Targeting Injury Pathways to Counteract Pulmonary Agent and Vesicant Toxicity

描述（由申请人提供）：氯（CI2）、光气、发泡剂和亲电反应性化学品（工业和防暴剂）被认为是最紧迫的化学威胁之一，可能被转用于恐怖主义袭击或在事故中释放。在过去的四年里，Jordt实验室的研究已经确定了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，防暴剂和工业化学品（如丙烯醛和异氰酸酯）的主要神经元靶点。用TRPA1拮抗剂对氯暴露小鼠进行暴露后治疗强烈降低了肺部炎症和损伤参数。相同的TRPA1拮抗剂增加了暴露于硫芥基因的小鼠的存活率，也抑制了硫芥类似物CEES诱导的水疱损伤。在我们最近的工作中，我们确定了TRPV4，一种在肺上皮和血管中表达的离子通道，作为氧化剂诱导的肺损伤的额外介质。TRPV4的激活导致严重的肺损伤和心血管抑制，我们表明TRPV4拮抗剂抑制臭氧诱导的氧化性肺水肿。TRPV3是角质形成细胞中的TRP离子通道，是由起泡剂和腐蚀性亲电试剂引起的皮肤损伤的候选介质。TRP通道通过钙离子内流激活p38 MAP激酶，这是损伤组织中炎症和细胞死亡的主要转导和激活剂。总之，我们假设TRP通道是化学战剂的主要靶点，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。在这项提案中，我们的目标是：1：开发先进的肌内制剂的TRPA1拮抗剂立即和持续释放，以抵消氯和起泡剂损伤，2：检查肺和皮肤的TRP离子通道在化学损伤中的作用，和3：调查的p38激酶拮抗剂在肺和皮肤的化学损伤的影响。 公共卫生相关性：我们的研究旨在进一步开发治疗由化学战剂和工业化学品造成的肺部和皮肤损伤的方法，这些化学品可以被转移到恐怖主义袭击中。我们发现了一组新的药物，可以有效地减少氯气和皮肤起泡剂造成的伤害。这项提案的目标是改进这些药物，并研究它们如何对抗伤害。

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.