title: Combinations of cytokines promote survival of mice and limit acute radiation damage in concert with amelioration of vascular damage.
abstract: Recovery from hematopoietic aplasia is a predominant factor in the survival of total-body-irradiated mice within 30 days after exposure. However, other radiation-induced pathophysiological events have been shown to play a role, among which an inflammatory reaction must be considered. In the present study, we evaluated the therapeutic potential of a hematopoietic growth factor (thrombopoietin, Tpo) and pleiotropic cytokines (Il4 or Il11), used alone or in combination, on the survival of mice, hematopoietic reconstitution, inflammatory reaction and vascular changes. All treatments including Tpo induced a higher level of survival than did treatment with a placebo, with combinations being the most efficient. The increased survival could not be explained solely by an improved hematopoietic recovery. Treatments with Tpo also reduced the level of the chemokine KC in plasma and the level of expression of mRNA for inflammatory and coagulation proteins in the lungs of irradiated mice. In addition, radiation- induced vascular hyperpermeability was reduced with the use of Tpo. In summary, our results show that Tpo may improve survival by limiting vascular leakage, which in turn could limit inflammatory reactions and the ensuing tissue damage.
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, Direction de la Radioprotection de l'Homme, Service de Radiobiologie et d'Epidémiologie, IRSN, F-92262 Fontenay-aux-Roses cedex, France. anne.vandermeeren@cea.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Van der Meeren
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Mouthon
authors.forename: Marie
authors.initials: M
authors.lastname: Vandamme
authors.forename: Claire
authors.initials: C
authors.lastname: Squiban
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Aigueperse
mesh_terms: D000208:Acute Disease; D000818:Animals; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines / Q000097:blood / Q000627:therapeutic use; D004338:Drug Combinations; D004357:Drug Synergism; D017370:Interleukin-11 / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011832:Radiation Injuries / Q000188:drug therapy* / Q000517:prevention & control*; D015996:Survival Rate; D013926:Thrombopoietin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014652:Vascular Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D014916:Whole-Body Irradiation
chemical_list: D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D004338:Drug Combinations; D017370:Interleukin-11; C074302:keratinocyte-derived chemokines; D015847:Interleukin-4; D013926:Thrombopoietin