title: Recovery from hematopoietic injury by modulating prostaglandin E(2) signaling post-irradiation.
abstract: While high dose total body irradiation (TBI) is used therapeutically, the proliferation of nuclear weapons, increasing use of nuclear power, and worldwide radical terrorism underscore the need to develop countermeasures to a radiological mass casualty event. The hematopoietic syndrome of the acute radiation syndrome (HS-ARS) results from severe compromise to the hematopoietic system, including lymphocytopenia, neutropenia, thrombocytopenia, and possible death from infection and/or hemorrhage. Given adequate time to recover, expand, and appropriately differentiate, bone marrow hematopoietic stem cells (HSC) and progenitor cells (HPC) may overcome HS-ARS and restore homeostasis of the hematopoietic system. Prostaglandin E(2) (PGE(2)) has been shown to have pleiotropic effects on hematopoiesis, acting to inhibit apoptosis and promote self-renewal of HSC, while inhibiting HPC proliferation. We assessed the radio-mitigating potential of modulating PGE(2) signaling in a mouse model of HS-ARS. Treatment with the PGE(2) analog 16,16 dimethyl PGE(2) (dmPGE(2)) 6h post-irradiation or inhibition of PGE(2) synthesis via delayed administration of the non-steroidal anti-inflammatory drug (NSAID) Meloxicam resulted in increased survival of lethally irradiated mice. Both early dmPGE(2) and delayed Meloxicam treatment were associated with increased HPC activity 35days following irradiation, demonstrating enhanced recovery of hematopoiesis. Our results define two different treatment modalities that are highly effective and safe to administer, and can be readily available.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hoggatt
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singh
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Stilger
authors.forename: P Artur
authors.initials: PA
authors.lastname: Plett
authors.forename: Carol H
authors.initials: CH
authors.lastname: Sampson
authors.forename: Hui Lin
authors.initials: HL
authors.lastname: Chua
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
authors.forename: Louis M
authors.initials: LM
authors.lastname: Pelus
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000528:radiation effects; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D015398:Signal Transduction; D014916:Whole-Body Irradiation
chemical_list: D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone