Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung.
The pathogenesis of reexpansion pulmonary edema is not yet fully understood. We therefore studied its mechanism in a rat model in which the left lung was collapsed by bronchial occlusion for 1 h and then reexpanded and ventilated for an additional 3 h. We then evaluated the production of reactive oxygen species in the lungs using fluorescent imaging and cerium deposition electron microscopic techniques and the incidence of apoptosis using the TdT-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. We found that pulmonary reexpansion induced production of reactive oxygen species and then apoptosis, mainly in endothelial and alveolar type II epithelial cells. Endothelial cells and alveolar type I and II epithelial cells in the reexpanded lung were positive for TUNEL and cleaved caspase-3. DNA fragmentation was also observed in the reexpanded lung. In addition, wet-dry ratios obtained with reexpanded lungs were significantly higher than those obtained with control lungs, indicating increased fluid content. All of these effects were attenuated by pretreating rats with a specific xanthine oxidase inhibitor, sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one. It thus appears that pulmonary reexpansion activates xanthine oxidase in both endothelial and alveolar type II epithelial cells and that the reactive oxygen species produced by the enzyme induce apoptosis among the endothelial and alveolar type I and II epithelial cells that make up the pulmonary water-air barrier, leading to reexpansion pulmonary edema.
Saito
Satoshi
S
Division of Thoracic Surgery, Department of Surgery, Akita University School of Medicine, Japan.
Ogawa
Jun-ichi
J
Minamiya
Yoshihiro
Y
D000818:Animals; D017209:Apoptosis; D042783:Endothelial Cells / Q000201:enzymology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008854:Microscopy, Electron; D011030:Pneumothorax / Q000628:therapy*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D011652:Pulmonary Circulation; D011654:Pulmonary Edema / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000097:blood; D012121:Respiration, Artificial / Q000009:adverse effects*; D014969:Xanthine Oxidase / Q000378:metabolism*
D017382:Reactive Oxygen Species; D014969:Xanthine Oxidase