Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity.
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.
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@cchmc.org
Hartmut
H
Geiger
Snehalata A
SA
Pawar
Edward J
EJ
Kerschen
Kalpana J
KJ
Nattamai
Irene
I
Hernandez
Hai Po H
HP
Liang
Jose Á
JÁ
Fernández
Jose A
JA
Cancelas
Marnie A
MA
Ryan
Olga
O
Kustikova
Axel
A
Schambach
Qiang
Q
Fu
Junru
J
Wang
Louis M
LM
Fink
Karl-Uwe
KU
Petersen
Daohong
D
Zhou
John H
JH
Griffin
Christopher
C
Baum
Hartmut
H
Weiler
Martin
M
Hauer-Jensen
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011832:Radiation Injuries / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D018179:Receptors, Thrombin; D011994:Recombinant Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D018180:Thrombomodulin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014916:Whole-Body Irradiation
D011486:Protein C; D012333:RNA, Messenger; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; D018180:Thrombomodulin; C485184:enhanced green fluorescent protein; C558438:solulin protein; D049452:Green Fluorescent Proteins