Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury.
Open accessAbstract
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 p16(INK4a) (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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Previous studies suggest that IR induces HSC senescence primarily via induction of oxidative stress.
“Our previous studies suggest that IR induces HSC senescence primarily via induction of oxidative stress,9,23,30”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [30]
Treating irradiated mice with various antioxidants after IR significantly attenuated TBI-induced LSK cell senescence and residual BM suppression.
“Treating the irradiated mice with various antioxidants after IR significantly attenuated TBI-induced LSK cell senescence and residual BM suppression.9,30”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [30]
Activation of p38 was involved in IR-induced BM hematopoietic cell senescence and dysfunction.
“activation of p38 was involved in IR-induced BM hematopoietic cell senescence and dysfunction.30,40”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [30]
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- Authors
- Wang, Y., Liu, L., & Zhou, D.
- Affiliations
- Medical University of South Carolina (US)
- Venue
- Radiation Research
- Publisher
- Radiation Research Society
- Published
- 2011-12
- Volume
- 176
- Issue
- 6
- Pages
- 743-752
- ISSN
- 0033-7587 (ISSN-L)
- 1938-5404
- PMC
- PMC3390189
- OpenAlex
- W2005986051
- Cited by
- 67
- References
- 30
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 5 · 2012: 2
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Radiation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BioOne Complete (BioOne) (submittedVersion)
- Funders
- National Cancer Institute (R01CA122023, R01CA086860)
- National Institute of Allergy and Infectious Diseases (R01AI080421)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- p38 MAPK, ionizing radiation, myelosuppression, hematopoietic stem cells, hematopoietic progenitor cells, p16INK4a, senescence-associated β-galactosidase, SB203580, radiation-induced senescence
- MeSH terms
- Animals, Bone Marrow, Enzyme Activation, Gene Expression Regulation, Hematopoietic Stem Cells, Male, Time Factors, Cellular Senescence, Protein Kinase Inhibitors, p38 Mitogen-Activated Protein Kinases, Mice
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