Boosting blood system protein complex protects against radiation
27 June 2012
Boosting a protein pathway in the blood-making system in the
bone marrow protects mice from otherwise fatal radiation poisoning,
according to a study reported in Nature Medicine.
The findings open the potential for new treatments against
radiation toxicity during cancer treatment or environmental
exposures — such as in a nuclear explosion or accident.
By identifying a target-specific intervention to protect the
hematopoietic system against radiation toxicity, the study addresses
a largely unmet challenge, according to the researchers.
"These findings suggest that pharmacologic augmentation of the
activity of the Thbd-aPC pathway by recombinant Thbd (thrombomodulin)
or aPC (activated protein C) might offer a rational approach to the
mitigation of tissue injury and lethality caused by ionizing
radiation," say the authors.
"Recombinant human aPC has undergone extensive clinical testing
in patients, and recombinant soluble human Thbd is currently being
investigated for efficacy in antithrombotic therapy in humans. Our
data encourage the further evaluation of these proteins for their
The study reveals a previously unknown function of the Thbd-aPC
pathway in radiation mitigation. The pathway is normally known for
its ability to prevent the formation of blood clots and help the
body fight infections. The researchers found the pathway helps blood
cells in the bone marrow recover from injury caused by radiation
They demonstrated that pharmacologic boosting of this pathway
with two drugs tested for the treatment of thrombosis or infection
(recombinant Thbd and aPC respectively) can be used in mice to
prevent death caused by exposure to lethal doses of radiation.
In all instances of treatment with recombinant soluble Thbd or
aPC, the result was accelerated recovery of hematopoietic progenitor
cell activity in bone marrow and a reduction in the harmful effects
of lethal total body irradiation. When treatment was with aPC, these
benefits occurred even when treatment was delayed for 24 hours.
The scientists caution their study involves early laboratory
research in mice, so it remains to be tested how the findings may
translate to human treatment. Researchers also need to determine
exactly why the protective function of the targeted Thbd-aPC protein
pathway seems to work so well in mice.
Researchers noted that the protective benefits of Thbd-aPC
occurred only in vivo in irradiated mouse models. The researchers
reported that over-expressed Thbd in irradiated laboratory cell
cultures did not offer the same protective benefits, as the cells
did not survive. This indicates the protective benefits of Thbd on
blood making cells in irradiated mouse models depends on the help of
additional cells or molecules in the body, which the researchers are
trying to identify in a follow-up study.
The study involves extensive multi-scientist collaborations that
combined previously independent lines of research by groups at
Cincinnati Children's Hospital Medical Center and the University of
Ulm, Germany; the University of Arkansas, Little Rock; the Blood
Research Institute in Milwaukee, Wis.; and The Scripps Research
Institute in La Jolla, California.
The research team said the current study exemplifies a global
shift to multi-investigator projects that allow a combination of
varied expertise by scientists tackling complex problems from the
perspective of their respective fields. This approach requires the
willingness of investigators to share unpublished data and engage in
an open collaboration. The researchers also said the study
underscores the importance of continued federal funding for leading
edge basic research that can benefit human health.