The Role of Macrophages in Vesicant Skin Injury and Repair

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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.