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

Hartmut Geiger, Snehalata A. Pawar, Edward J. Kerschen, Kalpana J. Nattamai, Irene Hernandez, Hai Po H. Liang, Jose Á Fernández, 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, Christopher Baum, Hartmut Weiler, Martin Hauer-Jensen

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

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 therapy. 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.

Original languageEnglish (US)
Pages (from-to)1123-1129
Number of pages7
JournalNature Medicine
Volume18
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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