New research in Nature Medicine shows that boosting a protein pathway in the body’s blood making system protects mice from otherwise fatal radiation poisoning.
Scientists in the multi-institutional study – posted online by the journal on June 24 – say their findings open the potential for new treatments against radiation toxicity during cancer therapy or environmental exposures – such as in a nuclear explosion or accident.
“Our study identifies a target-specific intervention that protects the hematopoietic system against levels of radiation that will lead to death, which largely is an unmet challenge,” said Hartmut Geiger, PhD, first author on the study and a scientist at Cincinnati Children’s Hospital Medical Center and Ulm University Medicine in Germany.
“Current treatments for such radiation, like blood transfusions, don’t help blood making cells survive radiation toxicity because they can only help expand what is still there. The advantage we have discovered is the ability to protect blood making cells in mice by drug intervention, even when given as late as 24 hours after irradiation.”
The scientists caution their study involves early laboratory research in mice, so it remains unclear how the findings may translate to human treatment. Researchers also need to determine exactly why the protective function of the targeted protein pathway – anchored by thrombomodulin (Thbd) and activated protein C (aPC) – works so well in mice.
The study involved extensive multi-institutional collaboration that included scientists at Cincinnati Children’s (Division of Experimental Hematology/Cancer Biology), the University of Ulm in Germany (Department of Dermatology/Allergic Diseases), the University of Arkansas for Medical Sciences (Division of Radiation Health and College of Pharmacy) in Little Rock, Ark., the Central Arkansas Veterans Healthcare System in Little Rock, and the Medical College of Wisconsin (Blood Research Institute) in Milwaukee.
Researchers started their project by looking for novel genes and molecular pathways that protect hematopoietic cells from radiation injury. Hematopoietic means to make blood. Conducting a series of what are known as retroviral insertional mutagenesis screens and related tests in irradiated mice, they identified a natural cell surface receptor called Thbd (thrombomodulin). Thbd helps regulate a number of cellular processes, including in the hematopoietic system.
Biochemically, Thbd relays signals to stimulate the protein thrombin in blood forming cells. This starts what is known as the Thbd/thrombin complex, which also includes activated protein C (aPC). aPC breaks down other proteins and assists the Thbd/thrombin complex in promoting the production, migration and healthy function of blood forming cells.
The researchers exposed mice to lethal doses of total body radiation (8.5 to 9.5 Gy), which if left untreated would normally result in death in 12 to 20 days. Researchers first treated irradiated mice with a soluble form of recombinant Thbd. Compared to control mice (all of which perished from radiation exposure) 40 to 80 percent of the Thbd-treated mice survived, depending on how soon their treatment followed irradiation.
To confirm whether the protective effects of soluble Thbd were related to the initiation of activated protein C (aPC), they conducted separate experiments, in which lethally irradiated mice were infused with recombinant aPC. In experiments at three separate laboratories participating in the study, aPC treatment also resulted in significant survival benefits for treated mice.
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. These benefits occurred even when treatment was delayed for 24 hours. The data “demonstrate a previously unrecognized role of the endogenous Thbd-aPC pathway in radiation mitigation,” the researchers write in their study.
For some reason, the protective benefits of Thbd-aPC occurred only in vivo, or in irradiated mouse models. The researchers report that overexpressed Thbd in irradiated laboratory cell cultures did not offer the same protective benefits as in living mice, as the cultured 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 living organism. The researchers are trying to identify these additional biological components in a follow-up study.
Also collaborating on research were scientists at the Scripps Research Institute in La Jolla, Calif. and the Hannover Medical School (Department of Experimental Hematology) in Germany. Co-authors on the current study include Snehalata A. Pawar, Edward J. Kerschen, Kalpana J. Nattamai, Hartmut Weiler, Martin Hauer-Jensen, Irene Hernandez, Hai-Po Liang, Jose A. Fernandez, Jose A. Cancelas, Marnie A. Ryan, Olga Kustikova, Axel Schambach, Qiang Fu, Junru Wang, Louis M. Fink, Karl-Uwe Petersen, Daohong Zhou, John H. Griffin and Christopher Baum.
Funding support came from the National Institutes of Health, the Edward P. Evans Foundation and the U.S. Department of Veterans Affairs.
Source: Cincinnati Children’s Hospital Medical Center