Targeting Injury Pathways to Counteract Pulmonary Agent and Vesicant Toxicity

描述（由申请人提供）：氯（CI2），光气，发泡剂和亲电活性化学品（工业和防暴剂）被认为是最紧迫的化学威胁，被转移到恐怖袭击中，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。使用TRPA1拮抗剂对氯暴露小鼠进行暴露后处理，可显著降低肺部炎症和损伤参数。同样的TRPA1拮抗剂增加了光气暴露小鼠的存活率，也抑制了硫芥类似物CEES引起的水肿损伤。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，作为氧化诱导肺损伤的额外介质。TRPV4的激活可导致严重的肺损伤和心血管抑制，我们发现TRPV4拮抗剂可抑制臭氧诱导的氧化性肺水肿。TRPV3是角质形成细胞中的一个TRP离子通道，是发泡剂和腐蚀性亲电试剂引起皮肤损伤的候选介质。TRP通道通过钙的流入激活p38 MAP激酶，p38 MAP激酶是损伤组织中炎症和细胞死亡的主要传感器和激活剂。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。在这个提议中，我们的目标是：1：开发先进的肌内TRPA1拮抗剂，用于立即和持续释放，以抵消氯和泡剂损伤；2：检查肺和皮肤TRP离子通道在化学损伤中的作用；3：研究p38激酶拮抗剂在肺和皮肤化学损伤中的作用。

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.