The Role of Macrophages in Vesicant Skin Injury and Repair

摘要 化学战剂，如芥子气和砷剂，引起皮肤损伤，其特征是红斑， 炎症和皮肤起泡，随后是延长的愈合期。尽管炎症细胞和 已知相关细胞因子在暴露于吗啡和砷剂的皮肤中增加， 这些细胞亚群在芥子气或砷诱导的皮肤损伤中的作用差异，以及 后续的治疗，仍有待阐明。这项建议的一个目标是发展能力，以研究 炎症反应，特别是巨噬细胞反应，使用最先进的单细胞技术， 芥子气和砷剂皮肤损伤。这将包括使用原型代理生成初步数据， 计划使用限制性药物进行实验，以支持未来NIH CounterACT拨款申请， 以下目标：对于具体目标1，我们将定义伤口炎性细胞亚群对发泡剂的反应， 以氮芥（NM）为原型芥子气和氧化苯胂（PAO）为原型的皮肤损伤 含砷的对于具体目标2，由于我们和其他人已经确定NLRP-3是一个关键的调节因子， 在皮肤损伤的炎症反应中，我们将确定NOD样受体（NLRP）-3 炎性小体在水疱性皮肤损伤和修复中的作用。对于具体目标3，我们将与 MRIGlobal使用限制性发泡剂进行研究。MRIGlobal是一家合同研究组织， 实验室被批准使用更有效的限制性起疱剂。该项目的成功完成将1） 将一个新的皮肤创伤愈合研究小组引入化学对抗领域，2）提高 了解炎性细胞亚群在对水疱性损伤的反应中的作用，3）建立 NLRP-3炎性体在调节这种炎症反应中的重要性，并测试NLRP-3 抑制剂作为潜在对策，以及4）与MRIGlobal建立关系，以便使用 局限性水疱。最终，我们计划利用我们的研究产生的知识来开发新的 针对炎症反应的对策。

Abstract Chemical warfare agents such as mustards and arsenicals cause skin damage characterized by erythema, inflammation, and skin blistering, followed by a prolonged healing period. Although inflammatory cells and related cytokines are known to be increased in skin exposed to both mustards and arsenicals, similarities and differences in the roles of subsets of these cells in mustard- or arsenical-induced skin damage, as well as subsequent healing, remain to be elucidated. A goal of this proposal is to develop capacity to study the role of the inflammatory response, particularly the macrophage response, using cutting edge single cell techniques, in mustard and arsenical skin injury. This will include generating preliminary data with prototype agents and planning for experiments with restricted agents to support future NIH CounterACT grant submissions in the following aims: for Specific Aim 1, we will define the response of wound inflammatory cell subsets to vesicant skin injury using nitrogen mustard (NM) as prototype mustard and phenylarsine oxide (PAO) as prototype arsenical. For Specific Aim 2, since we and others have identified NLRP-3 is a key regulator of the inflammatory response to skin injury, we will determine the role of the NOD-Like Receptor (NLRP)-3 inflammasome in vesicant skin injury and repair. For Specific Aim 3, we will develop a relationship with MRIGlobal to perform studies with restricted vesicants. MRIGlobal is a contract research organization whose laboratory is approved for use of more potent restricted vesicants. Successful completion of this project will 1) bring a new skin wound healing research group into the chemical countermeasure field, 2) improve understanding of the role of inflammatory cell subsets in the response to vesicant injury, 3) establish the importance of the NLRP-3 inflammasome in regulating this inflammatory response and test an NLRP-3 inhibitor as a potential countermeasure and 4) develop a relationship with MRIGlobal for future studies using restricted vesicants. Ultimately, we plan to use knowledge generated by our research to develop novel countermeasures that target the inflammatory response.