Novel Treatments of Acrolein-induced Cardiotoxicity

丙烯醛引起的心脏毒性的新疗法

• 批准号: 8740481
• 负责人: Daniel Joseph Conklin
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740481
• 关键词: 1 year old; 2-butenal; Accounting; Acrolein; Acute; Adult; Adverse effects; Age; Animals; Arthritis; Asthma; Autonomic nervous system; Biocide; Blood Pressure; Breathing; C57BL/6 Mouse; Calcium; Cardiac; Cardiopulmonary; Cardiotoxicity; Cardiovascular system; Chemical Warfare; Chemicals; Chronic; Clinical; Dermal; Development; Diesel Exhaust; Dose; Dyslipidemias; Echocardiography; Edema; Emergency Situation; Evaluation; Event; Exposure to; Extravasation; Eye; FDA approved; Female; Fire - disasters; Formaldehyde; Foundations; Gases; Goals; Heart; Herbicides; Human; Hydra Polyps; Industry; Inflammation; Injection of therapeutic agent; Injury; Intervention; Irrigation; Irritants; Lead; Lung; Measures; Mediating; Monitor; Mucins; Natural Disasters; Neurons; Nose; Oils; Pain; Pesticides; Pharmaceutical Preparations; Phase; Plasma; Production; Relative (related person); Research; Route; Safety; Shipping; Ships; Signal Transduction; Skin; Structure of parenchyma of lung; System; TRPA1 Channel; TRPV1 gene; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Translational Research; Troponin I; Water; activin A; atherogenesis; capsazepine; carbonyl compound; combat; effective intervention; effectiveness measure; efficacy testing; forest; human morbidity; human mortality; improved; inhibitor/antagonist; insight; irritation; male; member; novel; older women; preclinical study; preconditioning; prevent; public health relevance; receptor; respiratory; response; sex

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.

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，以预防与化学威胁相关的人类死亡和发病。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中释放的化学品可能造成这种威胁。与所有这些情况相关的最常见和最丰富的反应性化学品是反应性羰基化合物（RCC）。这类的典型成员是丙烯醛。丙烯醛和相关的RCCs是最丰富和有毒的成分，在森林和结构火灾中产生的致命量（600 ppm）。还描述了外源性和内源性RCC的深刻的呼吸和心血管效应;然而，RCC的毒理学效应及其毒性机制均未系统描述。同样，尚未评估青年人、老年人和妇女对接触RCC的具体脆弱性。最重要的是，目前没有有效的对策或治疗干预措施。可能的治疗干预包括用称为瞬时受体电位（TRP）通道的RCC受体抑制剂治疗。这些拮抗剂包括TRPV 1和TRPA 1抑制剂，有望减少与高剂量暴露于RCC相关的心血管和肺系统中的疼痛和炎症。高水平RCC暴露后缓解疗法的评价将提供第一步，以判断其在人类化学紧急威胁情况下的相对有效性。