Optimizing and Profiling Prostaglandin E2 as a Medical Countermeasure for the Hematopoietic Acute Radiation Syndrome

Patterson, Andrea M.; Wu, Tong; Chua, Hui Lin; Sampson, Carol H.; Fisher, Alexa; Singh, Pratibha; Guise, Theresa A.; Feng, Hui; Muldoon, J; Wright, Laura E.; Plett, P. Artur; Pelus, Louis M.; Orschell, Christie M.

doi:10.1667/rade-20-00181.1

Cited by 12 publications

(17 citation statements)

References 55 publications

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“…It's known that PGE2 enhances HSC homing, engraftment, survival, and expansion 148 , 150 , 151 . Researchers also reported that EP4 is a key receptor involving PGE2-mediated positive regulation of HSC/HSPC 152 , 153 . PGE2 can not only directly regulate HSC but also can stimulate the differentiation of bone marrow mesenchymal progenitor cells into hematopoietic progenitor cells via EP4 receptors in murine 152 .…”

Section: The Role Of Pge2 On Organ Repair and Regenerationmentioning

confidence: 99%

Role of prostaglandin E2 in tissue repair and regeneration

et al. 2021

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Tissue regeneration following injury from disease or medical treatment still represents a challenge in regeneration medicine. Prostaglandin E2 (PGE2), which involves diverse physiological processes via E-type prostanoid (EP) receptor family, favors the regeneration of various organ systems following injury for its capabilities such as activation of endogenous stem cells, immune regulation, and angiogenesis. Understanding how PGE2 modulates tissue regeneration and then exploring how to elevate the regenerative efficiency of PGE2 will provide key insights into the tissue repair and regeneration processes by PGE2. In this review, we summarized the application of PGE2 to guide the regeneration of different tissues, including skin, heart, liver, kidney, intestine, bone, skeletal muscle, and hematopoietic stem cell regeneration. Moreover, we introduced PGE2-based therapeutic strategies to accelerate the recovery of impaired tissue or organs, including 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors boosting endogenous PGE2 levels and biomaterial scaffolds to control PGE2 release.

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Section: The Role Of Pge2 On Organ Repair and Regenerationmentioning

confidence: 99%

Role of prostaglandin E2 in tissue repair and regeneration

et al. 2021

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“…Cohorts of mice received Veh or a single dose of 35 ug/ mouse dmPGE 2 at various time points before (PGE-pre) or after (PGE-post) lethal TBI (LD50/30, LD70/30, or LD90/ 30). As we reported, 90-100% of mice given dmPGE 2 prior to these doses of lethal TBI survive to day 30 whereas only ;60% of mice given dmPGE 2 after lethal TBI (LD70/30) survive to day 30 (23,30). However, whether dmPGE 2 given before or after lethal TBI has an impact on the lifespan of H-ARS survivors is unknown.…”

Section: Resultsmentioning

confidence: 88%

“…16,16-Dimethyl prostaglandin E 2 (dmPGE 2 ) was purchased from Cayman Chemical (Ann Arbor, MI). DmPGE 2 in methyl acetate (MeAc) was evaporated on ice under N 2 gas and reconstituted in 100% MULTI-ORGAN DEARE AND PROTECTION BY dmPGE 2 ethanol (ETOH) at 0.1 mg/ml as described elsewhere (23). Mice received a single subcutaneous (s.c.) injection of 35 lg dmPGE 2 regardless of weight or sex, or vehicle (Veh; 3.5% EtOH) in 200 lL saline.…”

Section: Reagentsmentioning

confidence: 99%

“…To prevent or mitigate multi-organ radiation injuries, it is important to understand the time and dose-dependent sequela of acute and delayed injuries in relevant animal models where exposures are ''subthreshold'', thereby mimicking more closely an actual malicious or accidental exposure, where multi-organ injuries develop with increased latency. To this end, we developed an H-ARS model in mice that is predictive of the activity of medical countermeasures (MCM) to protect from or mitigate H-ARS (23)(24)(25)(26) and evaluated the natural history and temporal occurrence of DEARE on hematopoiesis and the accompanying severe HSC dysfunction (9,10,27) and dysfunction in heart and kidney, in H-ARS survivors (28,29).…”

Section: Introductionmentioning

confidence: 99%

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Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome

Pelus

Plett

et al. 2023

Radiation Research

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Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.

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“…Regarding the types of radiation used in these models, photon sources such as cesium irradiators [ 25 , 26 ], X-rays [ 13 ], linear accelerators [ 15 , 18 ] as well as mixed fields of neutron and X-rays [ 27 ] have been applied. Such ionizing radiation manifests ARS and/or DEARE, depending on the dose of radiation delivered and the organs that are exposed.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers to Predict Lethal Radiation Injury to the Rat Lung

Medhora

Gao

Gasperetti

et al. 2023

IJMS

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Currently, there are no biomarkers to predict lethal lung injury by radiation. Since it is not ethical to irradiate humans, animal models must be used to identify biomarkers. Injury to the female WAG/RijCmcr rat has been well-characterized after exposure to eight doses of whole thorax irradiation: 0-, 5-, 10-, 11-, 12-, 13-, 14- and 15-Gy. End points such as SPECT imaging of the lung using molecular probes, measurement of circulating blood cells and specific miRNA have been shown to change after radiation. Our goal was to use these changes to predict lethal lung injury in the rat model, 2 weeks post-irradiation, before any symptoms manifest and after which a countermeasure can be given to enhance survival. SPECT imaging with 99mTc-MAA identified a decrease in perfusion in the lung after irradiation. A decrease in circulating white blood cells and an increase in five specific miRNAs in whole blood were also tested. Univariate analyses were then conducted on the combined dataset. The results indicated that a combination of percent change in lymphocytes and monocytes, as well as pulmonary perfusion volume could predict survival from radiation to the lungs with 88.5% accuracy (95% confidence intervals of 77.8, 95.3) with a p-value of < 0.0001 versus no information rate. This study is one of the first to report a set of minimally invasive endpoints to predict lethal radiation injury in female rats. Lung-specific injury can be visualized by 99mTc-MAA as early as 2 weeks after radiation.

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Optimizing and Profiling Prostaglandin E2 as a Medical Countermeasure for the Hematopoietic Acute Radiation Syndrome

Cited by 12 publications

References 55 publications

Role of prostaglandin E2 in tissue repair and regeneration

Role of prostaglandin E2 in tissue repair and regeneration

Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome

Biomarkers to Predict Lethal Radiation Injury to the Rat Lung

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