Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med 2012 Jul;18(7):1123-9
Date
06/26/2012Pubmed ID
22729286Pubmed Central ID
PMC3491776DOI
10.1038/nm.2813Scopus ID
2-s2.0-84863683494 (requires institutional sign-in at Scopus site) 94 CitationsAbstract
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.
Author List
Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP, Fernández JÁ, Cancelas JA, Ryan MA, Kustikova O, Schambach A, Fu Q, Wang J, Fink LM, Petersen KU, Zhou D, Griffin JH, Baum C, Weiler H, Hauer-Jensen MAuthor
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsGene Expression Regulation
Green Fluorescent Proteins
Hematopoietic Stem Cells
Humans
Mice
Mice, Inbred C57BL
Protein C
RNA, Messenger
Radiation Injuries
Radiation Tolerance
Receptors, Thrombin
Recombinant Proteins
Signal Transduction
Survival Analysis
Thrombomodulin
Whole-Body Irradiation