The Bad And The Good: Lung Late Effects After A Terrorism Event And Possible Mitigating Strategies

Since September 11, the hunt has been on for easily distributed countermeasures for use in the immediate aftermath of a radiological or nuclear event. However, even those that survive the acute radiation syndrome may be susceptible to late morbidities that could occur as part of a radiation-induced multi-organ dysfunction syndrome (RI-MODS). Therefore, late effects, seen in such organs as the lung after TBI, are of significant concern. Although the clinical progression to lung late effects (pneumonitis and fibrosis) is well recognized, the complex nature of the pathways leading to the development of RI-MODS, which includes cellular, molecular and temporal components, has led to our group's contention that no single agent or strategy is likely to be an effective measure against these potentially lethal endpoints. We therefore have developed a means of assessing combinations of agents for countermeasure use; such mitigating strategies are likely to be beneficial in the clinic. Using a systematic experimental system to test agents, involving an appropriate “2-strain” murine model with a TBI + lung irradiation schedule, we have assessed therapies that include a broad-based anti-inflammatory agent (simvastatin) administered in combination with a number of complementary agents, including captopril (an ACE inhibitor), and EUK-207 (an SOD-catalase mimetic); all agents were assessed using combinations of acute and chronic administration regimens. Currently, both captopril and EUK-270 appear to hold significant promise since, whether administered acutely or chronically, these agents result in improved survival, which is further enhanced when given in combination with simvastatin, although there is a differential strain effect. Survival in all cases was associated with a reduction in infiltrating inflammatory cells (as determined by image analysis) and downregulation of proinflammatory cytokines (e.g., IL-1ß, MCP-1). Interestingly, administration of simvastatin alone, a commonly used anti-cholesterol agent (Zocor) exacerbated acute lethality, possibly through an effect on the gastrointestinal tract. Two agents have been identified as potential mitigating agents and are undergoing further analysis. However, a commonly prescribed drug was shown to have possible toxic effects. These findings may have profound implications on the treatment of victims following a likely accident or terrorism event; potential mechanisms and novel routes of delivery (e.g., by aerosol) are currently being pursued.