Novel Treatments of Acrolein-induced Cardiotoxicity

描述（由申请人提供）：该项目的总体目标是开发新的和改进的对策和治疗方法，以防止与化学威胁相关的人类死亡和发病。这种威胁可能来自恐怖袭击，工业生产中使用的化学品意外泄漏，或自然灾害和火灾期间释放的化学品。与所有这些情况相关的最常见和最丰富的活性化学物质是活性羰基化合物（RCCs）。这类物质的一个典型成员是丙烯醛。丙烯醛和相关的rcc是在森林和结构火灾中产生致死量（600 ppm）的最丰富和最有毒的成分。外源性和内源性rcc对呼吸和心血管的深刻影响也已被描述；然而，rcc的毒理学效应及其毒性机制都没有系统的描述。同样，年轻人、老年人和妇女对RCC暴露的具体脆弱性尚未得到评估。最重要的是，目前没有有效的对策或治疗干预措施。可能的治疗干预措施包括使用被称为瞬时受体电位（TRP）通道的RCC受体抑制剂进行治疗。这些拮抗剂包括TRPV1和TRPA1抑制剂，有望减少与大剂量暴露于RCC相关的心血管和肺部系统的疼痛和炎症。对高水平RCC暴露后的缓解疗法进行评估，将是判断它们在人类面临化学紧急威胁情况下使用的相对效力的第一步。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop new and improved countermeasures and therapeutics for preventing human mortality and morbidity associated with chemical threats. Such threats might be imposed by a terrorist attack, accidental leakage of chemicals used in industrial production, or those released during natural disasters and fires. The most common and abundant reactive chemicals, relevant to all these situations are reactive carbonyl compounds (RCCs). A prototypical member of this class is acrolein. Acrolein and related RCCs are the most abundant and toxic constituents generated in lethal amounts (600 ppm) during forest and structural fires. Profound respiratory and cardiovascular effects of exogenous and endogenous RCCs have also been described; however, neither the toxicological effects of RCCs nor their mechanisms of toxicity have been systematically delineated. Similarly, the specific vulnerability of young, old and women to RCC exposure has not been assessed. Most importantly, no effective countermeasures or therapeutic interventions are currently available. Possible therapeutic interventions include treatment with inhibitors of RCC receptors known as transient receptor potential (TRP) channels. These antagonists including TRPV1 and TRPA1 inhibitors hold promise to diminish the pain and inflammation in the cardiovascular and pulmonary systems associated with high dose exposure to RCC. Evaluation of mitigation therapies following high level RCC exposure will provide the first step in judging their relative efficacy for use in the case of a chemical emergency threat in humans.