Ibuprofen prevents thrombin-induced lung vascular injury: mechanism of effect

We compared pulmonary vascular responses with thrombin-induced pulmonary microembolism in awake sheep pretreated with ibuprofen or meclofenamate. Control sheep with lung lymph fistulas (n = 6) were challenged with 80 U/kg of alpha-thrombin, the native enzyme. Two groups of similarly prepared sheep received the cyclooxygenase inhibitors, ibuprofen (n = 4) or meclofenamate (n = 4), before the thrombin challenge. Thrombin-induced pulmonary microembolism in control sheep increased pulmonary lymph flow and lymph protein clearance (lymph flow X lymph-to-plasma protein concentration ratio). These lymph changes were associated with sustained increases in mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) and a decrease in circulating neutrophil count. The steady-state pulmonary hemodynamic and lymph responses to thrombin persisted after cyclooxygenase inhibition with meclofenamate, although the increases in pulmonary lymph flow and lymph protein clearance were delayed. In contrast, ibuprofen reduced pulmonary lymph flow, lymph protein clearance, Ppa, and PVR responses. Neutrophil count in control and meclofenamate groups remained below base line after thrombin, whereas neutrophil count returned to base line in the ibuprofen group within 90 min after thrombin. Ibuprofen resulted in a greater decrease in vitro neutrophil adherence to pulmonary endothelium induced by serum generated by clotting whole blood with alpha-thrombin as compared with meclofenamate. Results indicate that ibuprofen attenuates the increases in Ppa and PVR and markedly attenuates the increase in pulmonary transvascular protein clearance after thrombin. The protective effect of ibuprofen may be due to reduction of neutrophil sequestration in lung.