Targeting Injury Pathways to Counteract Pulmonary Agent and Vesicant Toxicity

针对损伤途径来抵消肺部毒剂和糜烂剂毒性

基本信息

批准号：
8323288
负责人：
SVEN-ERIC JORDT
金额：
$ 67.52万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-29 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323288
关键词：
Accidents Acrolein Afferent Neurons Bulla Calcium Calcium Signaling Cardiovascular system Cell Death Chemical Exposure Chemical Industry Chemical Injury Chemical Warfare Agents Chemicals Chlorine Chronic Chronic Obstructive Airway Disease Corrosives Cutaneous Data Disinfection Drug Formulations Edema Environmental and Occupational Exposure Epithelial Epithelium Gases Genes Goals Human Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Intramuscular Ion Channel Isocyanates Laboratories Leukocytes Link Lung Lung Inflammation MAPK14 gene Mediating Mediator of activation protein Mental Depression Mus Mustard Gas Mutation Neurons Neuropeptides Oxidants Ozone Pain Pathway interactions Pharmaceutical Preparations Phosgene Phosphotransferases Play Preparation Principal Investigator Pulmonary Edema Reagent Reflex action Research Research Institute Riots Risk Role Signal Pathway Signal Transduction Skin Specialist Survival Rate TRP channel Terrorism Tissues Toxic effect Transducers Variant Vesicants Work afferent nerve airway epithelium airway hyperresponsiveness analog base chlorine gas efficacy testing improved injured irritation keratinocyte lung injury mitogen-activated protein kinase p38 novel public health relevance pulmonary agents receptor response to injury

项目摘要

DESCRIPTION (provided by applicant): Chlorine (CI2), phosgene, vesicants and electrophilic reactive chemicals (industrial and riot control agents) are considered among the most imminent chemical threats to be diverted for terrorism attacks, or released during accidents. In the last four years research in the Jordt laboratory has identified TRPA1, a Transient Receptor Potential ion channel expressed in sensory neurons, as the major neuronal target of chlorine, riot control agents and Industrial chemicals such as acrolein and isocyanates. Post-exposure treatment of chlorine-exposed mice with a TRPA1 antagonist strongly reduced lung inflammation and injury parameters. The same TRPA1 antagonist increased survival rates of phosgene-exposed mice, and also inhibited vesicant injury induced by the sulfur mustard analog, CEES. In our recent work we identified TRPV4, an ion channel expressed in the lung epithelium and vasculature, as an additional mediator of oxidant-induced pulmonary injury. Activation of TRPV4 leads to severe lung injury and cardiovascular depression, and we show that a TRPV4 antagonist inhibits ozone induced oxidative lung edema. TRPV3, a TRP ion channel in keratinocytes, is a candidate mediator of cutaneous injury by vesicants and corrosive electrophiles. TRP channel, through influx of calcium, activate p38 MAP kinase, a major transducer and activator of inflammation and cell death in injured tissue. In summary, we hypothesize that TRP channels are major targets of chemical warfare agents, mediating local and systemic injury and inflammation through neuronal and local cellular signaling. In this proposal we aim to 1: Develop advanced intramuscular formulations of TRPA1 antagonists for immediate and sustained release to counteract chlorine and vesicant injury, 2: Examine the role of pulmonary and cutaneous TRP ion channels in chemical injury, and 3: Investigate the effects of a p38 kinase antagonist in pulmonary and cutaneous chemical injury. Public Health Relevance: Our research is aimed to further develop treatments for lung and skin injury by chemical warfare agents and industrial chemicals that can be diverted for terrorism attacks. We identified a new group of drugs that we found to effectively diminish injury by chlorine gas and skin blistering agents. The goal of this proposal is to improve these drugs and investigate how they counteract injury.

描述（由申请人提供）：氯 (CI2)、光气、起泡剂和亲电活性化学品（工业和防暴剂）被认为是最紧迫的化学威胁，可用于恐怖袭击或在事故中释放。在过去四年中，Jordt 实验室的研究已确定 TRPA1（一种在感觉神经元中表达的瞬时受体电位离子通道）是氯、防暴剂以及丙烯醛和异氰酸酯等工业化学品的主要神经元靶标。使用 TRPA1 拮抗剂对接触氯的小鼠进行暴露后处理，可显着降低肺部炎症和损伤参数。相同的 TRPA1 拮抗剂提高了光气暴露小鼠的存活率，并且还抑制了硫芥类似物 CEES 引起的出疱损伤。在我们最近的工作中，我们确定了 TRPV4（一种在肺上皮和脉管系统中表达的离子通道）作为氧化剂诱导的肺损伤的额外介质。 TRPV4 的激活会导致严重的肺损伤和心血管抑制，我们发现 TRPV4 拮抗剂可抑制臭氧引起的氧化性肺水肿。 TRPV3 是角质形成细胞中的一种 TRP 离子通道，是起疱剂和腐蚀性亲电子试剂引起的皮肤损伤的候选介质。 TRP 通道通过钙的流入激活 p38 MAP 激酶，这是受损组织中炎症和细胞死亡的主要转导器和激活剂。总之，我们假设 TRP 通道是化学战剂的主要目标，通过神经元和局部细胞信号传导介导局部和全身损伤和炎症。在本提案中，我们的目标是 1：开发 TRPA1 拮抗剂的先进肌内制剂，用于立即和持续释放以抵消氯和糜烂性损伤，2：检查肺和皮肤 TRP 离子通道在化学损伤中的作用，以及 3：研究肺和皮肤化学损伤中的 p38 激酶拮抗剂。公共卫生相关性：我们的研究旨在进一步开发可用于恐怖袭击的化学战剂和工业化学品造成的肺部和皮肤损伤的治疗方法。我们发现了一组新药物，可以有效减少氯气和皮肤起泡剂造成的伤害。该提案的目标是改进这些药物并研究它们如何抵抗伤害。