title: Thrombomodulin contributes to gamma tocotrienol-mediated lethality protection and hematopoietic cell recovery in irradiated mice.
abstract: Systemic administration of recombinant thrombomodulin (TM) confers radiation protection partly by accelerating hematopoietic recovery. The uniquely potent radioprotector gamma tocotrienol (GT3), in addition to being a strong antioxidant, inhibits the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) and thereby likely modulates the expression of TM. We hypothesized that the mechanism underlying the exceptional radioprotective properties of GT3 partly depends on the presence of endothelial TM. In vitro studies confirmed that ionizing radiation suppresses endothelial TM (about 40% at 4 hr after 5 Gy γ-irradiation) and that GT3 induces TM expression (about 2 fold at the mRNA level after 5 μM GT3 treatment for 4 hr). In vivo survival studies showed that GT3 was significantly more effective as a radioprotector in TM wild type (TM+/+) mice than in mice with low TM function (TMPro/-). After exposure to 9 Gy TBI, GT3 pre-treatment conferred 85% survival in TM+/+ mice compared to only 50% in TMPro/-. Thus, GT3-mediated radiation lethality protection is partly dependent on endothelial TM. Significant post-TBI recovery of hematopoietic cells, particularly leukocytes, was observed in TM+/+ mice (p = 0.003), but not in TMPro/- mice, despite the fact that GT3 induced higher levels of granulocyte colony stimulating factor (G-CSF) in TMPro/- mice (p = 0.0001). These data demonstrate a critical, G-CSF-independent, role for endothelial TM in GT3-mediated lethality protection and hematopoietic recovery after exposure to TBI and may point to new strategies to enhance the efficacy of current medical countermeasures in radiological/nuclear emergencies.
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors: Rupak
authors: R
authors: Pathak
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors: Lijian
authors: L
authors: Shao
authors: Armed Forces Radiobiology Research Institute, USUHS, Bethesda, MD, United States of America.
authors: Sanchita P
authors: SP
authors: Ghosh
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors: Daohong
authors: D
authors: Zhou
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors: Marjan
authors: M
authors: Boerma
authors: Blood Research Institute, Blood Center of Wisconsin and the Medical College of Wisconsin, Milwaukee, WI, United States of America.
authors: Hartmut
authors: H
authors: Weiler
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States of America.
authors: Martin
authors: M
authors: Hauer-Jensen
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004727:Endothelium / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression; D006410:Hematopoiesis / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D018180:Thrombomodulin / Q000235:genetics*; D024508:Tocotrienols / Q000494:pharmacology*; D014916:Whole-Body Irradiation
chemical_list: D016207:Cytokines; D011837:Radiation-Protective Agents; D018180:Thrombomodulin; D024508:Tocotrienols