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Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury
Jeffrey M Dodd-o1, Laura E Welsh, Jorge D Salazar
1Department of Anesthesia and Critical Care, The Johns Hopkins Medical Institutions, Baltimore, MD 21287-9106, USA. jdoddo@jhmi.edu
Abstract:
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.
Insights
Cardiopulmonary bypass causes lung injury partly via NADPH oxidase-derived reactive oxygen species (ROS). Inhibiting this enzyme reduces hypoxemia but not other injury markers like cytokine release.
Area of Science:
- Cardiovascular Surgery
- Pulmonary Medicine
- Biochemistry
Background:
- Cardiopulmonary bypass (CPB) is associated with acute lung injury.
- Reactive oxygen species (ROS), particularly those generated by NADPH oxidase, are implicated in CPB-induced lung damage.
Purpose of the Study:
- To investigate the role of NADPH oxidase in CPB-induced acute lung injury.
- To evaluate the efficacy of NADPH oxidase inhibitors (apocynin and diphenyleneiodonium) in mitigating lung injury during CPB.
Main Methods:
- Pigs underwent 2 hours of CPB with lung injury induction.
- Animals were pretreated with apocynin, diphenyleneiodonium (DPI), or diluent.
- Pulmonary function, neutrophil ROS production (chemiluminescence), and endothelial ROS generation (electron paramagnetic resonance) were assessed.
Main Results:
- Both apocynin and DPI significantly attenuated neutrophil ROS production and post-CPB hypoxemia.
- NADPH oxidase inhibition blocked endothelial ROS generation following hypoxia-reoxygenation in vitro.
- Inhibitors did not prevent increased tracheal pressure, plasma cytokines (TNF-α, IL-6), extravascular lung water, or pulmonary vascular protein permeability.
Conclusions:
- NADPH oxidase-derived ROS contribute to hypoxemia following CPB.
- Inhibition of NADPH oxidase does not prevent all CPB-induced lung injury markers, such as cytokine release and increased vascular permeability.
- Xanthine oxidase inhibition was ineffective, supporting a specific role for NADPH oxidase in CPB-related ROS production.
