Radiation-induced hypoxia may perpetuate late normal tissue injury

doi:10.1016/S0360-3016(01)01593-0

International Journal of Radiation OncologyBiologyPhysics

Volume 50, Issue 4, 15 July 2001, Pages 851-855

https://doi.org/10.1016/S0360-3016(01)01593-0 Get rights and content

Abstract

Purpose: The purpose of this study was to determine whether or not hypoxia develops in rat lung tissue after radiation.

Methods and Materials: Fisher-344 rats were irradiated to the right hemithorax using a single dose of 28 Gy. Pulmonary function was assessed by measuring the changes in respiratory rate every 2 weeks, for 6 months after irradiation. The hypoxia marker was administered 3 h before euthanasia. The tissues were harvested at 6 weeks and 6 months after irradiation and processed for immunohistochemistry.

Results: A moderate hypoxia was detected in the rat lungs at 6 weeks after irradiation, before the onset of functional or histopathologic changes. The more severe hypoxia, that developed at the later time points (6 months) after irradiation, was associated with a significant increase in macrophage activity, collagen deposition, lung fibrosis, and elevation in the respiratory rate. Immunohistochemistry studies revealed an increase in TGF-β, VEGF, and CD-31 endothelial cell marker, suggesting a hypoxia-mediated activation of the profibrinogenic and proangiogenic pathways.

Conclusion: A new paradigm of radiation-induced lung injury should consider postradiation hypoxia to be an important contributing factor mediating a continuous production of a number of inflammatory and fibrogenic cytokines.

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.

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Rapid communicationRadiation-induced hypoxia may perpetuate late normal tissue injury☆

Abstract

Introduction

Section snippets

Animals

Irradiation

Results

Discussion

Acknowledgements

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Effects of radiation on normal tissueHypothetical mechanism and limitations of in situ assays of clonogenicity

Radiat Environ Biophys

Angiogenesis, and oxygen transport in solid tumors

Hypoxia regulatory elements of the human vascular endothelial growth factor gene

Cell Mol Biol Res

Oxygen regulation of TGF-beta 1 mRNA in human hepatoma (Hep G2) cells

Biochem Mol Biol Int

Rapid communication
Radiation-induced hypoxia may perpetuate late normal tissue injury☆