Sensory Neural Mechanisms of Pulmonary Agent and Vesicant Toxicity

描述(申请人提供)：皮肤、呼吸道、眼睛和粘膜中的感觉神经末梢被广泛的危险化学物质激活。这些包括肺部化学剂以及发泡剂和有毒工业化学品。鼻道和呼吸道感觉神经末梢的激活会导致疼痛、刺激和呼吸暂停。长期接触化学物质会导致炎性神经肽的释放，导致肺和皮肤浮肿、眼部损伤、粘液高分泌、肺阻塞和水泡形成，从而促进损伤。在动物模型中，这些效应可以通过预先的神经脱敏或去神经来强烈地减弱。因此，药物阻断神经激活，阻断靶组织的神经肽受体，可以作为预防和减轻肺部毒物和发泡剂有害作用的有效措施。肺毒剂和发泡剂在感觉神经元上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。创始成员TRPV1是辣椒素的受体，辣椒素是辣椒中的刺激性和炎症性成分，被用作致残剂。TRPA1是一种新的Trp离子通道，它被芥子油(异硫氰酸烯丙酯)激活，芥子油是一种有效的刺激性和神经炎性物质。我们发现，TRPA1仅在对辣椒素敏感的感觉纤维中表达。芥子油和其他植物衍生的TRPA1激活剂在结构上与硫磺芥末有有趣的相似之处。此外，我们发现TRPA1被危险的工业化学品强烈激活。其中包括a，p-不饱和醛，如丙烯醛，一种第一次世界大战中使用的肺剂。我们对TRPA1缺陷小鼠的功能和行为分析表明，TRPA1对于芥子油、丙烯醛和其他化学危险的感觉神经反应是必不可少的。因此，TRPA1，以及潜在的其他Trp通道，可能是预防和治疗肺部药物和发泡剂毒性作用的有效靶点。我们的具体目的是研究Trp通道在体外和体内对肺部毒剂和发泡剂的反应中的作用，并分析Trp通道阻滞剂和神经肽拮抗剂在降低战剂毒性方面的效果。

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.