by ecancer reporter Clare Sansom
Acute radiation syndrome, or radiation sickness, is a condition that arises following exposure to large doses of ionising radiation and which can be fatal if exposure is severe enough.
This syndrome affects some organs and systems more than others, with the bone marrow and the gastro-intestinal tract being particularly radiation-sensitive. Medical treatment of radiation sickness is considered most often in the context of planning for radiation-based emergencies, such as accidents at nuclear power stations.
However, it also has implications in cancer, as some types of radiotherapy are intense enough to have quite serious acute and long-term effects.
The molecular mechanisms underlying ionisation-induced toxicity are poorly understood, and consequently few prophylactic treatments other than physical shielding of bone marrow are available.
Hartmut Geiger from Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA and his co-workers have now used a mouse model to identify genes and pathways that are induced to protect the haematopoietic stem and progenitor cells (HSPCs) from radiation damage.
Geiger and his co-workers exposed transgenic mice to a single radiation dose of 3 gray over their whole bodies. Using a technique called retroviral insertion mutagenesis they identified sites within the mouse genome where viral integration occurred in bone marrow cells that were selected for after radiation-induced contraction and re-expansion of the haematopoietic system. This highlighted a trans-membrane protein, thrombomodulin, which is a receptor for the blood coagulation protein thrombin.
Transcription and translation of thrombomodulin mRNA and protein were increased in cells that were selected for after radiation exposure. Radiation had little effect on the expression of neighbouring genes, further implicating this protein in protection from radiation damage.
The researchers tested whether increased thrombomodulin expression was sufficient to protect haematopoietic cells from radiation damage by transplanting HSPCs that over-express this protein into similar mice and then exposing them to the same dose of radiation.
These cells were found to have a survival advantage following radiation exposure in vivo. However, thrombomodulin over-expression was not sufficient to protect HSPCs from radiation damage in vitro, which indicated that interactions with other cells or molecules were required for protection.
The complex between thrombomodulin and thrombin can convert the zymogen protein C into its activated form. Activated protein C (aPC) is a natural anti-coagulant that is known to have anti-inflammatory and cytoprotective effects, and the researchers considered it likely to be responsible for the observed radiation protection.
They tested this theory by injecting mice with aPC prior to radiation exposure, and found that this protein conferred a similar protective effect to thrombomodulin. Mitigation of radiation damage occurred even when the protein was injected as much as 24 hours after radiation exposure, and did not seem to depend on the genetic background of the mice tested.
Transgenic mice bearing a modified form of thrombomodulin that has limited ability to generate aPC were found to be more sensitive to the systemic administration of aPC than mice bearing the normal variant of the protein, and mice with constitutively high concentrations of aPC were protected from radiation damage in a similar way to wild-type mice that had been injected with aPC.
Taken together, these results implicate the pathway in which thrombomodulin binds to thrombin and the resultant complex activates protein C in protecting mouse HSPCs from radiation damage and mice from potentially lethal radiation-induced bone marrow toxicity.
Clinical trials of recombinant forms of both these proteins – aPC for treating severe sepsis and thrombomodulin as an anticoagulant – have shown them to be safe for use in patients. It is therefore possible that either or both may be useful as a prophylactic against radiation damage, for, among others, cancer patients facing extensive courses of radiation therapy.
Hartmut Geiger, H., Pawar, S.A., Kerschen, E.J. and 17 others (2012). Pharmacological targeting of the thrombomodulin–activated protein C pathway mitigates radiation toxicity. Nature Medicine, published online ahead of print 24 June 2012. doi:10.1038/nm.2813
(13 May 2013)
(13 May 2013)