C-EBPδ Deficiency Sensitizes Mice to Ionizing Radiation-Induced Hematopoietic and Intestinal InjuryReportar como inadecuado




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Knowledge of the mechanisms involved in the radiation response is critical for developing interventions to mitigate radiation-induced injury to normal tissues. Exposure to radiation leads to increased oxidative stress, DNA-damage, genomic instability and inflammation. The transcription factor CCAAT-enhancer binding protein delta Cebpd; C-EBPδ is implicated in regulation of these same processes, but its role in radiation response is not known. We investigated the role of C-EBPδ in radiation-induced hematopoietic and intestinal injury using a Cebpd knockout mouse model. Cebpd−-− mice showed increased lethality at 7.4 and 8.5 Gy total-body irradiation TBI, compared to Cebpd+-+ mice. Two weeks after a 6 Gy dose of TBI, Cebpd−-− mice showed decreased recovery of white blood cells, neutrophils, platelets, myeloid cells and bone marrow mononuclear cells, decreased colony-forming ability of bone marrow progenitor cells, and increased apoptosis of hematopoietic progenitor and stem cells compared to Cebpd+-+ controls. Cebpd−-− mice exhibited a significant dose-dependent decrease in intestinal crypt survival and in plasma citrulline levels compared to Cebpd+-+ mice after exposure to radiation. This was accompanied by significantly decreased expression of γ-H2AX in Cebpd−-− intestinal crypts and villi at 1 h post-TBI, increased mitotic index at 24 h post-TBI, and increase in apoptosis in intestinal crypts and stromal cells of Cebpd−-− compared to Cebpd+-+ mice at 4 h post-irradiation. This study uncovers a novel biological function for C-EBPδ in promoting the response to radiation-induced DNA-damage and in protecting hematopoietic and intestinal tissues from radiation-induced injury.



Autor: Snehalata A. Pawar , Lijian Shao , Jianhui Chang, Wenze Wang, Rupak Pathak, Xiaoyan Zhu, Junru Wang, Howard Hendrickson, Marjan B

Fuente: http://plos.srce.hr/



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