Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat

Abstract

2002.-Our objective was to test the effect of inhibition of thromboxane synthase versus inhibition of cyclooxygenase (COX)-1/2 on pulmonary gas exchange and heart function during simulated pulmonary embolism (PE) in the rat. PE was induced in rats via intrajugular injection of polystyrene microspheres (25 m). Rats were randomized to one of three posttreatments: 1) placebo (saline), 2) thromboxane synthase inhibition (furegrelate sodium), or 3) COX-1/2 inhibition (ketorolac tromethamine). Control rats received no PE. Compared with controls, placebo rats had increased thromboxane B2 (TxB2) in bronchoalveolar lavage fluid and increased urinary dinor TxB2. Furegrelate and ketorolac treatments reduced TxB2 and dinor TxB2 to control levels or lower. Both treatments significantly decreased the alveolar dead space fraction, but neither treatment altered arterial oxygenation compared with placebo. Ketorolac increased in vivo mean arterial pressure and ex vivo left ventricular pressure (LVP) and right ventricular pressure (RVP). Furegrelate improved RVP but not LVP. Experimental PE increased lung and systemic production of TxB 2. Inhibition at the COX-1/2 enzyme was equally as effective as inhibition of thromboxane synthase at reducing alveolar dead space and improving heart function after PE. thromboembolism/treatment; cyclooxygenase; thromboxane; leukotriene; ketorolac; heart failure; Langendorff; animal model PULMONARY EMBOLISM (PE) continues to be a major cause of morbidity and mortality in the United States. In one large autopsy-based study, massive PE was the second leading cause of sudden death in adults aged Ͻ65 yr (4). The primary treatment strategy for massive PE is the recanalization of occluded pulmonary vasculature by fibrinolytic agents (11), catheter fragmentation (32), or surgical removal of clot (16). However, up to one-half of patients with massive PE have contraindications to fibrinolysis (15), and few hospitals have facilities for invasive treatment of PE. Even under optimal conditions (e.g., immediate bolus infusion of a fibrinolytic agent), these interventions require Ͼ2 h to effect a significant reduction in pulmonary vascular resistance (20). PE may also cause pulmonary vasoconstriction through the liberation of vasoconstrictive agents, including PGF 2␣ and thromboxane (Tx) A 2 and B 2 (10). PE can cause hypoxemia and increased pulmonary arterial pressure in previously healthy patients (19). Both hypoxemia and increased shear forces in the pulmonary vascular bed have been found to increase expression of the cyclooxygenase (COX)-2 gene (3). In humans with PE, blood concentrations of thromboxane have been found to be elevated for up to 7 days after onset of symptoms (10). Both the mechanical vascular occlusion and release of vasoconstrictive agents from massive PE appear to produce a synergistic effect that causes acute pulmonary hypertension, worsened gas exchange, impaired right ventricular (RV) function that can culminate in acute cor pulmonale, circulatory shock, and even death (26,30,39).In the ...

Inhibition of CINC-1 Decreases Right Ventricular Damage Caused by Experimental Pulmonary Embolism in Rats

“…Histological studies of human RV tissue taken postmortem demonstrated the presence of neutrophil and monocyte/macrophage cells in a small series of human PE cases (27,28), but the contribution of those inflammatory cells to cardiac injury has not been defined in the clinical setting. To study mechanisms of cardiac injury, we have successfully developed a rat model of PE that employs polystyrene microspheres as emboli (29,32,34). Jones et al (32) demonstrated significant improvement in survival, mean arterial blood pressure, and heart function in rats with experimental PE treated with the anti-inflammatory agent ketorolac sodium.…”

“…Polystyrene microspheres were used to create pulmonary emboli as previously described (29,32). Microspheres (25 Ϯ 1 m; Duke Scientific catalog no.…”

Proinflammatory Events in Right Ventricular Damage During Pulmonary Embolism: Effects of Treatment With Ketorolac in Rats

“…41 Our previous studies showed that ketorolac treatment decreased prostaglandin formation (PGF 2a , PGE 2 , and TxB 2 ) without promoting leukotriene formation (leukotrienes C4, D4, and E4) after PE. 30 A reduction in alveolar dead space and cardiac protection was observed. Similar results were obtained with an inhibitor of thromboxane synthase, furegrelate, suggesting that vasoconstricting prostaglandin metabolites are important in PE.…”

“…This dose of ketorolac was chosen because we have previously shown that it prevents prostaglandin formation without promoting leukotriene formation during PE in rats. 30 …”

“…Our previous studies showed that delayed treatment with the nonsteroidal antiinflammatory drug (NSAID), ketorolac (Toradol), reduced the formation of vasoconstricting prostaglandins without enhancing leukotriene formation, reduced alveolar dead space, and afforded cardiac protection in our rat model of PE. 30 The focus of those studies was on pulmonary gas exchange. The present studies identify key steps in the conversion of hearts to the cardiac proinflammatory phenotype and provide evidence that early ketorolac treatment also reduces the upregulation of proinflammatory genes and neutrophil responsiveness to chemokine signal, reducing RV inflammation and subsequent cardiac dysfunction during PE.…”