the in vitro synthesis of TxB2 in lung tissue was increased. Dazoxiben and a specific rabbit anti-rat neutrophil serun reduced this synthesis of TxB in vitro. The lung weight (2.18 ± 0.20 g) and lung albumin concentration (21.4 ± 3.4 mg/g) was not affected by Dazoxiben. The results indicate that TxA2 in an important mediator of the pressure changes in the early phase after infusion of thrombin and that neutrophils are associated with thromboxane formation in the lung tissue. Rats pretreated with the antineutrophil serum had less pulmonary weight (1.69 ± 0.28 g) and the albumin concentration in the edema fluid was decreased (17.3 ± 3.6 mg/g), suggesting that polymorphonuclear leukocytes contributed to the pulmonary dysfunction. Dazoxiben when incubated with thrcmbin in a chromogenic substrate system had a linear, dose-related anti-thrombin effect. At a Dazoxiben concentration of 2.4 mM only a few percent of the thrombin activity remained.