Tan S, Yokoyama Y, Dickens E, Cash T G, Freeman B A, Parks D A
Department of Pediatrics, University of Alabama at Birmingham 35233-6810.
Free Radic Biol Med. 1993 Oct;15(4):407-14. doi: 10.1016/0891-5849(93)90040-2.
Reactive oxygen metabolites generated from xanthine oxidase play an important role in the pathogenesis of ischemia-induced tissue injury. In a hemorrhagic shock model of ischemia-reperfusion, the intracellular enzyme xanthine oxidase was released into the vasculature. This intravascular source of superoxide (O2.-) and hydrogen peroxide (H2O2) interacted reversibly with glycosaminoglycans of vascular endothelium and markedly concentrated xanthine oxidase at cell surfaces, enhancing its ability to produce extensive damage to remote tissues. Rats were made hypotensive by hemorrhage, maintained for 2h, and reinfused with shed blood. Blood samples were obtained prior to hemorrhage and 15, 30, 60, and 90 min after reperfusion for determination of xanthine oxidase (XO), lactate dehydrogenase (LDH), and alanine transaminase (AST). These enzymes were not significantly elevated in control animals. Reperfusion after hemorrhage-induced ischemia resulted in significantly elevated AST and LDH in both low heparin (100 U/h) and high heparin (1000 U/h) groups. Xanthine oxidase was detected in the circulation only after 90 min reperfusion in the low heparin group and was elevated during the entire reperfusion period in the high heparin group. Studies with cultured vascular endothelium showed significant heparin-reversible binding of XO to cellular glycosaminoglycans. These results suggest that XO can gain access to the circulation following ischemia, where it then binds to the vascular endothelial cells to produce site-specific oxidant injury to organs remote from the site of XO release.
黄嘌呤氧化酶产生的活性氧代谢产物在缺血性组织损伤的发病机制中起重要作用。在缺血再灌注的失血性休克模型中，细胞内酶黄嘌呤氧化酶释放到血管系统中。血管内超氧化物（O2.-）和过氧化氢（H2O2）的来源与血管内皮的糖胺聚糖可逆性相互作用，并在细胞表面显著浓缩黄嘌呤氧化酶，增强其对远处组织造成广泛损伤的能力。通过放血使大鼠血压降低，维持2小时，然后回输流出的血液。在放血前以及再灌注后15、30、60和90分钟采集血样，以测定黄嘌呤氧化酶（XO）、乳酸脱氢酶（LDH）和丙氨酸转氨酶（AST）。这些酶在对照动物中没有显著升高。出血性缺血后的再灌注导致低肝素（100 U/h）和高肝素（1000 U/h）组的AST和LDH显著升高。在低肝素组中，仅在再灌注90分钟后才在循环中检测到黄嘌呤氧化酶，而在高肝素组中，在整个再灌注期间黄嘌呤氧化酶都升高。对培养的血管内皮进行的研究表明，XO与细胞糖胺聚糖有显著的肝素可逆性结合。这些结果表明，XO在缺血后可进入循环，然后与血管内皮细胞结合，对远离XO释放部位的器官产生位点特异性氧化损伤。
