Abstract
Abstract 2638
The highly proliferative nature of hematopoietic stem (HSC) and progenitor (HPC) cells, particularly during stress induced hematopoiesis, makes them highly sensitive to radiation, and in extreme circumstances results in the Hematopoietic Syndrome of the Acute Radiation Syndrome (HS-ARS). In addition to the therapeutic use of high dose total body irradiation (TBI), the proliferation of nuclear weapons, increasing use of nuclear power, and worldwide radical terrorism has resulted in a rising need and increased research emphasis on developing countermeasures to a radiological mass casualty event. HS-ARS is characterized by life-threatening neutropenia, thrombocytopenia and lymphocytopenia, and possible death due to infection and/or bleeding. While HSC and HPC are susceptible to radiation exposure, surviving populations of these cells can recover hematopoiesis if given critical time to repair DNA damage, self-renew, expand and differentiate. We previously reported (Hoggatt et al, Blood 2009) that PGE2 increases HSC self-renewal and expression of the anti-apoptotic protein Survivin, resulting in reduced apoptosis and increased HSC number. Since PGE2 production is increased following radiation exposure, and tumors over-producing PGE2 are radioresistant, we hypothesized that PGE2 production may be an endogenous mechanism for recovery from radiation damage, and that enhancement of PGE2 signaling could improve post-irradiation hematopoiesis and survival. Mid-lethally irradiated mice were treated with a single dose of the long-acting PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2) or vehicle 6 hrs post-TBI and morbidity and mortality monitored for 30 days (n=20 mice/group). Treatment with dmPGE2 resulted in 95% survival (P=0.001) compared to only 50% survival in control mice. The number of marrow CFU-GM, BFU-E and CFU-GEMM were significantly higher in surviving mice from the dmPGE2 treated group compared to control mice (2.0±0.1 fold increase in CFC). While PGE2 is beneficial for HSC self-renewal and anti-apoptosis and our data clearly indicate that dmPGE2 treatment enhances hematopoietic recovery and survival post-TBI, we and others have previously shown that PGE2 is inhibitory to myelopoiesis. Therefore, we hypothesized that while exposure to PGE2 early after TBI is beneficial and can increase the number of surviving HSC, sustained exposure to PGE2 is inhibitory to HPC expansion, and may limit hematopoietic recovery. To test this hypothesis, we treated lethally irradiated mice with meloxicam, a cyclooxygenase inhibitor that blocks PGE2 production, for 4 consecutive days, starting either 6 hrs post-irradiation or delayed for 48 hours. While only 5% of control mice survived 30 days post-TBI, 35% of mice treated with meloxicam 6 hrs post-irradiation and 50% of mice receiving delayed meloxicam treatment survived. A faster and more robust recovery of white blood cells (WBC), neutrophils (PMN) and platelets (PLT) was observed at 15 and 30 days post-TBI with delayed meloxicam administration compared to control [15 days: (WBC 4.12 vs 1.15) (PMN 1.25 vs 0.27) (PLT 285 vs 85) x103/ul; 30 days: (WBC 11.3 vs 3.6) (PMN 6.8 vs 1.3) (PLT 819 vs 249) x103/ul], while administration 6 hrs post-irradiation resulted in more modest increases. In addition, analysis of marrow 30 days post-TBI demonstrated a significant enhancement in CFC in both non-delayed and delayed treatment groups compared to control (1.4 and 3.1 fold increase, respectively). These data suggest that inhibition of PGE2 synthesis post-TBI is beneficial for hematopoietic recovery and survival, but that allowing the positive effects of PGE2 on HSC to occur within the first 48 hours of TBI before inhibiting biosynthesis, results in a more efficacious treatment; a model supported by our results demonstrating enhanced recovery and survival with a single treatment of dmPGE2 shortly following TBI. Faced with the complexities of a mass casualty event and difficulty of individual dosimetry and triage, interventions that can mitigate or reduce the severity of exposure, but that are benign to those individuals with limited or no exposure are required. Our results define 2 different treatment modalities which are both highly effective and safe to administer, and can be readily available. In addition, the hematopoietic recovery demonstrated in these studies suggests a potential therapeutic benefit of cyclooxygenase inhibitors in TBI settings.
Disclosures:
No relevant conflicts of interest to declare.
Sweetness and bitterness taste of meals per se does not mediate gastric emptying in humans
