Boosting Blood System Protein Complex Protects Against Radiation Toxicity

Scientists reported findings from a multi-institutional study--posted online June 23, 2012, in the journal Nature Medicine--that open the possibility 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,” the scientists wrote in their article. “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 radio-mitigating activities.”

The study revealed an earlier unknown function of the Thbd-aPC pathway in radiation mitigation. The pathway is typically 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 exposure. They demonstrated that pharmacologic boosting of this pathway with two drugs assessed for the treatment of thrombosis or infection (recombinant Thbd and aPC, respectively) can be utilized in mice to prevent death caused by exposure to lethal doses of radiation.

In all cases of treatment with recombinant soluble Thbd or aPC, the result was faster recovery of hematopoietic progenitor cell activity in bone marrow and a decrease 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 cautioned that their study involves early laboratory research in mice, so it remains to be assessed how the findings may translate to human treatment. Researchers also need to determine precisely why the protective function of the targeted Thbd-aPC protein pathway appears to function so well in mice.

Researchers noted that the protective benefits of Thbd-aPC happened only in vivo in irradiated mouse models. The researchers reported that overexpressed 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 multiscientist collaborations that combined earlier independent lines of research by groups at Cincinnati Children’s Hospital Medical Center (OH, USA) and the University of Ulm (Germany), led by Hartmut Geiger, PhD, division of experimental hematology/cancer biology and the department of dermatology/allergic diseases; the University of Arkansas (Little Rock, USA), led by Martin Hauer-Jensen, MD, PhD, division of radiation Health, the College of Pharmacy and the Central Arkansas Veterans Healthcare System; the Blood Research Institute (Milwaukee, WI, USA), led by Hartmut Weiler, PhD, and The Scripps Research Institute (La Jolla, CA, USA), led by John H. Griffin, PhD, department of molecular and experimental medicine.

The researchers reported that this study reveals a global shift to multi-investigator projects that allow a combination of varied expertise by scientists tackling complicated problems from the standpoint of their respective fields. This approach requires the inclination of investigators to share unpublished data and engage in an open collaboration. The researchers also noted that the study highlights the significant of continued federal funding for cutting-edge research that can benefit human health.

Related Links:
Cincinnati Children’s Hospital Medical Center
University of Ulm
University of Arkansas