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 137Cs 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.

Angelica sinensis Polysaccharides Ameliorate Stress-Induced Premature Senescence of Hematopoietic Cell via Protecting Bone Marrow Stromal Cells from Oxidative Injuries Caused by 5-Fluorouracil

“…In contrast to acute myelosuppression, long-term BM suppression is manifested by a decrease in HSCs reserves and a defect in HSCs self-renewal; moreover, long-term BM suppression is long-lasting and exhibits little tendency for recovery. Previous studies have demonstrated that exposure to high doses of irradiation caused long-term bone marrow injury, in part, by selectively inducing HSCs senescence [ 91 , 92 ].…”

Establishment of a Novel CD34+ Hematopoietic Stem Cell-Derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

“…The body weight of mice did not decrease much, and their body condition was good in the 0 Gy irradiated group; however, the mice in the 2.5 Gy group survived approximately 17 days and were in poor condition, dying easily, which is unfavorable for the study of drug e cacy or the mechanism of HLL development. Importantly, irradiation can brie y result in serious myelosuppression [25] and lead to an inability to clearly observe leukemic cells in blood smears and bone marrow smears, making it di cult to assess whether the model was successful. Moreover, myelosuppression seriously affects routine blood tests and cannot truly allow the evaluation of changes in WBCs [26,27].…”

The protective effects of XH‐105 against radiation‐induced intestinal injury

“…13 Therefore, development of an effective method and drug to mitigate the radiation-induced intestinal injuries needs to be explored. Many studies have reported that Chinese herbal medicines or extracts and other drugs may be able to reduce TBI-induced injuries in the brain, oesophagus and haematopoietic system of irradiated animals, [14][15][16][17][18] but the study of protective drugs in IR-induced intestinal injuries still needs to be improved. [19][20][21] In the present study, we observed that the new compound XH-105 had protective effects on radiation-induced intestinal injuries.…”