title: p38 MAPK Inhibitor Insufficiently Attenuates HSC Senescence Administered Long-Term after 6 Gy Total Body Irradiation in Mice.
abstract: Senescent hematopoietic stem cells (HSCs) accumulate with age and exposure to stress, such as total-body irradiation (TBI), which may cause long-term myelosuppression in the clinic. However, the methods available for long-term myelosuppression remain limited. Previous studies have demonstrated that sustained p38 mitogen-activated protein kinases (p38 MAPK) activation in HSCs following exposure to TBI in mice and the administration of its inhibitor twenty-four hours after TBI may partially prevent long-term myelosuppression. However, long-term myelosuppression is latent and identified long after the administration of radiation. In this study, we investigated the effects of SB203580 (a small molecule inhibitor of p38 MAPK) on long-term myelosuppression induced by TBI. Mice with hematopoietic injury were injected intraperitoneally with SB203580 every other day five times beginning 70 days after 6 Gy of (137)Cs γ ray TBI. Our results at 80 days demonstrated that SB203580 did not significantly improve the TBI-induced long-term reduction of peripheral blood cell and bone marrow nucleated cell (BMNC) counts, or defects in hematopoietic progenitor cells (HPCs) and HSC clonogenic function. SB203580 reduced reactive oxygen species (ROS) production and p-p38 expression; however, SB203580 had no effect on p16 expression in the HSCs of mice. In conclusion, these findings suggest that treatment with SB203580 70 days after TBI in mice inhibits the ROS-p38 oxidative stress pathway; however, it has no therapeutic effect on long-term myelosuppression induced by TBI.
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical Collage, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China. lulu@irm-cams.ac.cn.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical Collage, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China. wangyueying2010@163.com.
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical Collage, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China. zhangjunling@irm-cams.ac.cn.
authors.forename: Jun-Ling
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical Collage, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China. lideguan@irm-cams.ac.cn.
authors.forename: De-Guan
authors.initials: DG
authors.lastname: Li
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical Collage, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China. ai_min_meng@126.com.|Institute of Laboratory Animal Science, Chinese Academy of Medical Science and Peking Union Medical Collage, Beijing 100021, China. ai_min_meng@126.com.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Meng
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects*; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014916:Whole-Body Irradiation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: bone marrow; ionizing radiation; long-term myelosuppression; p38