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(O(2)) = 1, arterial Po(2) (Pa(o(2))) 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(O(2)) 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-alpha 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.