Exposure to a moderate or high total-body dose of radiation induces not only acute bone marrow suppression but also residual (or long-term) bone marrow injury. The induction of residual bone marrow injury is primarily attributed to the induction of hematopoietic cell senescence by ionizing radiation. However, the mechanisms underlying radiation-induced hematopoietic cell senescence are not known and thus were investigated in the present study. Using a well-established long-term bone marrow cell culture system, we found that radiation induced hematopoietic cell senescence at least in part via activation of p38 mitogen-activated protein kinase (p38). This suggestion is supported by the finding that exposure to radiation selectively activated p38 in bone marrow hematopoietic cells. The activation was associated with a significant reduction in hematopoietic cell clonogenic function, an increased expression of p16INK4a (p16), and an elevated senescence-associated β-galactosidase (SA-β-gal) activity. All these changes were attenuated by p38 inhibition with a specific p38 inhibitor, SB203580 (SB). Selective activation of p38 was also observed in bone marrow hematopoietic stem cells (HSCs) after mice were exposed to a sublethal total-body dose (6.5 Gy) of radiation. Treatment of the irradiated mice with SB after total-body irradiation (TBI) increased the frequencies of HSCs and hematopoietic progenitor cells (HPCs) in their bone marrow and the clonogenic functions of the irradiated HSCs and HPCs. These findings suggest that activation of p38 plays a role in mediating radiation-induced hematopoietic cell senescence and residual bone marrow suppression.
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1 December 2011
REGULAR ARTICLES|
October 20 2011
Inhibition of p38 MAPK Attenuates Ionizing Radiation-Induced Hematopoietic Cell Senescence and Residual Bone Marrow Injury
Yong Wang;
Yong Wang
1
aDepartment of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425
1Addresses for correspondence: Department of Pathology, Medical University of South Carolina, 165 Ashley Ave., Suite 309, Charleston, SC 29425; e-mail: [email protected]; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W. Markham, #607, Little Rock, AR 72205; e-mail: [email protected].
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Lingbo Liu;
Lingbo Liu
aDepartment of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425
bInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Daohong Zhou
Daohong Zhou
1
aDepartment of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425
cDivision of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
1Addresses for correspondence: Department of Pathology, Medical University of South Carolina, 165 Ashley Ave., Suite 309, Charleston, SC 29425; e-mail: [email protected]; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W. Markham, #607, Little Rock, AR 72205; e-mail: [email protected].
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Radiat Res (2011) 176 (6): 743–752.
Article history
Received:
July 06 2011
Accepted:
September 21 2011
Citation
Yong Wang, Lingbo Liu, Daohong Zhou; Inhibition of p38 MAPK Attenuates Ionizing Radiation-Induced Hematopoietic Cell Senescence and Residual Bone Marrow Injury. Radiat Res 1 December 2011; 176 (6): 743–752. doi: https://doi.org/10.1667/RR2727.1
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