Selective Thromboxane A2Synthase Inhibition by OKY-046 Prevents Cardiopulmonary Dysfunction after Ovine Smoke Inhalation Injury

Abstract

Because thromboxane A2 is implicated in the pathophysiology of acute lung injury, the aim of this study was to evaluate the effects of selective thromboxane A2 synthase inhibition on cardiopulmonary function in the experimental setting of severe smoke inhalation injury. Sixteen adult sheep were operatively instrumented for chronic study. The injured intervention group was treated with the selective thromboxane A2 synthase inhibitor OKY-046, whereas the injured control group received only the vehicle (n = 8 each). The progressive increase in thromboxane B2 lung lymph concentrations in control animals was associated with increased transvascular fluid flux, augmented resistances in the pulmonary and systemic circulation, and a reciprocal decrease in cardiac output. In addition, end-systolic pressure-diameter relation and maximum +dp/dt were markedly depressed as compared with baseline (24 h: 14.3 +/- 0.9 vs. 8.9 +/- 0.5 mmHg/mm and 2,120 +/- 50 vs. 1,915 +/- 40 mmHg/s, respectively; each P < 0.05). Infusion of OKY-046 significantly inhibited pulmonary thromboxane B2 delivery, attenuated the early increase in pulmonary vascular resistance, and blocked the increase in systemic vascular resistance. In addition, OKY-046 blunted and delayed the decrease in cardiac output and maintained end-systolic pressure-diameter relation, +dp/dt, and lung lymph flow at baseline values. These findings suggest that selective thromboxane A2 synthase inhibition may represent a goal-directed therapeutic approach to alleviate cardiovascular and pulmonary dysfunction in the setting of smoke inhalation injury.