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Science to Practice |
Department of Radiology,
Lancaster General Hospital,
1400 Harrisburg Pike,
Lancaster, PA 17404,
john_stryker@hotmail.com
SUMMARY
Christiansen et al irradiated rat livers in vivo; isolated rat hepatocytes in vitro; and measured hepcidin, hemojuvelin, and ferroportin-1 gene expression. They also evaluated the influence of proinflammatory cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor [TNF]-
) on the expression of these proteins. In this issue of Radiology, Christiansen et al conclude that radiation-induced cell-cell interactions by way of the cytokines can lead to death of irradiated hepatocytes.
THE SETTING
An isolated hepatocyte irradiated in vitro is relatively radioresistant (1). Thus, one would expect that the liver irradiated in vivo would also be radioresistant. In clinical radiation oncology, however, the liver is known to be a radiosensitive organ (2). Fractionated doses greater than 20 Gy can result in life-threatening radiation-induced liver disease, a fact that limits treatment for patients requiring hepatic irradiation. Pathologic studies suggest that radiation-induced liver disease is a veno-occlusive process that originates from injury to endothelial cells of the central veins and results in collagen deposition and fibrosis (3,4).
In this issue of Radiology, Christiansen et al present evidence that there may be additional mechanisms as well (5). Their data suggest that following hepatic irradiation, cell-cell interactions mediated by way of proinflammatory cytokines such as IL-1ß, IL-6, and TNF- play an important role in radiation-induced liver disease (5).
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Christiansen et al performed irradiation in 35 rat livers in vivo and in isolated hepatocytes from eight rats in vitro to analyze hepcidin, hemojuvelin, and ferroportin-1 gene expression. The in vivo experiments involved groups of five rats that received 25 Gy in a single fraction to the whole liver. There were five sham-irradiated rats. The animals were sacrificed at 1, 3, 6, 12, 24, and 48 hours after irradiation, and the livers and serum samples were removed and frozen. RNA extracted from the livers was analyzed with real-time polymerase chain reaction and Northern blot. Cytokines and prohepcidin in the serum were measured with enzyme-linked immunosorbent assay. Within 48 hours after irradiation, hepcidin, IL-1ß, IL-6, and TNF- were increased, whereas hemojuvelin and ferroportin-1 were decreased.
The isolated hepatocytes were placed in a culture medium and plated. The cells received 8 Gy in a single fraction 24 hours after plating. Some cells were irradiated alone, whereas others were exposed to IL-1ß, IL-6, or TNF- immediately prior to irradiation. Also, some cells were sham irradiated and served as controls. RNA from the in vitro experiments was extracted at 1, 3, 6, 12, and 24 hours after irradiation. Hepcidin RNA was reduced in irradiated hepatocytes, but those incubated with IL-1ß, IL-6, or TNF- had increased levels of hepcidin up to 6 hours after irradiation, followed by reduced levels in those incubated with IL-1ß.
THE PRACTICE
Clinical use:
This study may advance our understanding of the mechanisms that lead to radiation-induced liver disease. Proinflammatory cytokines (IL-1ß, IL-6, and TNF-) released by way of cell-cell interactions may result in death of irradiated hepatocytes. Unfortunately, this information does not allow us to modify our clinical practice. Radiation oncologists must continue to shield as much normal hepatic tissue as possible when they are irradiating primary or metastatic neoplasms to prevent radiation-induced liver disease.
Future opportunities and challenges:
Clinical studies are needed to confirm that proinflammatory cytokines play a role in radiation-induced liver disease in human patients. Radiation doses employed in the study by Christiansen et al (5) were massive, whereas in radiation oncology daily doses in the range of 2 Gy are used, and these lower doses may not result in increased cytokine levels in patients. If increased cytokines are documented in patients, however, efforts to modify the levels of cytokines released would be justified. It is possible that efforts to modify cytokine release from irradiated hepatocytes with pharmacologic agents may allow clinicians to deliver higher radiation doses to hepatic neoplasms.
FOOTNOTES
See also the article by Christiansen et al in this issue.
References
Related Article
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