Inhibition of p38 MAPK Reduces Ionizing Radiation-Induced Hematopoietic Cell Injury.

Abstract

Our previous studies demonstrated that exposure to ionizing radiation (IR) causes long-term bone marrow (BM) damage by induction cellular senescence in hematopoietic cells. The senescent hematopoietic cells exhibited an elevated activity of the senescence associated β-galactosidase (SA-β-gal), a biomaker for senescent cells, and expressed increased levels of p16Ink4a (p16), whose expression has been implicated in the establishment and maintenance of cellular senescence. Activation of the p38 MAPK pathway has been implicated in the induction of cell cycle arrest and senescence in response to a variety of stressors in part by up-regulating the expression of p16. Therefore, in the present study we examined the role of the p38 MAPK pathway in IR-induced hematopoietic cell senescence. The results showed that exposure of male C57BL/6 mice to a sublethal dose (6.5 Gy) of total body irradiation (TBI) caused a sustained activation (>4 weeks) of p38 in Lin− c-kit+ Sca-1+ (LKS+) hematopoietic stem cells (HSCs). This activation was associated with a persistent up-regulation of p16 and quantitative and qualitative reduction of LKS+ HSCs. Inhibition of p38 activity with SB202190 (a specific p38 inhibitor) attenuated IR-induced inhibition of the hematopoietic function of BM hematopoietic cells in an in vitro colony forming cell (CFC) assay. Moreover, the production of hematopoietic progenitor cells (HPCs) in SB202190-treated BM cells was 7.5 fold higher than that of irradiated cells without SB202190 treatment after five weeks of long-term BM cell culture (LTBMC); and the cells treated with SB202190 after IR retained their clonogenic function while the control irradiated cells lose their ability to form colonies. These findings suggest that p38 may play an important role in mediating IR-induced suppression of hematopoietic cell function and pharmacological inhibition of the p38 pathway may potentially be developed as novel therapeutic strategy to ameliorate IR- and chemotherapy-induced BM toxicity.