Effects of neutrophil-mediated pulmonary endothelial injury on the localization and metastasis of circulating Walker carcinosarcoma cells.
The lung, a frequent site of cancer metastases, is also a susceptible target in several models of endothelial injury. In previous studies we have demonstrated that such injury, induced by bleomycin or by exposure to high concentrations of atmospheric oxygen, can facilitate the localization and metastasis of circulating tumor cells. Here we have tested the hypothesis that neutrophil-mediated injury to pulmonary endothelium has a similar effect. In Sprague-Dawley rats, intravenous injection of cobra venom factor resulted in complement activation, rapid sequestration of neutrophils in the lung, and endothelial damage, demonstrated by morphology, and by increased protein content and leakage of intravenous 125I-albumin into bronchoalveolar lavage fluids. When 125I-iododeoxyuridine-labeled Walker carcinosarcoma cells were injected intravenously during the period of endothelial injury, the pulmonary capillaries contained aggregates of neutrophils and tumor cells 2 h later, and there was a 3-fold increase in pulmonary tumor cell localization after 24 h in treated animals, compared to controls. Enhancement of tumor cell localization was prevented by pretreatment of the rats with catalase or by antineutrophil antisera. When animals were examined 2 weeks after cell injection, treatment groups had significantly more metastatic tumor nodules and a greater area of lung tissue involved by metastatic tumors. We conclude that neutrophil-mediated damage to the pulmonary endothelium can significantly increase the trapping of circulating tumor cells, and is likely to be clinically important since the large vascular bed of the lung is susceptible to host-mediated injury.