Sensory Neural Mechanisms of Pulmonary Agent and Vesicant Toxicity

描述（由申请人提供）：皮肤、气道、眼睛和粘膜中的感觉神经末梢被各种危险化学品激活。这些包括肺部化学制剂以及起疱剂和有毒工业化学品。鼻通道和气道中感觉神经末梢的激活引起疼痛、刺激和呼吸暂停。长时间的化学暴露通过引起炎症性神经肽的释放而促进损伤，所述炎症性神经肽促成肺和皮肤中的水肿形成、眼损伤、粘液分泌过多、肺阻塞和水疱形成。在动物模型中，这些影响可以通过预先的神经脱敏或去神经支配而大大降低。因此，神经激活的药理学阻断以及靶组织中神经肽受体的阻断可以代表预防和减轻肺部药物和水疱剂的有害作用的有效措施。肺剂和水疱剂对感觉神经元的分子靶点在很大程度上是未知的。最近，一类新的感觉化学感受器，TRP离子通道，被发现。其创始成员TRPV 1是辣椒素的受体，辣椒素是辣椒中的辛辣和炎症成分，用作失能剂。TRPA 1是一种新型TRP离子通道，可被芥子油（异硫氰酸烯丙酯）激活，芥子油是一种强刺激性和神经炎症剂。我们发现TRPA 1只在对辣椒素敏感的感觉纤维中表达。芥子油和其他植物来源的TRPA 1活化剂显示出与硫芥有趣的结构相似性。此外，我们发现TRPA 1被危险的工业化学品强烈激活。这些包括α，β-不饱和醛，如丙烯醛，一种用于第一次世界大战的肺剂。我们对TRPA 1缺陷小鼠的功能和行为分析表明，TRPA 1对于芥子油，丙烯醛和其他化学危害的感觉神经反应至关重要。因此，TRPA 1和潜在的其他TRP通道，可能代表有效的目标，以防止和治疗肺部药物和水疱剂的毒性作用。我们的具体目标是调查TRP通道的作用，在体外和体内的肺部药物和vesicants的反应，并分析TRP通道阻滞剂和神经肽拮抗剂在减少战争剂毒性的疗效。

DESCRIPTION (provided by applicant): Sensory nerve endings in the skin, airways, eyes and mucous membranes are activated by a wide range of hazardous chemicals. These include pulmonary chemical agents as well as vesicants and noxious industrial chemicals. Activation of sensory nerve endings in the nasal passages and airways induces pain, irritation and apnea. Extended chemical exposure promotes injury by causing the release of inflammatory neuropeptides that contribute to edema formation in the lung and skin, ocular damage, mucus hypersecretion, pulmonary obstruction, and blister formation. In animal models these effects can be strongly reduced by prior neural desensitization or denervation. Thus, pharmacological blockade of neural activation, as well as block of neuropeptide receptors in target tissues, could represent effective measures to prevent and alleviate the deleterious effects of pulmonary agents and vesicants. The molecular targets for pulmonary agents and vesicants on sensory neurons are largely unknown. Recently, a new class of sensory chemoreceptors, the TRP ion channels, was discovered. The founding member, TRPV1, is the receptor for capsaicin, the pungent and inflammatory ingredient in chili peppers that is used as an incapacitating agent. TRPA1, a novel TRP ion channel, is activated by mustard oil (allyl isothiocyanate), a potent irritant and neuroinflammatory agent. We found that TRPA1 is exclusively expressed in sensory fibers that are also sensitive to capsaicin. Mustard oil and other plant-derived activators of TRPA1 show intriguing structural similarities with sulfur mustard. In addition, we found that TRPA1 is strongly activated by hazardous industrial chemicals. These include a,p-unsaturated aldehydes such as acrolein, a pulmonary agent used in the First World War. Our functional and behavioral analysis of mice deficient in TRPA1 showed that TRPA1 is essential for sensory neural responses to mustard oil, acrolein and other chemical hazards. Thus TRPA1, and potentially other TRP channels, may represent effective targets to prevent and treat the toxic effects of pulmonary agents and vesicants. Our specific aims are to investigate the role of TRP channels in the response to pulmonary agents and vesicants in vitro and in vivo and to analyze the efficacy of TRP channel blockers and neuropeptide antagonists in the reduction of warfare agent toxicity.