Role of reactive oxygen species in reperfusion injury of the rabbit lung.

Abstract

We have developed a model of reperfusion injury in Krebs buffer-perfused rabbit lungs, characterized by pulmonary vasoconstriction, microvascular injury, and marked lung edema formation. During reperfusion there was a threefold increase in lung superoxide anion (0°) production, as measured by in vivo reduction of nitroblue tetrazolium, and a twofold increase in the release of 02 into lung perfusate, as measured by reduction of succinylated ferricytochrome c. Injury could be prevented by the xanthine oxidase inhibitor allopurinol, the 02 scavenger SOD, the hydrogen peroxide scavenger catalase, the iron chelator deferoxamine, or the thiols dimethylthiourea or Nacetylcysteine. The protective effect of SOD could be abolished by the anion channel blocker 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid, indicating that SOD consumes 02 in the extracellular medium, thereby creating a concentration gradient favorable for rapid diffusion of 02 out of cells. Our results extend information about the mechanisms of reperfusion lung injury that have been assembled by studies in other organs, and offer potential strategies for improved organ preservation, for treatment of reperfusion injury after pulmonary thromboembolectomy, and for explanation and therapy of many complications of pulmonary embolism.

Propofol alleviates acute lung injury following orthotopic autologous liver transplantation in rats via inhibition of the NADPH oxidase pathway

“…ROS directly damage lung parenchymal cells via lipid peroxidation, in addition to the basement membrane of capillaries and pulmonary interstitial cells, thereby resulting in severe pulmonary edema (26). Previous studies have indicated that a reduction in ROS production may alleviate liver or lung ischemia-reperfusion injury (27), as a sudden influx of ROS can overwhelm innate protective measures and lead to organ injury (28). ROS are formed through various key enzymes, including xanthine oxidase, NADPH oxidase and nitric oxide synthase (29)(30)(31), of which NADPH oxidase-dependent ROS formation is considered to be the most important.…”

Continuous Observation of Superoxide Generation in an In-Situ Ischemia - Reperfusion Rat Lung Model

“…times or intermittently. 1,6,15 In addition, oxygen free radical formation has been often indirectly estimated from the preventive effects of oxygen radical scavengers, such as SOD, 1,6,11,20,21 catalase, 1,6,8 and dimethylthiourea 1,6 or the effects of inhibitors of radical production, such as verapamil, 12 tungsten, 8 allopurinol, 6,8,20 lodoxamide, 9 ATP-MgCl2, 7 and nitric oxide 22 on reperfusion lung injury in isolated or in vivo lungs. These methods do not permit the continuous observation of oxygen free radical generation in ischemiareperfused lungs and have not provided direct evidence of oxygen free radical generation in an in vivo ischemiareperfusion lung model.…”

“…2,3 The same mechanism appears to be involved in the effect of ischemia-reperfusion on the pulmonary circulation, 4 but it remains unclear how oxygen free radicals are generated after a short period of occlusion of the pulmonary artery alone. Most previous studies investigating oxygen free radicals in reperfusion injury of the lungs have been performed in isolated lungs, 1,[5][6][7][8][9] or in animals with obstruction of both the airway and the pulmonary artery; that is, hilar occlusion. [10][11][12] In order to simulate clinical pulmonary artery occlusion and reperfusion, the generation of oxygen free radicals should be evaluated without obstructing either the airway or the bronchial circulation in in-vivo blood-perfused lungs.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Xanthine oxidase-dependent superoxide generation after IR is also a possible mechanism of lung injury (Kennedy, et al, 1989;Lynch, et al, 1988). Under ischemic conditions, xanthine dehydrogenase is converted to xanthine oxidase, which in turn converts hypoxanthine to xanthine and then further catalyzes the oxidation of xanthine to uric acid.…”

“…The xanthine oxidase-generated free radicals damage endothelial cells as well as aid the sequestration of neutrophils thereby leading to further injury after IR. Treatment with xanthine oxidase inhibitors, such as allopurinol or iodoxamide, has been shown to attenuate superoxide generation and lung IR injury in rabbit and mouse models of lung IR injury (Adkins & Taylor, 1990;Kennedy, et al, 1989;Lynch, et al, 1988). These investigations suggest an important role for xanthine oxidase in the production of ROS during lung IR.…”