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Am J Physiol Heart Circ Physiol 279: H303-H312, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 1, H303-H312, July 2000

Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury

Jeffrey M. Dodd-O1 and David B. Pearse2

2 Division of Pulmonary and Critical Care Medicine, Departments of 1 Anesthesia and Critical Care and Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21224

Apocynin (4-hydroxy-3-methoxy-acetophenone) inhibits NADPH oxidase in activated polymorphonuclear (PMN) leukocytes, preventing the generation of reactive oxygen species. To determine if apocynin attenuates ischemia-reperfusion lung injury, we examined the effects of apocynin (0.03, 0.3, and 3 mM) in isolated in situ sheep lungs. In diluent-treated lungs, reperfusion with blood (180 min) after 30 min of ischemia (ventilation 28% O2, 5% CO2) caused leukocyte sequestration in the lung and increased vascular permeability [reflection coefficient for albumin (sigma alb) 0.47 ± 0.10, filtration coefficient (Kf) 0.14 ± 0.03 g · min-1 · mmHg-1 · 100 g-1] compared with nonreperfused lungs (sigma alb 0.77 ± 0.03, Kf 0.03 ± 0.01 g · min-1 · mmHg-1 · 100 g-1; P < 0.05). Apocynin attenuated the increased protein permeability at 0.3 and 3 mM (sigma alb 0.69 ± 0.05 and 0.91 ± 0.03, respectively, P < 0.05); Kf was decreased by 3 mM apocynin (0.05 ± 0.01 g · min-1 · mmHg-1 · 100 g-1, P < 0.05). Diphenyleneiodonium (DPI, 5 µM), a structurally unrelated inhibitor of NADPH oxidase, worsened injury (Kf 0.32 ± 0.07 g · min-1 · mmHg-1 · 100 g-1, P < 0.05). Neither apocynin nor DPI affected leukocyte sequestration. Apocynin and DPI inhibited whole blood chemiluminescence and isolated PMN leukocyte-induced resazurin reduction, confirming NADPH oxidase inhibition. Apocynin inhibited pulmonary artery hypertension and perfusate concentrations of cyclooxygenase metabolites, including thromboxane B2. The cyclooxygenase inhibitor indomethacin had no effect on the increased vascular permeability, suggesting that cyclooxygenase inhibition was not the explanation for the apocynin results. Apocynin prevented ischemia-reperfusion lung injury, but the mechanism of protection remains unclear.

sheep; diphenyleneiodonium; pulmonary edema; vascular permeability


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