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Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury

Department of ¹Anesthesia and Critical Care; Division of Pulmonary and Critical Care Medicine, ²Department of Medicine; ³Division of Cardiac Surgery; Department of Surgery; ⁴Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287; and ⁵Center For Biomedical Electron Paramagnetic Resonance Spectroscopy and Imaging, Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio

Submitted 1 December 2003 ; accepted in final form 26 March 2004

Cardiopulmonary bypass (CPB) causes acute lung injury. Reactive oxygen species (ROS) from NADPH oxidase may contribute to this injury. To determine the role of NADPH oxidase, we pretreated pigs with structurally dissimilar NADPH oxidase inhibitors. Low-dose apocynin (4-hydroxy-3-methoxy-acetophenone; 200 mg/kg, n = 6), high-dose apocynin (400 mg/kg, n = 6), or diphenyleneiodonium (DPI; 8 mg/kg) was compared with diluent (n = 8). An additional group was treated with indomethacin (10 mg/kg, n = 3). CPB was performed for 2 h with deflated lungs, complete pulmonary artery occlusion, and bronchial artery ligation to maximize lung injury. Parameters of pulmonary function were evaluated for 25 min following CPB. Blood chemiluminescence indicated neutrophil ROS production. Electron paramagnetic resonance determined the effect of apocynin and DPI on in vitro pulmonary endothelial ROS production following hypoxia-reoxygenation. Both apocynin and DPI attenuated blood chemiluminescence and post-CPB hypoxemia. At 25 min post-CPB with FI_O2 = 1, arterial PO₂ (Pa_O2) averaged 52 ± 5, 162 ± 54, 335 ± 88, and 329 ± 119 mmHg in control, low-dose apocynin, high-dose apocynin, and DPI-treated groups, respectively (P < 0.01). Indomethacin had no effect. Pa_O2 correlated with blood chemiluminescence measured after drug administration before CPB (R = –0.60, P < 0.005). Neither apocynin nor DPI prevented the increased tracheal pressure, plasma cytokine concentrations (tumor necrosis factor- and IL-6), extravascular lung water, and pulmonary vascular protein permeability observed in control pigs. NADPH oxidase inhibition, but not xanthine oxidase inhibition, significantly blocked endothelial ROS generation following hypoxia-reoxygenation (P < 0.05). NADPH oxidase-derived ROS contribute to the severe hypoxemia but not to the increased cytokine generation and pulmonary vascular protein permeability, which occur following CPB.

diphenyleneiodonium; apocynin; reflection coefficient; pig; endothelium; hypoxia-reoxygenation; tumor necrosis factor; interleukin-6

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