Accelerating Inflammation Resolution to CounterACT Chemical Injury

描述(由申请人提供)：暴露于化学威胁剂往往会引发强烈的炎症组织反应，导致发病率增加，并阻止组织修复和恢复。肺暴露于氯会引发强烈的炎症反应，导致血管渗漏、心肺抑制、中性粒细胞渗入以及肺和全身高细胞分裂素血症，与败血症时观察到的细胞因子风暴类似。在吸入光气和酸性气体(HCl)或碱性气体(氨)和反应性工业化学品如丙烯醛、防暴剂(CS、CN或CR)以及皮肤暴露于发泡剂后，也观察到类似的炎症反应。针对化学损伤的经典抗炎治疗主要集中在干扰参与炎症启动和维持的靶通路。由于涉及的途径和病理种类繁多，这些策略只取得了部分成功。炎症反应分为启动、放大和维持、消退三个时间阶段。炎症研究的一个新领域集中在炎症消解过程，这是一种活跃的机制，涉及在炎症启动过程中激活信号通路，以及晚一代欧米茄3脂肪酸衍生的炎症消解介质，激活消解机制。在我们的初步研究中，我们观察到，暴露后使用消炎剂Resolvin D1处理，强烈抑制了暴露于发泡剂CEES和亲电暴乱控制剂CS的小鼠皮肤浮肿和炎症的形成。我们拟议的研究旨在1：在皮肤暴露于发泡剂和亲电化学威胁的小鼠模型中检测消炎剂的作用，2：研究消炎剂对氯气和盐酸暴露小鼠肺损伤进展的影响。

DESCRIPTION (provided by applicant): Exposures to chemical threat agents oftentimes induce strong inflammatory tissue responses that contribute to morbidity and prevent tissue repair and recovery. Pulmonary exposures to chlorine trigger a potent inflammatory response resulting in vascular leakage, cardiopulmonary depression, neutrophil infiltration and a pulmonary and systemic hypercytokinemia comparable to the cytokine storm observed in sepsis. Similar inflammatory responses are observed after inhalation exposures to phosgene and acidic (HCl) or alkaline gases (ammonia) and reactive industrial chemicals such as acrolein, and to riot control agents (CS, CN or CR), and following cutaneous exposures to vesicants. Classical anti-inflammatory treatments against chemical injury have focused on interference with target pathways involved in the initiation and maintenance of inflammation. These strategies have only been partially successful, due to the large variety of pathways and pathologies involved. The inflammatory response is divided into three temporal phases, initiation, amplification and maintenance, and resolution. A new area of inflammation research has focused on the process of inflammation resolution, an active mechanism involving the activation of signaling pathways during inflammation initiation, and the later generation of omega 3 fatty-acid derived inflammation-resolving mediators that activate resolution mechanisms. In our preliminary studies we observe that post exposure treatment with Resolvin D1, an inflammation-resolving agent, strongly inhibited skin edema formation and inflammation in mice exposed to the vesicant, CEES, and the electrophilic riot control agent, CS. Our proposed studies are designed to 1: Examine the effects of inflammation-resolving agents in mouse models of cutaneous exposures to vesicants and electrophilic chemical threats and, 2: Study the effects of inflammation-resolving agents on pulmonary injury progression in mice exposed to chlorine and HCl.