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

• Published in: Nature medicine Vol. 18; no. 7; pp. 1123 - 1129
• Main Authors: Geiger, Hartmut, Pawar, Snehalata A, Kerschen, Edward J, Nattamai, Kalpana J, Hernandez, Irene, Liang, Hai Po H, Fernández, Jose Á, Cancelas, Jose A, Ryan, Marnie A, Kustikova, Olga, Schambach, Axel, Fu, Qiang, Wang, Junru, Fink, Louis M, Petersen, Karl-Uwe, Zhou, Daohong, Griffin, John H, Baum, Christopher, Weiler, Hartmut, Hauer-Jensen, Martin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2012; Nature Publishing Group
• Subjects: 631/61/490; 692/698/1543/233; 692/700/565; Animals; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cancer Research; Gene Expression Regulation - drug effects; Green Fluorescent Proteins - metabolism; Health aspects; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Infectious Diseases; Ionizing radiation; Irradiation; letter; Metabolic Diseases; Mice; Mice, Inbred C57BL; Molecular Medicine; Mortality; Neurosciences; Pharmacology; Physiological aspects; Protein C; Protein C - antagonists & inhibitors; Protein C - metabolism; Proteins; Radiation Injuries - genetics; Radiation Injuries - pathology; Radiation Injuries - prevention & control; Radiation therapy; Radiation Tolerance - drug effects; Radiation Tolerance - genetics; Radiotherapy; Receptors, Thrombin; Recombinant Proteins - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Side effects; Signal Transduction - drug effects; Survival Analysis; Thrombomodulin - antagonists & inhibitors; Thrombomodulin - genetics; Thrombomodulin - metabolism; Toxicity; Whole-Body Irradiation; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2813

Using an unbiased genetic screen in mice, Hartmut Geiger et al . found that the thrombomodulin–activated protein C pathway, which controls blood coagulation among other functions, also protects from radiation damage. Administration of a recombinant variant of thrombomodulin or of recombinant activated protein C protected mice from total body irradiation, pointing to potential therapeutic applications. 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 therapy 1 , 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.