Specialized Pro-Resolving Lipid Mediators for Systemic Radiation Countermeasures - Specialized Pro-Resolving Lipid Mediators for Systemic Radiation Countermeasures Radioactivity, when harnessed for medical treatment can limit disease progression, but also carries potential to inflict mass harm to humans in the context of occupational exposure in the workforce, accidental release, and terrorism or warfare. There is an urgent and unmet clinical need to limit radiation-induced damage in the case of a nuclear incident. Protection using shielding is the most effective way to minimize radiation exposure, however in settings of accident or purposeful exposure, the magnitude of exposure and the short- and long- term consequences of exposure are not immediately known and difficult to assess. Hematopoietic growth factors, such as G-CSF (Neupogen or Neulasta) have been approved for acute radiation syndrome (ARS), but no therapies are currently approved for the delayed effects of acute radiation exposure (DEARE). Radiation- induced DNA damage can not only result in programmed cell death, it can cause cellular senescence, where cells are unable to continue proliferating, but also resistant to cell death. Senescent cells generate copious amounts of inflammatory cytokines that impact neighboring cells, thus contributing to chronic inflammation and dysfunctional tissue repair mechanisms. Radiation injury has been characterized as an accelerated aging phenotype, and the inability to resolve inflammation fully is a culprit in various age-associated inflammatory disorders and thought to underlie fibrosis Typically, inflammation resolves via endogenous programs that rely on omega-3 derived specialized pro- resolving lipid mediators (SPMs, including lipoxins and resolvins), and evidence supports a balance between SPMs and pro-inflammatory lipid mediators, such as prostaglandins (PGs), in timely inflammation resolution. This proposal is based on our preliminary studies demonstrating protection against DEARE and age-associated fibrosis with treatment of SPMs called Resolvin D1 (RvD1) and RvD2. We hypothesize that RvD1 and RvD2 modulate monocyte and macrophage production and function and will limit fibrosis and organ dysfunction, thus improving outcomes in models DEARE. Central to our overall hypothesis is the concept that effective inflammation resolution program requires balanced hematopoietic output and production of pro-resolving macrophages. We further predict that the combined treatment of RvD1 and RvD2 will offer synergistic benefit in mitigating ARS and DEARE. The goal of this proposed work is to demonstrate efficacy of SPMs and identify treatment strategies to reverse and regenerate tissues post-radiation injury.
