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Pharmacological targeting of the thrombomodulin–activated protein C pathway mitigates radiation toxicity

Nature Medicine volume 18, pages 1123–1129 (2012)Cite this article

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Abstract

Tissue damage induced by ionizing radiation in the hematopoietic and gastrointestinal systems is the major cause of lethality in radiological emergency scenarios and underlies some deleterious side effects in patients undergoing radiation therapy1,2. The identification of target-specific interventions that confer radiomitigating activity is an unmet challenge. Here we identify the thrombomodulin (Thbd)–activated protein C (aPC) pathway as a new mechanism for the mitigation of total body irradiation (TBI)-induced mortality. Although the effects of the endogenous Thbd-aPC pathway were largely confined to the local microenvironment of Thbd-expressing cells, systemic administration of soluble Thbd or aPC could reproduce and augment the radioprotective effect of the endogenous Thbd-aPC pathway. Therapeutic administration of recombinant, soluble Thbd or aPC to lethally irradiated wild-type mice resulted in an accelerated recovery of hematopoietic progenitor activity in bone marrow and a mitigation of lethal TBI. Starting infusion of aPC as late as 24 h after exposure to radiation was sufficient to mitigate radiation-induced mortality in these mice. These findings suggest that pharmacologic augmentation of the activity of the Thbd-aPC pathway by recombinant Thbd or aPC might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation.

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Figure 1: Elevated expression of Thbd selects for primitive hematopoietic cells after irradiation in vivo.
Figure 2: Solulin and recombinant aPC confer mitigation of radiation toxicity after TBI.
Figure 3: Mechanisms of the action of toxicity mitigation by soluble Thbd and aPC.
Figure 4: The role of endogenous Thbd in radiation protection.

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Acknowledgements

This work was supported by the US National Institutes of Health (grants CA71382 and AI67798 to M.H.-J., AI080557 to H.W., J.Á.F. and H.G., HL31950 and HL052246 to J.H.G., HL44612 to H.W. and CA122023 and AI080421 to D.Z.), the Edward P. Evans Foundation (M.H.-J., D.Z. and H.G.), the Ziegler Family Chair for Research (H.W.) and the Veterans Administration. We thank J. Bailey and V. Summey from the Comprehensive Mouse and Cancer Core at Cincinnati Children's Hospital Medical Center (CCHMC) for their support and services. We are grateful to M. Monestier (Temple University School of Medicine, Philadelphia, Pennsylvania, USA) for the BWA3 antibody, S.J. Kennel (University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, USA) for the antibodies to Thbd (273-34A and 411-201B) and D. Gailani and A. Gruber (Vanderbilt University, Nashville, Tennessee, USA) for providing the 14E11 antibody.

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  1. Hartmut Geiger, Snehalata A Pawar, Edward J Kerschen, Kalpana J Nattamai, Hartmut Weiler and Martin Hauer-Jensen: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA

    Hartmut Geiger, Kalpana J Nattamai, Jose A Cancelas & Marnie A Ryan

  2. Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany

    Hartmut Geiger

  3. Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Snehalata A Pawar, Qiang Fu, Junru Wang, Daohong Zhou & Martin Hauer-Jensen

  4. Blood Research Institute, Blood Center of Wisconsin and the Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Edward J Kerschen, Irene Hernandez, Hai Po H Liang & Hartmut Weiler

  5. Scripps Research Institute, La Jolla, California, USA

    Jose Á Fernández & John H Griffin

  6. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany

    Olga Kustikova, Axel Schambach & Christopher Baum

  7. Desert Research Institute, Las Vegas, Nevada, USA

    Louis M Fink

  8. PAION Deutschland GmbH, Aachen, Germany

    Karl-Uwe Petersen

  9. Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA

    Martin Hauer-Jensen

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Contributions

H.G. and H.W. designed and performed experiments, and wrote the paper. S.A.P. collected, analyzed and summarized data. E.J.K., I.H., H.P.H.L., J.A.C. and M.A.R. performed experiments. K.J.N. performed experiments and wrote parts of the paper. J.Á.F., A.S. and J.H.G. provided reagents and advised on experimental design. O.K., D.Z. and C.B. advised on experimental design and provided experimental expertise. Q.F. and J.W. performed in vivo studies. L.M.F. advised on experimental design and participated in writing the manuscript. K.-U.P. performed pharmacokinetics studies with Solulin and advised on experimental details. M.H.-J. designed experiments and wrote the paper.

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Correspondence to Hartmut Geiger.

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K.-U.P. is employed by PAION Deutschland GmbH.

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Geiger, H., Pawar, S., Kerschen, E. et al. Pharmacological targeting of the thrombomodulin–activated protein C pathway mitigates radiation toxicity. Nat Med 18, 1123–1129 (2012). https://doi.org/10.1038/nm.2813

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