Extracellular RNA as therapeutic target after toxic chemical inhalation

描述（由申请人提供）：暴露于有毒的吸入化学物质，如芥子气（SM）会导致呼吸系统，眼睛，皮肤受伤，也经常导致死亡。硫芥诱导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种途径，包括凝血和炎症途径。细胞外RNA （exRNA）和缺氧信号事件驱动涉及这些途径的几个因素。本研究的重点是了解细胞外RNA和相关炎症途径在sm诱导损伤中的作用。这些研究将使用硫芥和硫芥的替代品CEES进行。我们假设CEES/SM暴露释放exRNA，导致凝血途径的激活和hif的抑制，进而激活促炎途径。阻断exRNA和稳定hfs可减轻毒性和肺损伤。拟议的研究分为三个目的。目的1将测试使用RNase或合成阳离子聚合物阻断exRNA是否可以减轻CEES/ sm引起的损伤。第二个目的是测试缺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。目的3将确定CEES引起损伤的机制。这一目标还将测试治疗性抑制来自氯等其他化学物质吸入的exRNA是否可以减少伤害。由于我们小组和其他人之前的研究表明联合治疗有有益的效果，本目的还将测试将上述目标1和2中测试的两种疗法结合是否能提供更好的保护。拟议研究的结果将有助于确定硫芥暴露的治疗方案，以及与exRNA增加和代谢性中毒相关的其他潜在有毒化学吸入。

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.