Extracellular RNA as therapeutic target after toxic chemical inhalation

描述(申请人提供)：接触有毒的吸入性化学品，如硫磺芥末(SM)，会对呼吸系统、眼睛、皮肤造成伤害，并经常导致死亡。硫芥所致损伤的发病机制尚不完全清楚，寻找有效的治疗方案一直是一个挑战。SM诱导的毒性激活了几个途径，包括凝血和炎症途径。细胞外RNA(ExRNA)和低氧信号事件驱动几个与这些通路有关的因子。这项建议侧重于了解细胞外RNA和相关的炎症途径在SM诱导的损伤中的作用。这些研究将使用CEES进行，CEES是硫磺芥末和硫磺芥末的替代品。我们假设CEES/SM暴露释放exRNA，导致凝血途径的激活，也抑制HIF，进而激活促炎途径。阻断外源RNA和稳定HIFs可以减轻毒性和肺损伤。建议的研究分为三个目标。目的1将测试用RNase或合成阳离子聚合物阻断exRNA是否可以减轻CEES/SM诱导的损伤。第二个目的是测试低氧诱导转录因子的激活是否会减少炎症和减轻CEES诱导的损伤。目标3将确定CEES导致损伤的机制。这一目标还将测试对氯等其他化学品吸入的exRNA进行治疗性抑制是否可以减少伤害。既然我们小组和其他人之前的研究已经表明联合疗法具有有益的效果，这个目的也将测试上面目标1和2中测试的两种疗法结合起来是否可以提供更好的保护。拟议的研究结果将有助于确定硫芥末暴露以及与exRNA增加和代谢中毒相关的其他潜在有毒化学品吸入的治疗方案。

DESCRIPTION (provided by applicant): Exposure to toxic inhaled chemicals like sulfur mustard (SM) can cause injuries to the respiratory system, eyes, skin and also frequently leads to death. The pathogenesis of sulfur mustard-induced injury is incompletely understood and a search for effective treatment regimens has been a challenge. SM-induced toxicities activate several pathways that include the coagulation and inflammatory pathways. Extracellular RNA (exRNA) and hypoxic signaling events drive several factors implicated in these pathways. This proposal focuses on understanding the role of extracellular RNA and associated inflammatory pathways in SM-induced injuries. These studies will be carried out using CEES, a surrogate of sulfur mustard as well as sulfur mustard. We hypothesize that CEES/SM exposures release exRNA that causes activation of the coagulation pathway and also inhibition of HIFs that in turn activate proinflammatory pathways. And that blocking of exRNA and stabilization of HIFs can alleviate toxicity and lung injury. The proposed studies are divided into three aims. Aim 1 will test whether blockage of exRNA using RNase or synthetic cationic polymers can mitigate CEES/SM-induced injury. The second aim will test whether activation of the hypoxia- inducible transcription factor will decrease inflammation and mitigate CEES-induced injury. Aim 3 will determine mechanisms by which CEES causes injury. This aim will also test whether therapeutic inhibition of exRNA from other chemical inhalations like chlorine can reduce injury. Since previous studies from our group and others have indicated a beneficial effect with combination therapies this aim will also test whether combining the two therapies tested in Aims 1 and 2 above can provide a better protection. Results of the proposed research will help identify treatment options for sulfur mustard exposures as well as other potentially toxic chemical inhalations associated with increased exRNA and metabolic poisoning.