Accelerating Inflammation Resolution to Counteract Chemical Cutaneous Injury

Abstract

Running title: Lipid mediators mitigate chemical skin injury Abbreviations:RvD1 (Resolvin D1); RvD2 (Resolvin D2); CS (2-Chlorobenzalmalononitrile); CEES (2-chloroethylethyl-sulfide); SM (sulfur mustard); HD (sulfur mustard); MMP-9 (matrix metallo protein-9), IL-1β (Interleukin-1 beta), KC/CXCL1 (keratinocyte chemoattractant)/(chemokine (C-X-C motif) ligand 1); CXCL2 (chemokine (C-X-C motif) ligand 2); IL-6 (interleukin-6); ELISA (enzyme linked immune sorbent assay); PBS (phosphate buffer saline); MEVM (mouse ear vesicant model); i.p (intraperitoneal); i.v (intravenous); NSAIDs (nonsteroidal anti-inflammatory drugs) AbstractChemical exposure to vesicants such as sulfur mustard (SM), and electrophilic riot control agents such as 2-chlorobenzalmalononitrile (CS) tear gas agent, cause strong cutaneous inflammation. Classical antiinflammatory treatments have focused on interference with target initiation and maintenance of inflammation, with mixed outcomes. Inflammation is broadly classified into three temporal phases, initiation, amplification and maintenance, and resolution. Resolution of inflammation was thought to be a passive process but the recent body of literature shows that resolution is an active process and is mediated by fatty acid-derived mediators (specialized pro-resolving mediators, SPMs). We hypothesized that accelerating resolution phase of inflammation may attenuate the exaggerated inflammatory response following chemical threat exposure, leading to decreased morbidity and improved recovery. In this study, SPMs, such as Resolvin D1 (RvD1) and Resolvin D2 (RvD2), were administered to mice at nanogram doses post-exposure to an SM analog, 2-chloroethyl-ethyl-sulfide (CEES) or CS tear gas agent.SPMs decreased edema (ear thickness and punch biopsy weights), pro-inflammatory cytokines (IL-1β, CXCL1/KC, MIP2) and protease marker (MMP-9), and vascular leakage (determined by IRDye 800 CW PEG) while improving histopathology in cutaneous chemical injury mouse models. These results support our hypothesis and pave the way for SPMs for further development as potential medical countermeasures for chemical threat agents-induced skin injuries.A new area of inflammation research has focused on the process of inflammation resolution (29-32). Resolution of inflammation was thought to occur due to the lack of inflammatory drive when concentrations of inflammation-initiating and -maintaining mediators are removed or in decline.However, new studies show that the resolution of inflammation is an active mechanism involving the activation of signaling pathways during inflammation initiation, and the later generation of fatty-acidderived specialized pro-resolving mediators (SPMs) that activate resolution mechanisms. These mediators include resolvins, lipoxins, protectins, and maresins. Resolvins and protectins are omega-3 fatty acids derived from docosahexaenoic acid (DHA; C22:6) or eicosapentaenoic acid (EPA; C20:5),We appreciate thoughtful discussions of Drs. Conflict of interestAuthors do not have any conflicts of interes...