title: Blockade of CD47 increases survival of mice exposed to lethal total body irradiation.
abstract: Accidental or therapeutic total body exposure to ionizing radiation has profound pathophysiological consequences including acute radiation syndrome. Currently only investigational drugs are available in case of radiological or nuclear accidents or terrorism. Lack of selective radioprotectants for normal tissues also limits the therapeutic doses that can be delivered to treat cancers. CD47 is a receptor for the secreted protein thrombospondin-1. Blockade of thrombospondin-1 or CD47 provides local radioprotection of soft tissues and bone marrow. We now report that suppression of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation. Increased survival is associated with increased peripheral circulating blood cell counts and increased proliferative capacity of bone marrow derived cells. Moreover, CD47 blockade decreased cell death while inducing a protective autophagy response in radiosensitive gastrointestinal tissues. Thus, CD47 is a new target for radiomitigation that prevents both hematopoietic and gastrointestinal radiation syndromes.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Soto-Pantoja
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy* / Q000517:prevention & control*; D000818:Animals; D001772:Blood Cell Count; D001853:Bone Marrow / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D051928:CD47 Antigen / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004947:Esophagus / Q000187:drug effects / Q000528:radiation effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D060172:Morpholinos / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013534:Survival; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000096:biosynthesis; D014916:Whole-Body Irradiation
chemical_list: D051928:CD47 Antigen; C490981:Gtf2h1 protein, mouse; D060172:Morpholinos; D011837:Radiation-Protective Agents; D019700:Thrombospondin 1; D014157:Transcription Factors; D051758:Transcription Factor TFIIH