International Journal of Radiation Oncology*Biology*Physics
Rapid communicationRadiation-induced hypoxia may perpetuate late normal tissue injury☆
Introduction
The ability of radiation therapy to treat tumors involving the thoracic region is significantly limited by tolerance of lung to radiation. Currently, radiation therapy–related pulmonary symptoms occur in up to 30% of patients irradiated for lung cancer, breast cancer, lymphoma, or thymoma (1). The precise mechanisms underlying radiation-induced lung injury remain unclear. The classic hypothesis states that radiation killing and depletion of critical target cells in lungs leads to late injury. The prolonged latent period (months to years) preceding development of late sequelae was attributed to the long cell-cycle time of target cells 2, 3. This classic concept has been recently challenged by findings that radiation triggers a cascade of genetic and molecular events that proceed during a period of clinically occult pulmonary injury, ultimately leading to expression of functional damage (4). However, it is still unclear how this response to injury, involving a number of inflammatory and fibrogenic cytokines, can be sustained for months to years after irradiation.
In this study, we propose that tissue hypoxia contributes to the underlying pathophysiologic process that perpetuates development of radiation-induced lung injury. Tissue hypoxia has been shown to induce a number of cytokines from a wide variety of cells involved in tissue repair, including fibroblasts, endothelial cells, and macrophages. It is also considered to be a major signal that initiates and regulates angiogenesis and stroma formation during wound healing and tumor growth 5, 6, 7. The objective of this study was to determine whether or not hypoxia develops in rat lung tissue after radiation, and whether this is associated with increased expression of profibrogenic (TGF-β) and proangiogenic (VEGF) cytokines known to be involved in tissue repair.
Section snippets
Animals
Experiments were performed using female Fisher-344 rats with prior approval from the Duke University Institutional Animal Care and Use Committee. All animals were housed 4 per cage and maintained under identical standard laboratory conditions. Food and water were provided ad libitum. Rats weighing 150–170 g were anesthetized before irradiation with i.p. ketamine (67.5 mg/kg) and xylazine (4.5 mg/kg).
Irradiation
Hemithoracic irradiation was delivered to the right lung using 4-MV photons to deliver a single
Results
The mean baseline breathing frequency (± standard error) in the control group of animals was 108.4 ± 5.3 breaths per minute. It did not significantly change during the 6-month follow-up period. Irradiated animals developed a significant increase (p < 0.01) in respiratory rate beginning 8 weeks after irradiation, with a peak increase of 80% at 14 weeks after treatment (Fig. 1).
Masson’s trichrome collagen staining showed no evidence of lung fibrosis at 6 weeks after irradiation (Fig. 2A).
Discussion
This is the first study to document the presence of hypoxia in lung tissue as a consequence of radiation-induced injury. Using pimonidazole as a hypoxia marker, we were able to detect moderate hypoxia in rat lungs at 6 weeks after irradiation, before the onset of functional or histopathologic changes Fig. 1, Fig. 2. More severe hypoxia was observed at 6 months after irradiation. The latter was associated with significant increases in collagen deposition and lung fibrosis (Fig. 2B, E, and F).
Acknowledgements
The authors express great appreciation to Dr. Su-min Zhou and Dale Huang for their excellent technical assistance.
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This investigation was supported in part by the Duke Comprehensive Cancer Center and NCI Grant P30 CA14236. Dr Feng was supported in part by UICC Fellowships—ICRETT 945.