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品，如硫芥（SM），可导致呼吸系统，眼睛，皮肤损伤，并经常导致死亡。硫芥诱导的损伤的发病机制尚未完全了解，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）和缺氧信号传导事件驱动涉及这些途径的几个因子。该提案的重点是了解细胞外RNA和相关炎症通路在SM诱导的损伤中的作用。这些研究将使用CEES进行，CEES是硫芥和硫芥的替代品。我们假设CEES/SM暴露释放exRNA，其引起凝血途径的激活以及抑制HIF，其反过来激活促炎途径。阻断exRNA和稳定HIFs可以减轻毒性和肺损伤。拟议的研究分为三个目标。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诱导的损伤。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并减轻CEES诱导的损伤。目标3将确定CEES造成损伤的机制。该目标还将测试来自其他化学吸入物（如氯）的exRNA的治疗性抑制是否可以减少损伤。由于我们小组和其他人先前的研究表明联合治疗具有有益效果，因此该目的还将测试上述目的1和2中测试的两种治疗组合是否可以提供更好的保护。拟议研究的结果将有助于确定硫芥暴露以及与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.