Using the Prostaglandin E2 Signaling Cascade to Mitigate the Effects of Acute and Delayed Radiation Exposure to Hematopoiesis and Blood Stem Cell Function
Abstract
The growing threat of terrorist events involving radiation and the potential for radiation accidents stresses the need for medical preparedness for effective treatment of military and civilian personnel exposed to lethal doses of radiation. Victims of high dose radiation exposure will face a myriad of acute and chronic organ injuries requiring multi-faceted approaches to treatment. The hematopoietic system that forms all blood cells is the most sensitive tissue to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) after significant exposure that if untreated leads to death within weeks from opportunistic infection and/or hemorrhage due to loss of white blood cells that fight bacteria and secrete clotting factors. Survivors of ARS are plagued later in life by delayed effects of radiation exposure (DEARE), chronic illnesses that affect multiple organ systems, including bone marrow, heart and blood vessels, intestines, lung, and kidneys, which become exacerbated with age. There are currently no drugs approved for severely irradiated personnel. Neupogen, used to treat radiotherapy-induced bone marrow blood stem cell suppression, has been shown by our group to increase survival for H-ARS and will likely be the first medical countermeasure (MCM) licensed by the Food and Drug Administration (FDA). However, Neupogen must be given for prolonged times for optimal effects, and while generally safe, rare life-threatening side effects have been reported. Additionally, despite improving survival and recovery from the acute effects of radiation on blood cell production, Neupogen has not shown activity against DEARE. Thus, there is an unmet medical need for effective medical countermeasure (MCM) to protect and mitigate the effects of both acute and delayed effects of radiation exposure. We have found that 16,16 dimethyl prostaglandin E2 (dmPGE2) , a metabolically more stable analog of PGE2, the major member of a family of small lipids that are involved in many physiologic systems, stimulates survival pathways and self-renewal in the hematopoietic stem cells (HSC) responsible for blood cell production that are damaged by radiation exposure, and enhances survival and recovery of all hematopoietic lineages in our H-ARS model in mice that is predicative of human response. DmPGE2 protects HSC from cell death by stimulating production of the intracellular anti-apoptotic protein Survivin, allowing them to repair DNA damage and produce more HSC. PGE2 is produced in the bone marrow after radiation exposure and inhibiting its production is highly detrimental, which indicates that it is part of the normal recovery response. However, it doesn t reach maximum for several days. Our evidence indicates that augmenting PGE2 signaling in bone marrow early after radiation exposure by single administration of dmPGE2 enhances 30-day survival of mice with faster and more robust recovery of hematopoietic stem (HSC) and progenitor (HPC) cells and all blood elements. Early studies in less defined models also suggest that dmPGE2 can protect stem cells from radiation damage and enhance survival if administered before radiation. A radiological/nuclear accident/event cannot be predicted in advance. The civilian population will require MCMs that prevent death or morbidity when administered 24 hours or more after radiation exposure (radiomitigation), while military personnel and first responders who will be first to arrive on the scene require MCM that prevent death or morbidity prior to exposure (radioprotection). To address the problems of challenging timing, we will develop strategies for both radiomitigation and radioprotection from acute radiation exposure. We will also characterize progression of multiple organ dysfunctions/DEARE in H-ARS survivors and evaluate if a once monthly administration schedule of dmPGE2 in H-ARS survivors will have therapeutic activity against DEARE. The EP receptor responsible for the H-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510254
Entities
People
- Louis M. Pelus
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army