THE EFFECTS OF OXYGEN RADICAL MEDIATED PULMONARY ENDOTHELIAL DAMAGE ON CANCER METASTASIS
THE EFFECTS OF OXYGEN RADICAL MEDIATED PULMONARY ENDOTHELIAL DAMAGE ON CANCER METASTASIS
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DOI：
10.1007/bf00421054
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发表时间：
1988-12-01
影响因子：
4.3
通讯作者：
YOUNG, L
中科院分区：
文献类型：
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作者：
ORR, FW;ADAMSON, IYR;YOUNG, L
肺的血管床容易受到环境和宿主介导的自由基损伤。肺也是癌症转移形成的常见部位。由于循环对癌症的扩散很重要，而且内皮是循环和血管外组织之间的屏障，我们推测自由基对肺微血管的破坏会促进转移的形成。博莱霉素120 mg/kg静脉注射致小鼠肺内皮细胞损伤。或暴露在90%的氧气中2-4天。在大鼠中，静脉注射眼镜蛇毒因子可激活循环中的白细胞，从而引起损伤。通过形态学和肺灌洗液中先前静脉注射的蛋白增加和/或125I-白蛋白渗漏的测量，证实了内皮损伤。当在肺内皮损伤期间将放射性标记的癌细胞注入尾静脉时，24小时后位于肺内的这些细胞的数量增加了3-36倍。随后，在肺损伤的动物中形成了更多的转移性肿瘤。在大鼠中，用过氧化氢酶或抗中性粒细胞抗体预处理可阻止这种增强的定位。我们还证明了趋化肽N-fMLP刺激大鼠癌细胞后，在鲁米诺存在下放大的化学发光。这些细胞产生氧自由基的证据包括在无氧或在超氧化物歧化酶、过氧化氢酶和甘露醇存在的情况下抑制反应，以及乙酰化细胞色素C的剂量依赖性减少。我们得出结论，自由基介导的肺内皮损伤显著增加了循环中肿瘤细胞的转移，我们推测一些癌细胞可能通过产生自由基直接促进其扩散。
The vascular bed of the lung is susceptible to environmental and host-mediated injury from free radicals. The lung is also a frequent site for the formation of cancer metastases. Since the circulation is important for the spread of cancer and because the endothelium is a barrier between the circulation and extravascular tissue, we have postulated that free radical damage to the pulmonary microvasculature enhances the formation of metastases. Pulmonary endothelial injury was induced in mice by bleomycin (120 mg/kg i.v.) or by exposure to 90% oxygen for 2–4 days. In rats, damage was elicited by intravenous injection of cobra venom factor which activates the circulating leukocytes. Endothelial damage was demonstrated by morphology and by measurement, in lung lavage fluids, of increased protein and/or leakage of125I-albumin, previously injected intravenously. When radiolabeled cancer cells were injected into the tail vein during periods of pulmonary endothelial damage, there was a 3–36 fold increase in the numbers of these cells located in the lung after 24 hours. Subsequently more metastatic tumors formed in the animals with injured lungs. In rats, the enhanced localization was prevented by pretreatment of the animals with catalase or with antineutrophil antibodies. We have also demonstrated that stimulation of rat cancer cells by the chemotactic peptide N-fMLP is followed by chemiluminescence, amplified in the presence of luminol. Evidence for the generation of oxygen radicals by these cells includes inhibition of the response in the absence of oxygen or in the presence of superoxide dismutase, catalase, and mannitol, and dose-dependent reduction of acetylated cytochrome C. We conclude that free radical-mediated damage to the pulmonary endothelium significantly increases the metastasis of circulating tumor cells and we postulate that some cancer cells may directly facilitate their spread by generating free radicals.