Accelerating Inflammation Resolution to CounterACT Chemical Injury

描述（由申请人提供）：暴露于化学威胁剂通常会引起强烈的炎症组织反应，从而导致发病率并阻止组织修复和恢复。肺部暴露于氯会引发强烈的炎症反应，导致血管渗漏、心肺抑制、中性粒细胞浸润以及肺部和全身高细胞因子血症，类似于在败血症中观察到的细胞因子风暴。在吸入光气、酸性（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）以及皮肤接触发泡剂后，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炎症启动和维持的靶通路。由于涉及多种途径和病理，这些策略仅部分成功。炎症反应可分为三个时间阶段：起始、扩大和维持以及消退。炎症研究的一个新领域集中在炎症解决的过程，炎症启动过程中涉及信号通路激活的活跃机制，以及激活解决机制的下一代omega - 3脂肪酸衍生的炎症解决介质。在我们的初步研究中，我们观察到，在暴露于发泡剂CEES和亲电性防暴剂CS的小鼠中，用消炎剂Resolvin D1进行暴露后处理，可以强烈抑制皮肤水肿和炎症的形成。我们提出的研究旨在：1：检查消炎剂对皮肤暴露于发泡剂和亲电化学威胁的小鼠模型的影响；2：研究消炎剂对暴露于氯和盐酸的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. PUBLIC HEALTH RELEVANCE: Chemical warfare agents and industrial chemicals oftentimes cause severe inflammation that aggravates the injuries and prevents healing. Our proposed research will investigate the therapeutic effects of a group of newly discovered natural drugs that terminate inflammation before it causes tissue damage.