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

Jeffrey M Dodd-o, Laura E. Welsh, Jorge D. Salazar, Peter L. Walinsky, Eric A. Peck, Jay G. Shake, David J. Caparrelli, Roy Ziegelstein, Jay L. Zweier, William A Baumgartner, David B Pearse

Research output: Contribution to journalArticle

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 FIO2 = 1, arterial PO2 (PaO2) 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. PaO2 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-α 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number2 56-2
DOIs
StatePublished - Aug 2004

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NADPH Oxidase
Lung Injury
Cardiopulmonary Bypass
Reactive Oxygen Species
Lung
Luminescence
Capillary Permeability
Indomethacin
Swine
Extravascular Lung Water
Bronchial Arteries
Cytokines
Xanthine Oxidase
Acute Lung Injury
Electron Spin Resonance Spectroscopy
acetovanillone
Pulmonary Artery
Ligation
Interleukin-6
Proteins

Keywords

  • Apocynin
  • Diphenyleneiodonium
  • Endothelium
  • Hypoxia-reoxygenation
  • Interleukin-6
  • Pig
  • Reflection coefficient
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Physiology

Cite this

Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury. / Dodd-o, Jeffrey M; Welsh, Laura E.; Salazar, Jorge D.; Walinsky, Peter L.; Peck, Eric A.; Shake, Jay G.; Caparrelli, David J.; Ziegelstein, Roy; Zweier, Jay L.; Baumgartner, William A; Pearse, David B.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 287, No. 2 56-2, 08.2004.

Research output: Contribution to journalArticle

Dodd-o, Jeffrey M ; Welsh, Laura E. ; Salazar, Jorge D. ; Walinsky, Peter L. ; Peck, Eric A. ; Shake, Jay G. ; Caparrelli, David J. ; Ziegelstein, Roy ; Zweier, Jay L. ; Baumgartner, William A ; Pearse, David B. / Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury. In: American Journal of Physiology - Heart and Circulatory Physiology. 2004 ; Vol. 287, No. 2 56-2.
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AU - Shake, Jay G.

AU - Caparrelli, David J.

AU - Ziegelstein, Roy

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AU - Pearse, David B

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N2 - 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 FIO2 = 1, arterial PO2 (PaO2) 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. PaO2 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-α 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.

AB - 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 FIO2 = 1, arterial PO2 (PaO2) 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. PaO2 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-α 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.

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