A Novel Model for Development of Countermeasures to Mitigate Radiation-induced Cardiotoxicity

A radiological or nuclear incident (e.g., an accident at a nuclear reactor site or a terrorist attack involving the detonation of an improvised nuclear device) could result in the exposure of thousands of people to lethal or potentially lethal doses of ionizing radiation (IR). While good progress has been made in developing mitigators to treat individuals that received doses high enough to trigger the hematopoietic acute radiation syndrome (H- ARS), there are no approved strategies to mitigate the delayed effects of acute radiation exposure (DEARE) that would subsequently manifest in H-ARS survivors. Several life-threatening or debilitating cardiac DEARE- related pathologies are observed months to years after the heart is exposed to doses known to elicit symptoms of the H-ARS. Thus, it is necessary to develop compounds or strategies that can mitigate cardiovascular dysfunction if administered 24 h or more after irradiation, involve easy deployment and use protocols, and are non-toxic. We previously identified and partially characterized a novel non-pharmacological strategy which we found to be very effective at mitigating the lethal effects of total body irradiation (TBI) in mice if administered after exposure. Our approach involves the creation of a small (3 mm) subcutaneous (SC) incision post- irradiation. We found that SC wounding several minutes after exposure to a range of IR doses greatly protected against lethality, and that mitigation of IR effects and the resulting H-ARS may be mediated by enhanced recovery of hematopoiesis (likely due to modulation of specific cytokines). We refer to this strategy as “protective wounding.” Most recently, we accumulated preliminary data which also suggest that cardiac function measured 30 days post-irradiation is preserved in mice that receive a SC cut after irradiation, compared to mice that do not. We propose to use “protective wounding” as a novel model for interrogating the proteins modulated and pathways involved in the mitigation of cardiotoxicity induced after TBI exposure. We will first determine optimal parameters after irradiation for our wounding model that will produce the greatest mitigation of cardiovascular dysfunction, and demonstrate the validity and applicability of the strategy as a mitigator of IR-induced cardiotoxicity. To accomplish this, various endpoints of cardiac function/structure in mice that receive a cut up to 5 days after receiving a single TBI exposure will be compared with sham-cut mice. We will next determine whether SC wounding (after exposure to a TBI dose expected to result in cardiotoxicity in H-ARS survivors) results in changes in cytokine and cardiac proteomics profiles that impact post-irradiation cardiovascular damage or recovery by correlating cytokine and proteomics data with structural and fuctional cardiovascular endpoints. Data accumulated will then be used to identify the pathways and begin to identify the mechanisms by which IR-induced effects on cardiac structure and function may be mitigated. These experiments should ultimately lead to the development of pharmacological mitigators of IR-induced cardiotoxicity that can be administered to mass casualties 24 h or more after a radiological/nuclear incident.